Safety amid the scalpels: creating psychological safety in the operating room.

PURPOSE OF REVIEW: We briefly review the concept of psychological safety and discuss the actions that can create it in the anesthesiologist's work environment. RECENT FINDINGS: The interest in psychological safety has grown in popularity since the publication of Amy Edmondson's book The Fearless Organization in 2018. While the concept and its benefits are described in the healthcare literature, the specific actions necessary to create it are often not. SUMMARY: To ensure patient safety, we want members of the teams we lead to be comfortable sharing emerging problems that they see before we become aware of them. As educators, we want trainees to approach us when they do not understand something and openly participate and contribute without the fear of how others will perceive them. These scenarios require an environment of psychological safety - the ability to ask for help, admit mistakes, and be respectfully forthright with unpopular beliefs without the fear of being ostracized or ignored. Methods for creating an environment of psychological safety will be discussed.

Bloodless surgery in urologic oncology: A review of hematologic, anesthetic, and surgical considerations.

The urologic oncology patient who refuses blood transfusion can present unique challenges in perioperative blood management. Since blood loss and associated transfusion can be expected in many complex urologic oncology surgeries, a multidisciplinary approach may be required for optimal outcomes. Through collaboration with the hematologist, anesthesiologist, and urologist, various techniques can be employed in the perioperative phases to minimize blood loss and the need for transfusion. We review the risks and benefits of these techniques and offer recommendations specific to the urologic oncology patient.

Separating Proactive Conservation from Species Listing Decisions.

Proactive Conservation is a paradigm of natural resource management in the United States that encourages voluntary, collaborative efforts to restore species before they need to be protected through government regulations. This paradigm is widely used to conserve at-risk species today, and when used in conjunction with the Policy for Evaluation of Conservation Efforts (PECE), it allows for successful conservation actions to preclude listing of species under the Endangered Species Act (ESA). Despite the popularity of this paradigm, and recent flagship examples of its use (e.g., greater sage grouse, Centrocercus urophasianus), critical assessments of the outcomes of Proactive Conservation are lacking from the standpoint of species status and recovery metrics. Here, we provide such an evaluation, using the New England cottontail (Sylvilagus transitionalis), heralded as a success of Proactive Conservation efforts in the northeastern United States, as a case study. We review the history and current status of the species, based on the state of the science, in the context of the Conservation Initiative, and the 2015 PECE decision not to the list the species under the ESA. In addition to the impacts of the PECE decision on the New England cottontail conservation specifically, our review also evaluates the benefits and limits of the Proactive Conservation paradigm more broadly, and we make recommendations for its role in relation to ESA implementation for the future of at-risk species management. We find that the status and assurances for recovery under the PECE policy, presented at the time of the New England cottontail listing decision, were overly optimistic, and the status of the species has worsened in subsequent years. We suggest that use of PECE to avoid listing may occur because of the perception of the ESA as a punitive law and a misconception that it is a failure, although very few listed species have gone extinct. Redefining recovery to decouple it from delisting and instead link it to probability of persistence under recommended conservation measures would remove some of the stigma of listing, and it would strengthen the role of Species Status Assessments in endangered species conservation.

Parallels between our response to COVID-19 and approach to patient safety.

The response to the COVID-19 pandemic and the approach to patient safety share three important concepts: the challenges of preventing rare events, use of rules, and tolerance for uncertainty. We discuss how each of these ideas can be utilised in perioperative safety to create a high-reliability system.

Factors that affect migratory Western Atlantic red knots (Calidris canutus rufa) and their prey during spring staging on Virginia's barrier islands.

