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Anthony Cahn,1 J Nicole Hamblin,2 Jon Robertson,3 Malcolm Begg,2 Emily Jarvis,3 Robert Wilson,1 Gordon Dear,4 Claudia Leemereise,5 Yi Cui,6 Maki Mizuma,7 Mickael Montembault,8 Cedric Van Holsbeke,9 Wim Vos,9 Wilfried De Backer,10 Jan De Backer,9 Edith M Hessel2 1Discovery Medicine, GlaxoSmithKline, Stevenage, UK; 2Refractory Respiratory Inflammation Discovery Performance Unit, GlaxoSmithKline, Stevenage, UK; 3Biostatistics, GlaxoSmithKline, Stevenage, UK; 4Mechanistic Safety & Disposition, GlaxoSmithKline, Ware, UK; 5Global Clinical Sciences & Delivery, GlaxoSmithKline, Amersfoort, the Netherlands; 6Pharma Safety, GlaxoSmithKline, Brentford, Middlesex, UK; 7Data Management & Strategy, GlaxoSmithKline, Tokyo, Japan; 8Global Clinical Sciences & Delivery, GlaxoSmithKline, Brentford, Middlesex, UK; 9FLUIDDA nv, Kontich, 2550, Belgium; 10Pulmonary Medicine & Pulmonary Rehabilitation, University of Antwerp, Antwerp, BelgiumCorrespondence: Anthony CahnDiscovery Medicine, GlaxoSmithKline, Stevenage, UKTel +44 1438766374Email tony.x.cahn@gsk.comPurpose: This study evaluated the safety and efficacy of inhaled nemiralisib, a phosphoinositide 3-kinase δ (PI3Kδ) inhibitor, in patients with an acute exacerbation of chronic obstructive pulmonary disease (COPD).Methods: In this double-blind, placebo-controlled study, 126 patients (40– 80 years with a post-bronchodilator forced expiratory volume in 1 sec (FEV1) ≤ 80% of predicted (previously documented)) were randomized 1:1 to once daily inhaled nemiralisib (1 mg) or placebo for 84 days, added to standard of care. The primary endpoint was specific imaging airway volume (siVaw) after 28 treatment days and was analyzed using a Bayesian repeated measures model (clintrials.gov: NCT02294734).Results: A total of 126 patients were randomized to treatment; 55 on active treatment and 49 on placebo completed the study. When comparing nemiralisib and placebo-treated patients, an 18% placebo-corrected increase from baseline in distal siVaw (95% credible intervals (Cr I) (− 1%, 42%)) was observed on Day 28. The probability that the true treatment ratio was > 0% (Pr(θ> 0)) was 96%, suggestive of a real treatment effect. Improvements were observed across all lung lobes. Patients treated with nemiralisib experienced a 107.3 mL improvement in posterior median FEV1 (change from baseline, 95% Cr I (− 2.1, 215.5)) at day 84, compared with placebo. Adverse events were reported by 41 patients on placebo and 49 on nemiralisib, the most common being post-inhalation cough on nemiralisib (35%) vs placebo (3%).Conclusion: These data show that addition of nemiralisib to usual care delivers more effective recovery from an acute exacerbation and improves lung function parameters including siVaw and FEV1. Although post-inhalation cough was identified, nemiralisib was otherwise well tolerated, providing a promising novel therapy for this acutely ill patient group.Keywords: acute exacerbation, COPD, nemiralisib

Gas exchange occurring in the abdominal cavity during laparoscopy, using carbon dioxide as the insufflating gas, was investigated in 25 female patients being ventilated with 66.6% nitrous oxide and 33.3% oxygen. The gas remaining in the abdomen at the end of the procedure was collected and measurements were made using an infrared spectrometer, a paramagnetic analyser and a mass spectrometer. The mean duration of the laparoscopy was 9.5 minutes and the mean volume of carbon dioxide delivered was 6.8 litres. Nitrous oxide concentration in the abdomen was found to increase significantly with the duration of the procedure, varying from 1.4% to 12.8% with a mean of 4.3% (s.d.±2.4). Oxygen concentration measured from 0.1 to 1.8% with a mean of 0.7% (s.d.±0.4). Nitrogen concentration varied from zero to 1.8%, having a mean concentration of 0.8% (s.d.±0.5). Carbon dioxide content was from 85.7 to 99.6% with a mean concentration of 94.2% (s.d. #x00B1;3.1). [ABSTRACT FROM AUTHOR]

