Dexmedetomidine depresses neuronal activity in the subthalamic nucleus during deep brain stimulation electrode implantation surgery.

Background: Micro-electrode recordings are often necessary during electrode implantation for deep brain stimulation of the subthalamic nucleus. Dexmedetomidine may be a useful sedative for these procedures, but there is limited information regarding its effect on neural activity in the subthalamic nucleus and on micro-electrode recording quality. Methods: We recorded neural activity in five patients undergoing deep brain stimulation implantation to the subthalamic nucleus. Activity was recorded after subthalamic nucleus identification while patients received dexmedetomidine sedation (loading - 1 µg kg-1 over 10-15 min, maintenance - 0.7 µg kg-1 h-1). We compared the root-mean square (RMS) and beta band (13-30 Hz) oscillation power of multi-unit activity recorded by microelectrode before, during and after recovery from dexmedetomidine sedation. RMS was normalised to values recorded in the white matter. Results: Multi-unit activity decreased during sedation in all five patients. Mean normalised RMS decreased from 2.8 (1.5) to 1.6 (1.1) during sedation (43% drop, p = 0.056). Beta band power dropped by 48.4%, but this was not significant (p = 0.15). Normalised RMS values failed to return to baseline levels during the time allocated for the study (30 min). Conclusions: In this small sample, we demonstrate that dexmedetomidine decreases neuronal firing in the subthalamic nucleus as expressed in the RMS of the multi-unit activity. As multi-unit activity is a factor in determining the subthalamic nucleus borders during micro-electrode recordings, dexmedetomidine should be used with caution for sedation during these procedures. Clinical trial number: NCT01721460.

Contrasting Effects of the γ-Aminobutyric Acid Type A Receptor ß3 Subunit N265M Mutation on Loss of Righting Reflexes Induced by Etomidate and the Novel Anesthetic Barbiturate R-mTFD-MPAB.

BACKGROUND: Previous studies have shown that etomidate modulates γ-aminobutyric acid type A receptors by binding at the ß-α subunit interface within the transmembrane domain of receptors that incorporate ß2 or ß3 subunits. Introducing an asparagine-to-methionine (N265M) mutation at position 265 of the ß3 subunit, which sits within the etomidate-binding site, attenuates the hypnotic effect of etomidate in vivo. It was reported recently that the photoactivatable barbiturate R-mTFD-MPAB also acts on γ-aminobutyric acid type A receptors primarily by binding to a homologous site at the γ-ß interface. Given this difference in drug-binding sites established by the in vitro experiments, we hypothesized that the ß3-N265M-mutant mice would not be resistant to the anesthetic effects of R-mTFD-MPAB in vivo, whereas the same mutant mice would be resistant to the anesthetic effects of R-etomidate. METHODS: We measured the effects of IV injection of etomidate and R-mTFD-MPAB on loss and recovery of righting reflex in wild-type mice and in mice carrying the ß3-N265M mutation. RESULTS: Etomidate-induced hypnosis, as measured by the duration of loss of righting reflex, was attenuated in the N265M knock-in mice, confirming prior results. By contrast, recovery of balance and coordinated movement, as measured by the ability to maintain all 4 paws on the ground, was unaffected by the mutation. Neither hypnosis nor impairment of coordinated movement produced by the barbiturate R-mTFD-MPAB was affected by the mutation. CONCLUSIONS: The findings confirmed our hypothesis that mutating the etomidate-binding site would not alter the response to the barbiturate R-mTFD-MPAB. Furthermore, we confirmed previous studies indicating that etomidate-induced hypnosis is mediated in part by ß3-containing receptors. We also extended previous findings by showing that etomidate-impaired balance and coordinated movement are not mediated by ß3-containing receptors, thus implicating ß2-containing receptors in this end point.

Lipid-free Fluoropolymer-based Propofol Emulsions and Lipid Reversal of Propofol Anesthesia in Rats.

BACKGROUND: Propofol, as a lipid-based emulsion, is effective at inducing anesthesia. It does, however, suffer from several drawbacks, including microbial growth, hyperlipidemia, and pain on injection. In this study, the authors examined the ability of four lipid-free propofol nanoemulsions to induce anesthesia in rats and tested whether a subsequent lipid bolus would accelerate emergence from anesthesia. METHODS: The authors administered five formulations of propofol intravenously to six rats, delivering five different doses five times each, in a repeated-measures randomized crossover design and measured time to loss and recovery of righting reflex. The formulations included (1) Diprivan (AstraZeneca, United Kingdom); (2) L3, incorporating a semifluorinated surfactant plus egg lecithin; (3) B8, incorporating a semifluorinated surfactant only; (4) F8, incorporating a semifluorinated surfactant plus perfluorooctyl bromide; and (5) L80, incorporating egg lecithin only. In a second phase of the study, the authors administered a lipid bolus immediately after a dose of B8 or Diprivan. RESULTS: All formulations except L80 impaired the righting reflex without apparent toxic effects. The authors estimated the threshold dose for induction by determining the x-intercept of the linear regression between time to recovery versus log dose. Threshold doses ranged from 5.8 (95% CI, 5.5 to 6.2) to 8.6 (95% CI, 7.2 to 10.2) mg/kg. A 15 ml/kg lipid bolus resulted in an accelerated clearance. CONCLUSIONS: Three of the four novel lipid-free fluoropolymer-based formulations showed efficacy in producing anesthesia, which was comparable to that of Diprivan, and a lipid bolus hastened recovery. These novel propofol formulations have the potential to avoid complications seen with the existing lipid-based formulation.