Understanding factors that influence a species' distribution and abundance across the annual cycle is required for range-wide conservation. Thousands of imperiled red knots (Calidris cantus rufa) stop on Virginia's barrier islands each year to replenish fat during spring migration. We investigated the variation in red knot presence and flock size, the effects of prey on this variation, and factors influencing prey abundance on Virginia's barrier islands. We counted red knots and collected potential prey samples at randomly selected sites from 2007-2018 during a two-week period during early and peak migration. Core samples contained crustaceans (Orders Amphipoda and Calanoida), blue mussels (Mytilus edulis), coquina clams (Donax variabilis), and miscellaneous prey (horseshoe crab eggs (Limulus polyphemus), angel wing clams (Cyrtopleura costata), and other organisms (e.g., insect larvae, snails, worms)). Estimated red knot peak counts in Virginia during 21-27 May were highest in 2012 (11,959) and lowest in 2014 (2,857; 12-year peak migration [Formula: see text] = 7,175, SD = 2,869). Red knot and prey numbers varied across sampling periods and substrates (i.e., peat and sand). Red knots generally used sites with more prey. Miscellaneous prey ([Formula: see text] = 2401.00/m2, SE = 169.16) influenced red knot presence at a site early in migration, when we only sampled on peat banks. Coquina clams ([Formula: see text] = 1383.54/m2, SE = 125.32) and blue mussels ([Formula: see text] = 777.91/m2, SE = 259.31) affected red knot presence at a site during peak migration, when we sampled both substrates. Few relationships between prey and red knot flock size existed, suggesting that other unmeasured factors determined red knot numbers at occupied sites. Tide and mean daily water temperature affected prey abundance. Maximizing the diversity, availability, and abundance of prey for red knots on barrier islands requires management that encourages the presence of both sand and peat bank intertidal habitats.

Efficacy and safety of CD24Fc in hospitalised patients with COVID-19: a randomised, double-blind, placebo-controlled, phase 3 study.

BACKGROUND: Non-antiviral therapeutic options are required for the treatment of hospitalised patients with COVID-19. CD24Fc is an immunomodulator with potential to reduce the exaggerated inflammatory response to tissue injuries. We aimed to evaluate the safety and efficacy of CD24Fc in hospitalised adults with COVID-19 receiving oxygen support. METHODS: We conducted a randomised, double-blind, placebo-controlled, phase 3 study at nine medical centres in the USA. Hospitalised patients (age ≥18 years) with confirmed SARS-CoV-2 infection who were receiving oxygen support and standard of care were randomly assigned (1:1) by site-stratified block randomisation to receive a single intravenous infusion of CD24Fc 480 mg or placebo. The study funder, investigators, and patients were masked to treatment group assignment. The primary endpoint was time to clinical improvement over 28 days, defined as time that elapsed between a baseline National Institute of Allergy and Infectious Diseases ordinal scale score of 2-4 and reaching a score of 5 or higher or hospital discharge. The prespecified primary interim analysis was done when 146 participants reached the time to clinical improvement endpoint. Efficacy was assessed in the intention-to-treat population. Safety was assessed in the as-treated population. This study is registered with ClinicalTrials.gov, NCT04317040. FINDINGS: Between April 24 and Sept 22, 2020, 243 hospitalised patients were assessed for eligibility and 234 were enrolled and randomly assigned to receive CD24Fc (n=116) or placebo (n=118). The prespecified interim analysis was done when 146 participants reached the time to clinical improvement endpoint among 197 randomised participants. In the interim analysis, the 28-day clinical improvement rate was 82% (81 of 99) for CD24Fc versus 66% (65 of 98) for placebo; median time to clinical improvement was 6·0 days (95% CI 5·0-8·0) in the CD24Fc group versus 10·0 days (7·0-15·0) in the placebo group (hazard ratio [HR] 1·61, 95% CI 1·16-2·23; log-rank p=0·0028, which crossed the prespecified efficacy boundary [α=0·0147]). 37 participants were randomly assigned after the interim analysis data cutoff date; among the 234 randomised participants, median time to clinical improvement was 6·0 days (95% CI 5·0-9·0) in the CD24Fc group versus 10·5 days (7·0-15·0) in the placebo group (HR 1·40, 95% CI 1·02-1·92; log-rank p=0·037). The proportion of participants with disease progression within 28 days was 19% (22 of 116) in the CD24Fc group versus 31% (36 of 118) in the placebo group (HR 0·56, 95% CI 0·33-0·95; unadjusted p=0·031). The incidences of adverse events and serious adverse events were similar in both groups. No treatment-related adverse events were observed. INTERPRETATION: CD24Fc is generally well tolerated and accelerates clinical improvement of hospitalised patients with COVID-19 who are receiving oxygen support. These data suggest that targeting inflammation in response to tissue injuries might provide a therapeutic option for patients hospitalised with COVID-19. FUNDING: Merck & Co, National Cancer Institute, OncoImmune.