Operating rooms (ORs) use energy-intensive equipment such as anesthesia gas machines, patient monitors, and lights. They are major contributors to an institution's carbon footprint; yet ORs are unoccupied 40% of the time. Implementing an initiative to power down electrical devices can reduce energy consumption, equipment failure, and financial outlay. This quality improvement project developed and implemented a power down initiative for anesthesia staff to use in ORs. The initiative included turning off anesthesia gas machines, patient monitors, auxiliary oxygen delivery, and room lights at the end of scheduled cases in ORs that were not used for emergencies. Convenience audits were conducted. Pre- and postimplementation compliance outcomes showed that there was an increase in powering down the anesthesia gas machine, patient monitor, auxiliary oxygen, and room lights. Powering down unnecessary equipment at this facility has the potential to save approximately $50,000 and prevent the emission of over 80 metric tons of CO2 per year. Other facilities can implement a similar quality improvement project aimed at fiscal and ecological conservation., Competing Interests: Name: Christine Parilli-Johnson, DNP, CRNA Contribution: This author made significant contributions to the conception, synthesis, writing, and final editing and approval of the manuscript to justify inclusion as an author. Disclosures: None. Name: Jessica Szydlowski Pitman, DNP, CRNA, ACNP, CHSE Contribution: This author made significant contributions to the conception, synthesis, writing, and final editing and approval of the manuscript to justify inclusion as an author. Disclosures: None. Name: Kristal Barbee, MSN, CRNA Contribution: This author made significant contributions to the conception, synthesis, writing, and final editing and approval of the manuscript to justify inclusion as an author. Disclosures: None. Name: Adam Flowe, MSN, CRNA Contribution: This author made significant contributions to the conception, synthesis, writing, and final editing and approval of the manuscript to justify inclusion as an author. Disclosures: None. Name: Nicolette Hooge, DNP, MBA, CRNA Contribution: This author made significant contributions to the conception and final editing and approval of the manuscript to justify inclusion as an author. Disclosures: None Name: Julie A. Thompson, PhD Contribution: This author made significant contributions to the conception, synthesis, writing, and final editing and approval of the manuscript to justify inclusion as an author. Disclosures: None Name: Guy Dear, MA, MB, BChir, FRCA, FUHM Contribution: This author made significant contributions to the conception, synthesis, writing, and final editing and approval of the manuscript to justify inclusion as an author. Disclosures: None. Name: Emily M. Funk DNP, CRNA Contribution: This author made significant contributions to the conception, synthesis, writing, and final editing and approval of the manuscript to justify inclusion as an author; she is the corresponding author for this article. Disclosures: None. Disclosure statements are available upon request., (Copyright © by the American Association of Nurse Anesthetists.)

