Katarina J. Ruscic

IKs channels open slowly because KCNE1 accessory subunits slow the movement of S4 voltage sensors in KCNQ1 pore-forming subunits

Significance E1 and Q1 protein subunits assemble to form IKslow channels in the heart and ear. Inherited mutations in either subunit that decrease protein level or alter function can cause life-threatening cardiac arrhythmias and deafness. The mechanism by which E1 slows channel opening has been the subject of active debate. Here, we use gating current measurements and simultaneous recordings of ionic currents and changes in fluorescence of a probe on the Q1 voltage sensors to demonstrate that E1 slows the movement of sensors in a manner that is both necessary and sufficient to determine the slow activation time course of IKs channels. Human IKs channels activate slowly with the onset of cardiac action potentials to repolarize the myocardium. IKs channels are composed of KCNQ1 (Q1) pore-forming subunits that carry S4 voltage-sensor segments and KCNE1 (E1) accessory subunits. Together, Q1 and E1 subunits recapitulate the conductive and kinetic properties of IKs. How E1 modulates Q1 has been unclear. Investigators have variously posited that E1 slows the movement of S4 segments, slows opening and closing of the conduction pore, or modifies both aspects of electromechanical coupling. Here, we show that Q1 gating current can be resolved in the absence of E1, but not in its presence, consistent with slowed movement of the voltage sensor. E1 was directly demonstrated to slow S4 movement with a fluorescent probe on the Q1 voltage sensor. Direct correlation of the kinetics of S4 motion and ionic current indicated that slowing of sensor movement by E1 was both necessary and sufficient to determine the slow-activation time course of IKs.

Dose-dependent Protective Effect of Inhalational Anesthetics Against Postoperative Respiratory Complications: A Prospective Analysis of Data on File From Three Hospitals in New England

Objectives: Inhalational anesthetics are bronchodilators with immunomodulatory effects. We sought to determine the effect of inhalational anesthetic dose on risk of severe postoperative respiratory complications. Design: Prospective analysis of data on file in surgical cases between January 2007 and December 2015. Setting: Massachusetts General Hospital (tertiary referral center) and two affiliated community hospitals. Patients: A total of 124,497 adult patients (105,267 in the study cohort and 19,230 in the validation cohort) undergoing noncardiac surgical procedures and requiring general anesthesia with endotracheal intubation. Interventions: Median effective dose equivalent of inhalational anesthetics during surgery (derived from mean end-tidal inhalational anesthetic concentrations). Measurements and Main Results: Postoperative respiratory complications occurred in 6,979 of 124,497 cases (5.61%). High inhalational anesthetic dose of 1.20 (1.13–1.30) (median [interquartile range])-fold median effective dose equivalent versus 0.57 (0.45–0.64)-fold median effective dose equivalent was associated with lower odds of postoperative respiratory complications (odds ratio, 0.59; 95% CI, 0.53–0.65; p < 0.001). Additionally, high inhalational anesthetic dose was associated with lower 30-day mortality and lower cost. Inhalational anesthetic dose increase and reduced risk of postoperative respiratory complications remained significant in sensitivity analyses stratified by preoperative and intraoperative risk factors. Conclusions: Intraoperative use of higher inhalational anesthetic doses is strongly associated with lower odds of postoperative respiratory complications, lower 30-day mortality, and lower cost of hospital care. The authors speculate based on these data that sedation with inhalational anesthetics outside of the operating room may likewise have protective effects that decrease the risk of respiratory complications in vulnerable patients.

Prevention of respiratory complications of the surgical patient: actionable plan for continued process improvement.

Purpose of review Postoperative respiratory complications (PRCs) increase hospitalization time, 30-day mortality and costs by up to

Supplemental Carbon Dioxide Stabilizes the Upper Airway in Volunteers Anesthetized with Propofol