Is conservation based on best available science creating an ecological trap for an imperiled lagomorph?

Habitat quality regulates fitness and population density, making it a key driver of population size. Hence, increasing habitat quality is often a primary goal of species conservation. Yet, assessments of fitness and density are difficult and costly to obtain. Therefore, species conservation often uses "best available science," extending inferences across taxa, space, or time, and inferring habitat quality from studies of habitat selection. However, there are scenarios where habitat selection is not reflective of habitat quality, and this can lead to maladaptive management strategies. The New England cottontail (Sylvilagus transitionalis) is an imperiled shrubland obligate lagomorph whose successful recovery hinges on creation of suitable habitat. Recovery of this species is also negatively impacted by the non-native eastern cottontail (Sylvilagus floridanus), which can competitively exclude New England cottontails from preferred habitat. Herein, we evaluate habitat quality for adult and juvenile New England and eastern cottontails using survival and density as indicators. Our findings did not support selection following an ideal free distribution by New England cottontails. Instead, selected resources, which are a target of habitat management, were associated with low survival and density and pointed to a complex trade-off between density, survival, habitat, and the presence of eastern cottontails. Further, movement distance was inversely correlated with survival in both species, suggesting that habitat fragmentation limits the ability of cottontails to freely distribute based on habitat quality. While habitat did not directly regulate survival of juvenile cottontails, tick burden had a strong negative impact on juvenile cottontails in poor body condition. Given the complex interactions among New England cottontails, eastern cottontails, and habitat, directly assessing and accounting for factors that limit New England cottontail habitat quality in management plans is vital to their recovery. Our study demonstrates an example of management for possible ecological trap conditions via the application of incomplete knowledge.

Over 12 Years Single Institutional Experience Performing Percutaneous Hepatic Perfusion for Unresectable Liver Metastases.

Patients with unresectable hepatic metastases, from uveal or ocular melanoma, are challenging to treat with an overall poor prognosis. Although over the past decade significant advances in systemic therapies have been made, metastatic disease to the liver, especially from uveal melanoma, continues to be a poor prognosis. Percutaneous hepatic perfusion (PHP) is a safe, viable treatment option for these patients. PHP utilizes high dose chemotherapy delivered directly to the liver while minimizing systemic exposure and can be repeated up to 6 times. Isolation of the hepatic vasculature with a double-balloon catheter allows for high concentration cytotoxic therapy to be administered with minimal systemic adverse effects. A detailed description of the multidisciplinary treatment protocol used at an institution with over 12 years of experience is discussed and recommendations are given. A dedicated team of a surgical or medical oncology, interventional radiology, anesthesiology and a perfusionist allows PHP to be repeatedly performed as a safe treatment strategy for unresectable hepatic metastases.

Photoaffinity labeling identifies an intersubunit steroid-binding site in heteromeric GABA type A (GABAA) receptors.

Allopregnanolone (3α5α-P), pregnanolone, and their synthetic derivatives are potent positive allosteric modulators (PAMs) of GABAA receptors (GABAARs) with in vivo anesthetic, anxiolytic, and anti-convulsant effects. Mutational analysis, photoaffinity labeling, and structural studies have provided evidence for intersubunit and intrasubunit steroid-binding sites in the GABAAR transmembrane domain, but revealed only little definition of their binding properties. Here, we identified steroid-binding sites in purified human α1ß3 and α1ß3γ2 GABAARs by photoaffinity labeling with [3H]21-[4-(3-(trifluoromethyl)-3H-diazirine-3-yl)benzoxy]allopregnanolone ([3H]21-pTFDBzox-AP), a potent GABAAR PAM. Protein microsequencing established 3α5α-P inhibitable photolabeling of amino acids near the cytoplasmic end of the ß subunit M4 (ß3Pro-415, ß3Leu-417, and ß3Thr-418) and M3 (ß3Arg-309) helices located at the base of a pocket in the ß+-α- subunit interface that extends to the level of αGln-242, a steroid sensitivity determinant in the αM1 helix. Competition photolabeling established that this site binds with high affinity a structurally diverse group of 3α-OH steroids that act as anesthetics, anti-epileptics, and anti-depressants. The presence of a 3α-OH was crucial: 3-acetylated, 3-deoxy, and 3-oxo analogs of 3α5α-P, as well as 3ß-OH analogs that are GABAAR antagonists, bound with at least 1000-fold lower affinity than 3α5α-P. Similarly, for GABAAR PAMs with the C-20 carbonyl of 3α5α-P or pregnanolone reduced to a hydroxyl, binding affinity is reduced by 1,000-fold, whereas binding is retained after deoxygenation at the C-20 position. These results provide a first insight into the structure-activity relationship at the GABAAR ß+-α- subunit interface steroid-binding site and identify several steroid PAMs that act via other sites.