The following case report describes a 13-year-old child with alternating hemiplegia of childhood (AHC) who underwent magnetic resonance imaging MRI with general anesthesia and experienced a hemiplegic spell, seizure, apnea, and sudden cardiac arrest with successful resuscitation. AHC is a rare neurodevelopmental disorder characterized by repeated episodes of weakness or paralysis affecting one or both sides of the body and multiple other neurologic problems. The challenges associated with this disorder include management of developmental delay, dystonia, hemiplegia, cerebrovascular dysfunction, apnea, and autonomic dysfunction. The current literature is extremely limited in describing the effects of general anesthesia for a patient with AHC. While the neurologic manifestations of AHC are well described, autonomic dysfunction and the potential for sudden cardiac arrest have not been widely reported. To our knowledge, this is the first case report to emphasize anesthetic considerations in a pediatric patient with AHC, specifically the unrecognized potential for cardiac arrhythmia and sudden cardiac arrest., Competing Interests: Name: Emily M. Funk, DNP, CRNA Contribution: This author made significant contributions to the conception, synthesis, writing, and final editing and approval of the manuscript to justify inclusion as an author. Disclosures: None. Name: Mohamad A. Mikati, MD Contribution: This author made significant contributions to the conception, synthesis, writing, and final editing and approval of the manuscript to justify inclusion as an author. Disclosures: This author has a pending patent for treatment of Alternating Hemiplegia of Childhood. Name: Andrew P. Landstrom, MD, PhD Contribution: This author made significant contributions to the conception, synthesis, writing, and final editing and approval of the manuscript to justify inclusion as an author. Disclosures: None. Name: Mary E. Moya-Mendez, MS Contribution: This author made significant contributions to the conception, synthesis, writing, and final editing and approval of the manuscript to justify inclusion as an author. Disclosures: None. Name: Keri R. Wallace, BS Contribution: This author made significant contributions to the conception, synthesis, writing, and final editing and approval of the manuscript to justify inclusion as an author. Disclosures: None. Name: Milton O. Pratt, BS Contribution: This author made significant contributions to the conception, synthesis, writing, and final editing and approval of the manuscript to justify inclusion as an author. Disclosures: None Name: Matthew E. Heyes, DNP, CRNA Contribution: This author made significant contributions to the conception, synthesis, writing, and final editing and approval of the manuscript to justify inclusion as an author. Disclosures: None Name: Guy Dear, MA, MB, BChir, FRCA, FUHM Contribution: This author made significant contributions to the conception, synthesis, writing, and final editing and approval of the manuscript to justify inclusion as an author. Disclosures: None. The authors did not discuss off-label use within the article. Disclosure statements are available upon request., (Copyright © by the American Association of Nurse Anesthetists.)

Objectives: The operating room is a specialized, complex environment with many factors that can impede effective communication during transitions of care between anesthesia clinicians. We postulated that an efficient, accessible, standardized tool for intraoperative handoffs built into standard workflow would improve communication and handoff safety. Most institutions now use an electronic health record (EHR) system for patient care and have independently designed intraoperative handoff tools, but these home-grown tools are not scalable to other organizations and lack vendor-supported features. The goal of this project was to create a standardized, intraoperative handoff tool supported by EHR functionality., Methods: The Multicenter Handoff Collaborative, with support from the Anesthesia Patient Safety Foundation, created a working group of frontline anesthesia experts to collaborate with a development team from the EHR vendor (Epic Systems) to design a standardized intraoperative handoff tool. Over 2 years, the working group identified the critical elements for the tool and software usability, and the EHR team designed a standardized intraoperative handoff tool that is accessible to any institution using this EHR., Results: The first iteration of the intraoperative handoff tool was released in August 2019, with a second version in February 2020. The tool is standardized but customizable by individual institutions., Conclusion: We demonstrate that work on complex health care processes critical to patient safety, such as handoffs, can be performed on a national scale through cross-industry collaboration. Frontline experts can partner with health care industry vendors to design, build, and release a product on an accelerated timeline., Competing Interests: Author F.L.'s work documented in this manuscript was performed as part of his employment at Epic Systems. All other authors report no conflict of interest., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Investigative Toxicology describes the de-risking and mechanistic elucidation of toxicities, supporting early safety decisions in the pharmaceutical industry. Recently, Investigative Toxicology has contributed to a shift in pharmaceutical toxicology, from a descriptive to an evidence-based, mechanistic discipline. This was triggered by high costs and low throughput of Good Laboratory Practice in vivo studies, and increasing demands for adhering to the 3R (Replacement, Reduction and Refinement) principles of animal welfare. Outside the boundaries of regulatory toxicology, Investigative Toxicology has the flexibility to embrace new technologies, enhancing translational steps from in silico, in vitro to in vivo mechanistic understanding to eventually predict human response. One major goal of Investigative Toxicology is improving preclinical decisions, which coincides with the concept of animal-free safety testing. Currently, compounds under preclinical development are being discarded due to the use of inappropriate animal models. Progress in Investigative Toxicology could lead to humanized in vitro test systems and the development of medicines less reliant on animal tests. To advance this field a group of 14 European-based leaders from the pharmaceutical industry founded the Investigative Toxicology Leaders Forum (ITLF), an open, non-exclusive and pre-competitive group that shares knowledge and experience. The ITLF collaborated with the Centre for Alternatives to Animal Testing Europe (CAAT-Europe) to organize an "Investigative Toxicology Think-Tank", which aimed to enhance the interaction with experts from academia and regulatory bodies in the field. Summarizing the topics and discussion of the workshop, this article highlights Investigative Toxicology's position by identifying key challenges and perspectives.