Out-of-plane ultrasound-guided paravertebral blocks improve analgesic outcomes in patients undergoing video-assisted thoracoscopic surgery.

PURPOSE: Paravertebral blocks (PVBs) are a method of limiting postoperative pain for patients undergoing video-assisted thoracoscopic surgery (VATS). We began providing ultrasound-guided PVBs for patients undergoing VATS in the spring of 2011, using an out-of-plane approach. The aim of this study was to evaluate this practice change. METHODS: Following institutional review board approval, we reviewed the charts of 114 patients undergoing VATS by one surgeon at our institution between January 2011 and July 2012. Of the 78 eligible patients, 49 patients received a PVB prior to surgery. We evaluated opioids administered in the perioperative period, pain scores, and side effects from pain medications. RESULTS: Patients who received a preoperative PVB required fewer narcotics intraoperatively and during their hospital stay (P=0.001 and 0.011, respectively). Pain scores on initial assessment and in recovery were lower in patients who received a PVB (P=0.005), as were dynamic and resting pain scores at 24 hours after surgery (P=0.003 and P<0.001, respectively). Patients receiving a PVB had fewer episodes of treated nausea both in the postanesthesia care unit (P=0.004) and for the first 24 hours after surgery (P=0.001). These patients also spent less time in recovery (P=0.025) than the patients who did not receive a block. CONCLUSION: The current study suggests improved outcomes in patients who underwent VATS with a preoperative PVB. All variables showed a trend toward improved results in patients who obtained a preoperative PVB.

The analgesic efficacy of transversus abdominis plane blocks in ileostomy takedowns: a retrospective analysis.

STUDY OBJECTIVE: To evaluate the analgesic efficacy of transversus abdominis plane (TAP) blocks in patients undergoing ileostomy reversal. DESIGN: Retrospective chart review. SETTING: University-affiliated hospital. SUBJECTS: The charts of 104 consecutive patients who underwent ileostomy reversal between November 1, 2008 and December 31, 2009 were reviewed. The charts of 69 patients were included in the study. Of these, 31 received a preoperative TAP block. MEASUREMENTS: Patients' opioid requirements intraoperatively, in the Postanesthesia Care Unit (PACU), and during the 24-hour period after discharge from the PACU were recorded and converted to intravenous (IV) morphine equivalents. Patient-reported numerical pain scores (0-10) from the PACU and from the 24-hour postoperative period also were recorded. Additional nonopioid means of perioperative analgesia were noted, as were duration of stay in the PACU and the hospital. MAIN RESULTS: Patients receiving TAP blocks required statistically significantly fewer opioids intraoperatively (P = 0.002), in the PACU (P = 0.003), and over the 24-hour period postoperatively (P = 0.01) than did patients who did not receive a TAP block. Mean numerical pain scores while in the PACU and for 24 hours postoperatively also were significantly lower (P = 0.015 and P = 0.019, respectively) in patients receiving a TAP block, as were numerical pain scores immediately on arrival at the PACU (P = 0.013). CONCLUSION: TAP blocks are an effective means of reducing perioperative pain in patients undergoing ileostomy reversal.

A small molecule polyamine oxidase inhibitor blocks androgen-induced oxidative stress and delays prostate cancer progression in the transgenic adenocarcinoma of the mouse prostate model.

High levels of reactive oxygen species (ROS) present in human prostate epithelia are an important etiologic factor in prostate cancer (CaP) occurrence, recurrence, and progression. Androgen induces ROS production in the prostate by a yet unknown mechanism. Here, to the best of our knowledge, we report for the first time that androgen induces an overexpression of spermidine/spermine N1-acetyltransferase, the rate-limiting enzyme in the polyamine oxidation pathway. As prostatic epithelia produce a large excess of polyamines, the androgen-induced polyamine oxidation that produces H2O2 could be a major reason for the high ROS levels in the prostate epithelia. A small molecule polyamine oxidase inhibitor N,N'-butanedienyl butanediamine (MDL 72,527 or CPC-200) effectively blocks androgen-induced ROS production in human CaP cells, as well as significantly delays CaP progression and death in animals developing spontaneous CaP. These data show that polyamine oxidation is not only a major pathway for ROS production in prostate, but inhibiting this pathway also successfully delays CaP progression.

Anti-interleukin-15 prevents arthritis in Borrelia-vaccinated and -infected mice.

We showed previously that interleukin-17 (IL-17) plays a significant role in the induction of arthritis associated with Borrelia vaccination and challenge. Little information, however, is available about the chain of immunologic events that leads to the release of IL-17. The production of IL-17 has been linked to stimulation of memory cells by IL-15. Therefore, we hypothesized that IL-15 is involved in the induction of arthritis associated with Borrelia vaccination and infection of mice. Here we present evidence that treatment of Borrelia-vaccinated and -infected mice with anti-IL-15 antibody prevents swelling of the hind paws. More importantly, both anti-IL-15 antibody- and recombinant IL-15 receptor alpha-treated Borrelia-vaccinated and -infected mice were free of major histopathologic indications of arthritis, including hyperplasia, hypertrophy, and vilus formation of the synovium. Similarly, the synovial space and perisynovium were free of inflammatory cells. By contrast, the synovium of nontreated Borrelia-vaccinated and -infected mice had overt hyperplasia, hypertrophy, and vilus formation. Moreover, the synovial space and perisynovium were infiltrated with neutrophils, macrophages, and lymphocytes. Finally, we show that recombinant IL-15 stimulates the release of IL-17 from lymph node cells obtained near the arthritic site. These results suggest that IL-15 plays a major role in orchestrating IL-17 induction of arthritis associated with Borrelia-vaccinated and -infected mice.