Competitive Antagonism of Etomidate Action by Diazepam: In Vitro GABAA Receptor and In Vivo Zebrafish Studies.

BACKGROUND: Recent cryo-electron microscopic imaging studies have shown that in addition to binding to the classical extracellular benzodiazepine binding site of the α1ß3γ2L γ-aminobutyric acid type A (GABAA) receptor, diazepam also binds to etomidate binding sites located in the transmembrane receptor domain. Because such binding is characterized by low modulatory efficacy, the authors hypothesized that diazepam would act in vitro and in vivo as a competitive etomidate antagonist. METHODS: The concentration-dependent actions of diazepam on 20 µM etomidate-activated and 6 µM GABA-activated currents were defined (in the absence and presence of flumazenil) in oocyte-expressed α1ß3γ2L GABAA receptors using voltage clamp electrophysiology. The ability of diazepam to inhibit receptor labeling of purified α1ß3γ2L GABAA receptors by [H]azietomidate was assessed in photoaffinity labeling protection studies. The impact of diazepam (in the absence and presence of flumazenil) on the anesthetic potencies of etomidate and ketamine was compared in a zebrafish model. RESULTS: At nanomolar concentrations, diazepam comparably potentiated etomidate-activated and GABA-activated GABAA receptor peak current amplitudes in a flumazenil-reversible manner. The half-maximal potentiating concentrations were 39 nM (95% CI, 27 to 55 nM) and 26 nM (95% CI, 16 to 41 nM), respectively. However, at micromolar concentrations, diazepam reduced etomidate-activated, but not GABA-activated, GABAA receptor peak current amplitudes in a concentration-dependent manner with a half-maximal inhibitory concentration of 9.6 µM (95% CI, 7.6 to 12 µM). Diazepam (12.5 to 50 µM) also right-shifted the etomidate-concentration response curve for direct activation without reducing the maximal response and inhibited receptor photoaffinity labeling by [H]azietomidate. When administered with flumazenil, 50 µM diazepam shifted the etomidate (but not the ketamine) concentration-response curve for anesthesia rightward, increasing the etomidate EC50 by 18-fold. CONCLUSIONS: At micromolar concentrations and in the presence of flumazenil to inhibit allosteric modulation via the classical benzodiazepine binding site of the GABAA receptor, diazepam acts as an in vitro and in vivo competitive etomidate antagonist.

Impact of Treatment Beyond Progression with Immune Checkpoint Blockade in Hodgkin Lymphoma.

Atypical response patterns following immune checkpoint blockade (ICB) in Hodgkin lymphoma (HL) led to the concept of continuation of treatment beyond progression (TBP); however, the longitudinal benefit of this approach is unclear. We therefore performed a retrospective analysis of 64 patients treated with ICB; 20 who received TBP (TBP cohort) and 44 who stopped ICB at initial progression (non-TBP cohort). The TBP cohort received ICB for a median of 4.7 months after initial progression and delayed subsequent treatment by a median of 6.6 months. Despite receiving more prior lines of therapy, the TBP cohort achieved longer progression-free survival with post-ICB treatment (median, 17.5 months vs. 6.1 months, p = .035) and longer time-to-subsequent treatment failure, defined as time from initial ICB progression to failure of subsequent treatment (median, 34.6 months vs. 9.9 months, p = .003). With the limitations of a retrospective study, these results support the clinical benefit of TBP with ICB for selected patients.

A potent photoreactive general anesthetic with novel binding site selectivity for GABAA receptors.