Background: The cause of emergence agitation (EA) in children is unknown. Rapid emergence from inhaled anesthesia has been implicated because EA is more common with sevoflurane than with halothane. A dose-dependent effect of sevoflurane, which increases seizure-like electroencephalogram activity, has also been proposed., Methods: To determine whether depth of anesthesia as measured by bispectral index (BIS) affects EA, 40 ASA physical status I to II children aged 2 to 8 years undergoing ophthalmic surgery were enrolled in a blinded randomized controlled trial of low-normal (40-45, deep) versus high-normal (55-60, light) anesthesia. To distinguish transient irritability from severe EA, the primary outcome was first-stage postanesthesia care unit (PACU I) peak Pediatric Assessment of Emergence Delirium (PAED) score, with secondary outcomes of PAED and Face, Legs, Activity, Cry, and Consolability scores at emergence, postoperative fentanyl dose, emergence time, and discharge time. Subjects received a standard anesthesia protocol with oral midazolam followed by mask induction with sevoflurane 8%, fentanyl 1 to 1.5 μg/kg IV (then as needed), neuromuscular blockade, and endotracheal intubation. Providers titrated expired sevoflurane (in N2O 67%) from 0.5% to 3% to maintain BIS range. PAED, Richmond Agitation Sedation Scale, and Face, Legs, Activity, Cry, and Consolability scores were measured at emergence, at PACU I arrival, and during PACU I stay., Results: There was little difference between the groups in the primary outcome, peak PACU I PAED score (light: 7.7 ± 4.6; deep: 8.6 ± 5.3; mean difference, 0.9; 95% confidence interval, 4.1 to -2.3; effect size, 0.18). Discharge times were similar between groups. Treatment for severe EA was rare., Conclusions: There was no significant effect of BIS-guided deep versus light anesthesia on severe EA.

Postoperative nausea and vomiting (PONV) are unpleasant experiences. However, there is no drug that is completely effective in preventing PONV. Whereas cost effectiveness analyses rely on specific health outcomes (e.g., years of life saved), cost-benefit analyses assess the cost and benefit of medical therapy in terms of dollars. We hypothesized that patients were willing to pay for a hypothetical new drug that would eliminate PONV. Eighty elective day surgical patients using general anesthesia participated in the study. After their recovery in the postanesthetic care unit, they were asked to complete an interactive computer questionnaire on demographics, the value of avoiding PONV, and their willingness to pay for an antiemetic. Patients were willing to pay US$56 (US$26--US$97; median, 25%--75%) for an antiemetic that would completely prevent PONV. Patients who developed nausea (n = 21; 26%) and vomiting (n = 9; 11%) were willing to pay US$73 (US$44--US$110) and $100 (US$61--US$200; median, 25%--75%), respectively (P < 0.05). Seventy-six percent of patients considered avoiding postoperative nausea and 78% of patients considered avoiding vomiting as important (> or = 50 mm on a 0--100-mm visual analog scale). Nausea or vomiting in the postanesthetic care unit, greater patient income, previous history of PONV, more importance placed on avoiding nausea and vomiting, increasing age, and being married are independent covariates that increase the willingness to pay estimates. Patients associated a value with the avoidance of PONV and were willing to pay between US$56 and US$100 for a completely effective antiemetic.