35 000. These outcomes measures have gained prominence as bundled payments have become more common. Recent findings Results of recent quantitative effectiveness studies and clinical trials provide a framework that helps develop center-specific treatment guidelines, tailored to minimize the risk of PRCs. The implementation of those protocols should be guided by a local, respected, and visible facilitator who leads proper implementation while inviting center-specific input from surgeons, anesthesiologists, and other perioperative stakeholders. Summary Preoperatively, patients should be risk-stratified for PRCs to individualize intraoperative choices and postoperative pathways. Laparoscopic compared with open surgery improves respiratory outcomes. High-risk patients should be treated by experienced providers based on locally developed bundle-interventions to optimize intraoperative treatment and ICU bed utilization. Intraoperatively, lung-protective ventilation (procedure-specific positive end-expiratory pressure utilization, and low driving pressure) and moderately restrictive fluid therapy should be used. To achieve surgical relaxation, high-dose neuromuscular blocking agents (and reversal agents) as well as high-dose opioids should be avoided; inhaled anesthetics improve surgical conditions while protecting the lungs. Patients should be extubated in reverse Trendelenburg position. Postoperatively, continuous positive airway pressure helps prevent airway collapse and protocolized, early mobilization improves cognitive and respiratory function.

Gating Current of the KCNQ1 Voltage-Gated Potassium Channel

Background: Propofol impairs upper airway dilator muscle tone and increases upper airway collapsibility. Preclinical studies show that carbon dioxide decreases propofol-mediated respiratory depression. We studied whether elevation of end-tidal carbon dioxide (PETCO2) via carbon dioxide insufflation reverses the airway collapsibility (primary hypothesis) and impaired genioglossus muscle electromyogram that accompany propofol anesthesia. Methods: We present a prespecified, secondary analysis of previously published experiments in 12 volunteers breathing via a high-flow respiratory circuit used to control upper airway pressure under propofol anesthesia at two levels, with the deep level titrated to suppression of motor response. Ventilation, mask pressure, negative pharyngeal pressure, upper airway closing pressure, genioglossus electromyogram, bispectral index, and change in end-expiratory lung volume were measured as a function of elevation of PETCO2 above baseline and depth of propofol anesthesia. Results: PETCO2 augmentation dose-dependently lowered upper airway closing pressure with a decrease of 3.1 cm H2O (95% CI, 2.2 to 3.9; P < 0.001) under deep anesthesia, indicating improved upper airway stability. In parallel, the phasic genioglossus electromyogram increased by 28% (23 to 34; P < 0.001). We found that genioglossus electromyogram activity was a significant modifier of the effect of PETCO2 elevation on closing pressure (P = 0.005 for interaction term). Conclusions: Upper airway collapsibility induced by propofol anesthesia can be reversed in a dose-dependent manner by insufflation of supplemental carbon dioxide. This effect is at least partly mediated by increased genioglossus muscle activity.

954 - Fluid Administration and Surgical Outcomes after Pancreatoduodenectomy: External Validation of Variable Fluid Regimenes at a Tertiary Referral Center

KCNQ1 pore-forming alpha-subunits are crucial to physiology, operating in vivo with KCNE1 and KCNE3 beta-subunits in the heart and stomach, respectively. Recently, the gating currents of KCNQ4 and KCNQ5 channels were characterized (Miceli, Channels, 2009); here, equivalent measurements are described for KCNQ1 channels formed in the absence of beta-subunits. Human KCNQ1 was studied in Xenopus oocytes with the cut-open oocyte voltage clamp technique. To record gating currents, cells were depleted of internal potassium ions and residual ionic current was blocked with tetraethyammonium and barium. At room temperature, gating currents were too small to resolve. At 28°C, ON gating current gave rise to peak charge movement at +40 mV of ∼0.7 nC / µA of ionic current. The total charge movement at each test potential was conserved in the OFF-gating currents. Analysis of the charge-voltage (QV) relationship and conductance-voltage (GV) relationship showed a 10 mV hyperpolarizing shift of the half-maximal voltage of activation of the normalized QV curve with respect to the normalized GV curve. KCNQ1 ON-gating current decay constants were 4-fold slower than in KCNQ4 and required longer test pulses to fully resolve. Overlays of gating and ionic currents revealed that, as for KCNQ4, gating charges were still moving even after KCNQ1 channels started to open, indicating that charge movement was a rate-limiting factor in channel opening. These first characterizations of KCNQ1 gating currents and are an important step towards understanding mutations that lead to cardiac arrhythmias, such as long-QT syndrome, and the effects of beta-subunits on channel function. Supported by NIH GM030376, University of Chicago MSTP, and The Paul and Daisy Soros Fellowship for New Americans.