The pentameric γ-aminobutyric acid type A receptors (GABAARs) are the major inhibitory ligand-gated ion channels in the central nervous system. They mediate diverse physiological functions, mutations in them are associated with mental disorders and they are the target of many drugs such as general anesthetics, anxiolytics and anti-convulsants. The five subunits of synaptic GABAARs are arranged around a central pore in the order ß-α-ß-α-γ. In the outer third of the transmembrane domain (TMD) drugs may bind to five homologous intersubunit binding sites. Etomidate binds between the pair of ß - α subunit interfaces (designated as ß+/α-) and R-mTFD-MPAB binds to an α+/ß- and an γ+/ß- subunit interface (a ß- selective ligand). Ligands that bind selectively to other homologous sites have not been characterized. We have synthesized a novel photolabel, (2,6-diisopropyl-4-(3-(trifluoromethyl)-3H-diazirin-3-yl)phenyl)methanol or pTFD-di-iPr-BnOH). It is a potent general anesthetic that positively modulates agonist and benzodiazepine binding. It enhances GABA-induced currents, shifting the GABA concentration-response curve to lower concentrations. Photolabeling-protection studies show that it has negligible affinity for the etomidate sites and high affinity for only one of the two R-mTFD-MPAB sites. Exploratory site-directed mutagenesis studies confirm the latter conclusions and hint that pTFD-di-iPr-BnOH may bind between the α+/ß- and α+/γ- subunits in the TMD, making it an α+ ligand. The latter α+/γ- site has not previously been implicated in ligand binding. Thus, pTFD-di-iPr-BnOH is a promising new photolabel that may open up a new pharmacology for synaptic GABAARs.

How Sweet Is This? A Review and Evaluation of Preoperative Carbohydrate Loading in the Enhanced Recovery After Surgery Model.

Preoperative carbohydrate loading is a contemporary element of the enhanced recovery after surgery (ERAS) paradigm. In addition to intraoperative surgical and anesthetic modifications and postoperative care practices, preoperative optimization is essential to good postsurgical outcomes. What was long held as dogma, a period of prolonged fasting prior to the administration of anesthesia, was later re-examined and challenged. Along with the proposed physiologic effects of decreasing the surgical stress response and insulin resistance, preoperative carbohydrate loading was also demonstrated to improve patient satisfaction and well-being, without an increase in perioperative complications. The benefits are most strongly observed in abdominal and cardiac surgery patients, but there has also been data which support its use in other specialties and surgeries. Barriers to the adoption of perioperative carbohydrate loading are few, but importantly include overcoming the inertia to modify older and more restrictive fasting guidelines and achieving the multidisciplinary consensus necessary to implement such changes. Despite these challenges, and with an existing body of evidence supporting its benefits, preoperative carbohydrate loading presents a significant contribution to the ERAS programs.

Anesthetic Management of Right Single-lung Ventilation in a Patient with Anomalous Left Superior Pulmonary Venous Return for Left Pulmonary Lobectomy.

Partial anomalous pulmonary venous return (PAPVR) is a rare congenital anomaly in which one or more of the pulmonary veins are connected to the right atrium or to the systemic venous system. One lung ventilation (OLV) is required for a number of thoracic procedures. When switching to OLV, right-to-left shunt fraction increases, oxygenation is impaired, and hypoxemia may occur. Hypoxemia during OLV may affect the safety of the patient and is a challenge for the anesthesiologist and the surgeon. This case details the intraoperative anesthetic management of an elderly patient with a PAPVR who underwent single-lung ventilation for lung resection surgery.

Framework for quantifying population responses to disturbance reveals that coastal birds are highly resilient to hurricanes.

Changes in the frequency and severity of extreme weather may introduce new threats to species that are already under stress from gradual habitat loss and climate change. We provide a probabilistic framework that quantifies potential threats by applying concepts from ecological resilience to single populations. Our approach uses computation to compare disturbance-impacted projections to a population's normal range of variation, quantifying the full range of potential impacts. We illustrate this framework with projection models for coastal birds, which are commonly depicted as vulnerable to disturbances, especially hurricanes and oil spills. We found that populations of coastal specialists are resilient to extreme disturbances, with high resistance to the effects of short-term reductions in vital rates and recovery within 20 years. Applying the general framework presented here across disturbance-prone species and ecosystems would improve understanding of population resilience and generate specific projections of resilience that are needed for effective conservation planning.