Background: Medical informatics provide a new way to evaluate the practice of medicine. Anesthesia automated record keepers have introduced anesthesiologists to computerized medical records. To derive useful information from the stored data requires programming that is not currently commercially available. The authors describe how they custom-programmed an automated record keeper's database to perform cost calculations, how they validated the programming, and how they used the data in a successful pharmaceutical cost-containment program., Methods: The Arkive (San Diego, CA) automated record keeper database was programmed at Duke University Medical Center as an independent noncommercial project to calculate costs according to standard formulae and to follow adherence to Duke University Department of Anesthesiology's prescribing guidelines for anesthetic drugs. Validation of that programming (including analysis of discarded drugs) was accomplished by comparing database calculated costs with actual pharmacy distribution of drugs during a 1-month period., Results: Validation data demonstrated a 99% accuracy rate for total costs of the drugs studied (atracurium, vecuronium, rocuronium, propofol, midazolam, fentanyl, and isoflurane). The study drugs represented approximately 67% of all drug costs for the period studied., Conclusions: Programming of an anesthesia automated record keeper's database yields essential information for management of an anesthetic practice. Accurate economic evaluation of anesthetic drug use is now possible. In the future, as definitive identification of best anesthetic practices that yield optimal patient outcomes and higher measures of patient satisfaction is pursued, large numbers of patients should be studied. This is only possible through database analysis and complete computerization of the perioperative medical record.

Background: Although approximately 2,000 medical practice guidelines have been proposed, few have been successfully implemented and sustained. We hypothesized that we could develop and institute practice guidelines to promote more appropriate use of costly anesthetics, to generate and sustain widespread compliance from a large physician group, and to decrease costs without adversely affecting clinical outcomes., Methods: A prospective before and after comparison study was performed at a tertiary care medical center. Clinical outcomes data and times indicative of perioperative patient flow were collected on the first of two sets of patients 1 month before discussion of practice guidelines. Practice guidelines were developed by the physicians and their associated care team for the intraoperative use of anesthetic drugs. A drug distribution process was developed to aid compliance. Clinical outcomes data and times indicative of perioperative patient flow were collected on the second set of patients 1 month after institution of practice guidelines. Hospital drug costs and adherence to guidelines were noted throughout the study period and for each of the following 9 months by querying the database of an automated anesthesia record keeper., Results: A total of 1,744 patients were studied. Drug costs decreased from 56 dollars per case to 32 dollars per case as a result of adherence to practice guidelines. Perioperative patient flow was minimally affected. Time (mean +/- SD) from end of surgery to arrival in the post-anesthesia care unit (PACU) increased from 11 +/- 7 min before the authors instituted practice guidelines to 14 +/- 8 min after practice guidelines (P < 0.0001). Admission of inpatients to the PACU receiving monitored anesthesia care increased from 6.5 to 12.9% (P < 0.02). Perioperative patient flow and clinical outcomes were not otherwise adversely affected. Compliance and cost savings have been sustained., Conclusions: This study is an example of a successful physician-directed program to promote more appropriate utilization of health care resources. Cost savings were obtained without any substantial changes in clinical outcomes. Institution of similar practice guidelines should result in pharmaceutical savings in the range of 50% at tertiary care centers around the country, with a slightly smaller degree of savings expected at institutions with more ambulatory surgery.

Background: This study determined the accuracy of previously defined adult fentanyl pharmacokinetics in children having surgery; from this population, the pharmacokinetics of fentanyl were characterized in children when administered via a computerized assisted continuous-infusion device., Methods: Twenty children between the ages of 2.7 and 11 y scheduled to undergo elective noncardiac surgery were studied. After induction, anesthesia was maintained with 60% nitrous oxide in oxygen supplemented with fentanyl (n = 10) or fentanyl plus isoflurane (n = 10). Fentanyl was administered via computerized assisted continuous-infusion to target concentrations determined by clinical requirements. Plasma fentanyl concentrations were measured and used to evaluate the performance of the fentanyl pharmacokinetics and then to determine a new set of pharmacokinetic parameters and the variance in the context-sensitive half-times simulated for these patients., Results: The original adult fentanyl pharmacokinetics resulted in a positive bias (10.4%), indicating that measured concentrations were mostly greater than predicted. A two-compartment model with age and weight as covariates provided the optimal pharmacokinetic parameters. These resulted in a residual performance error of -1.1% and a median absolute performance error of 17.4%. The context-sensitive times determined from this pediatric population were considerably shorter than the context-sensitive times previously published for adults., Conclusions: The pharmacokinetics of fentanyl administered by computerized assisted continuous-infusion differ between adults and children. The newly derived parameters are probably more suitable to determine infusion schemes of up to 4 h in children between the ages of 2 and 11 y.