Non-thoracic Source of Bleeding During Left-sided Thoracic Surgery.

Hypotension during thoracic surgery is traditionally attributed to intrathoracic causes such as pulmonary bleeding, ventilation, causing decreased venous return, and a decrease in myocardial contractility. We present a case of unexplained hypotension presenting at the end of left-sided thoracic surgery. The cause of hypotension was ultimately found to be due to intra-abdominal bleeding from a splenic injury. This case reminds the anesthesiologist to be vigilant of non-thoracic causes of hypotension during left-sided lung surgery.

Begging behavior as an honest signal of need and parent-offspring association during the postfledging dependency period.

Honest signaling mechanisms can function to appropriate care to hungry offspring and avoid misdirected care of unrelated offspring. Begging, the behavior by which offspring solicit food and parental care, may be an honest signaling mechanism for need, as well as association of parents and offspring. Roseate terns (Sterna dougallii) exhibit prolonged parental care during the postbreeding staging period, offering an ideal system in which to study begging as an honest signaling mechanism. We conducted focal sampling during two premigratory staging seasons (2014 and 2015) at Cape Cod National Seashore, Massachusetts, USA to determine whether postfledging tern begging behavior was an honest signal for need and parent-offspring association. Based on honest signaling theory, we expected begging behavior to be highest during times of high perceived need, and we expected to see a decrease in begging behavior as young terns became increasingly independent of the care-giving parent. Also, we predicted that young terns would be more likely to beg at parents than nonparents. We found that young roseate terns begged at their parents more often than nonparents; however, they did not always beg at parents. Model predictions of begging probability showed a linear relationship between begging and time of day and date of season, such that begging increased with time of day and decreased with date of season, respectively. Our results provide evidence for honest parent-offspring interactions and are inconsistent with parent-offspring conflict theory but suggest that begging may play a complex role in postfledging parent-offspring interactions. OPEN RESEARCH BADGES: This article has been awarded Open Data, Open materials Badges. All materials and data are publicly accessible via the Open Science Framework at https://doi.org/10.5281/zenodo.2656718.

Identifying Drugs that Bind Selectively to Intersubunit General Anesthetic Sites in the α1ß3γ2 GABAAR Transmembrane Domain.

GABAA receptors (GABAARs) are targets for important classes of clinical agents (e.g., anxiolytics, anticonvulsants, and general anesthetics) that act as positive allosteric modulators (PAMs). Previously, using photoreactive analogs of etomidate ([3H]azietomidate) and mephobarbital [[3H]1-methyl-5-allyl-5-(m-trifluoromethyl-diazirynylphenyl)barbituric acid ([3H]R-mTFD-MPAB)], we identified two homologous but pharmacologically distinct classes of general anesthetic binding sites in the α1ß3γ2 GABAAR transmembrane domain at ß +-α - (ß + sites) and α +-ß -/γ +-ß - (ß - sites) subunit interfaces. We now use competition photolabeling with [3H]azietomidate and [3H]R-mTFD-MPAB to identify para-substituted propofol analogs and other drugs that bind selectively to intersubunit anesthetic sites. Propofol and 4-chloro-propofol bind with 5-fold selectivity to ß +, while derivatives with bulkier lipophilic substitutions [4-(tert-butyl)-propofol and 4-(hydroxyl(phenyl)methyl)-propofol] bind with ∼10-fold higher affinity to ß - sites. Similar to R-mTFD-MPAB and propofol, these drugs bind in the presence of GABA with similar affinity to the α +-ß - and γ +-ß - sites. However, we discovered four compounds that bind with different affinities to the two ß - interface sites. Two of these bind with higher affinity to one of the ß - sites than to the ß + sites. We deduce that 4-benzoyl-propofol binds with >100-fold higher affinity to the γ +-ß - site than to the α +-ß - or ß +-α - sites, whereas loreclezole, an anticonvulsant, binds with 5- and 100-fold higher affinity to the α +-ß - site than to the ß + and γ +-ß - sites. These studies provide a first identification of PAMs that bind selectively to a single intersubunit site in the GABAAR transmembrane domain, a property that may facilitate the development of subtype selective GABAAR PAMs.