Hippocampal HDAC6 promotes POCD by regulating NLRP3-induced microglia pyroptosis via HSP90/HSP70 in aged mice.

BACKGROUND: Postoperative Cognitive Dysfunction (POCD) has attracted increased attention, but its precise mechanism remains to be explored. This study aimed to figure out whether HDAC6 could regulate NLRP3-induced pyroptosis by modulating the functions of HSP70 and HSP90 in microglia to participate in postoperative cognitive dysfunction in aged mice. METHODS: Animal models of postoperative cognitive dysfunction in aged mice were established by splenectomy under sevoflurane anesthesia. Morris water maze was used to examine the cognitive function and motor ability. Sixteen-months-old C57BL/6 male mice were randomly divided into six groups: control group (C group), sham surgery group (SA group), splenectomy group (S group), splenectomy + HDAC6 inhibitor ACY-1215 group (ACY group), splenectomy + HDAC6 inhibitor ACY-1215 + HSP70 inhibitor Apoptozole group (AP group), splenectomy + solvent control group (SC group). The serum and hippocampus of mice were taken after mice were executed. The protein levels of HDAC6, HSP90, HSP70, NLRP3, GSDMD-N, cleaved-Caspase-1 (P20), IL-1ß were detected by western blotting. Serum IL-1ß, IL-6 and S100ß were measured using ELISA assay, and cell localization of HDAC6 was detected by immunofluorescence. In vitro experiments, BV2 cells were used to validate whether this mechanism worked in microglia. The protein levels of HDAC6, HSP90, HSP70, NLRP3, GSDMD-N, P20, IL-1ß were detected by western blotting and the content of IL-1ß in the supernatant was measured using ELISA assay. The degree of acetylation of HSP90, the interaction of HSP70, HSP90 and NLRP3 were analyzed by coimmunoprecipitation assay. RESULTS: Splenectomy under sevoflurane anesthesia in aged mice could prolong the escape latency, reduce the number of crossing platforms, increase the expression of HDAC6 and activate the NLRP3 inflammasome to induce pyroptosis in hippocampus microglia. Using ACY-1215 could reduce the activation of NLRP3 inflammasome, the pyroptosis of microglia and the degree of spatial memory impairment. Apoptozole could inhibit the binding of HSP70 to NLRP3, reduce the degradation of NLRP3 and reverse the protective effect of HDAC6 inhibitors. The results acquired in vitro experiments closely resembled those in vivo, LPS stimulation led to the pyroptosis of BV2 microglia cells and the release of IL-1ß due to the activation of the NLRP3 inflammasome, ACY-1215 showed the anti-inflammatory effect and Apoptozole exerted the opposite effect. CONCLUSIONS: Our findings suggest that hippocampal HDAC6 promotes POCD by regulating NLRP3-induced microglia pyroptosis via HSP90/HSP70 in aged mice.

Transcription factor EBF1 mitigates neuropathic pain by rescuing Kv1.2 expression in primary sensory neurons.

Nerve injury-induced alternations of gene expression in primary sensory neurons of the dorsal root ganglion (DRG) are molecular basis of neuropathic pain genesis. Transcription factors regulate gene expression. In this study, we examined whether early B cell factor 1 (EBF1), a transcription factor, in the DRG, participated in neuropathic pain caused by chronic constriction injury (CCI) of the sciatic nerve. EBF1 was distributed exclusively in the neuronal nucleus and coexpressed with cytoplasmic/membrane Kv1.2 in individual DRG neurons. The expression of Ebf1 mRNA and protein was time-dependently downregulated in the ipsilateral lumbar (L) 3/4 DRGs after unilateral CCI. Rescuing this downregulation through microinjection of the adeno-associated virus 5 expressing full-length Ebf1 mRNA into the ipsilateral L3/4 DRGs reversed the CCI-induced decrease of DRG Kv1.2 expression and alleviated the development and maintenance of mechanical, heat and cold hypersensitivities. Conversely, mimicking the downregulation of DRG EBF1 through microinjection of AAV5-expressing Ebf1 shRNA into unilateral L3/4 DRGs produced a reduction of Kv1.2 expression in the ipsilateral L3/4 DRGs, spontaneous pain, and the enhanced responses to mechanical, heat and cold stimuli in naive mice. Mechanistically, EBF1 not only bound to the Kcna2 gene (encoding Kv1.2) promoter but also directly activated its activity. CCI decreased the EBF1 binding to the Kcna2 promoter in the ipsilateral L3/4 DRGs. Our findings suggest that DRG EBF1 downregulation contributes to neuropathic pain likely by losing its binding to Kcna2 promoter and subsequently silencing Kv1.2 expression in primary sensory neurons. Exogenous EBF1 administration may mitigate neuropathic pain by rescuing DRG Kv1.2 expression.

Surgeon Perspectives on Daily Presentation of Ethical Dilemmas: A Qualitative Study.

BACKGROUND: Surgeons encounter and navigate a unique set of ethical dilemmas. The American College of Surgeons (ACS) previously identified 6 core ethical issues central to the practice of surgery, but there have been no reports of the true range and complexity of ethical dilemmas encountered by surgeons in their daily practice. Qualitative research is well positioned to address this question. STUDY DESIGN: We conducted in-depth interviews with attending surgeons across multiple surgical subspecialties at a large, urban, academic medical center asking them to describe the most common ethical dilemmas they encounter in day-to-day practice. Interviews were recorded, transcribed, and coded according to a grounded theory, inductive approach. RESULTS: Thirty attending surgeons were interviewed, representing twelve different general surgery subspecialties. The majority of dilemmas identified pertained to 4 of the 6 ACS identified core ethical issues: professional obligations, competition of interests, truth telling, and end-of-life care. No participants described dilemmas relating to the themes of confidentiality or surrogate decision-making. Approximately one-third of participants identified ethical issues not well characterized by the ACS core principles, most often relating to the pressure to provide care that is not medically indicated. There was strong support for a formalized surgical ethics curriculum. CONCLUSIONS: Although the ACS-defined core ethical issues in surgery appropriately captured many ethical dilemmas identified by participants, surgeons described several scenarios not well characterized by these themes. A dedicated surgical ethics curriculum may help to better equip surgeons to navigate the ethical dilemmas they are likely to face in practice.

Society for Cardiovascular Angiography and Interventions Shock Classification to Stratify Outcomes of Extracorporeal Membrane Oxygenation.

We applied the Society for Cardiovascular Angiography and Interventions (SCAI) schema to cardiogenic shock (CS) patients treated with venoarterial extracorporeal membrane oxygenation (VA-ECMO) to assess performance in this high acuity group of patients. Records of adult patients receiving VA-ECMO for CS at our institution from 01/2015 to 12/2019 were reviewed. Post-cardiotomy and noncardiogenic shock patients were excluded. A total of 245 patients were included, with a median age of 59 years [IQR: 48-67]; 159 (65%) were male. There were 34 (14%) patients in Stage C, 82 (33%) in D, and 129 (53%) in E. Of E patients, 88 (68%) were undergoing cardiopulmonary resuscitation. Median ECMO duration decreased with stage (C:7, D:6, E:4 days, P < 0.001). In-hospital mortality increased (C:35%, D:56%, E:71%, P < 0.001) and myocardial recovery decreased with stage (C:65%, D:35%, E:30%, P < 0.001). Acute kidney injury (C:35%, D:45%, E:54%, P = 0.045), acute liver failure (C:32%, D:66%, E:76%, P < 0.001), and infection (C:35%, D:28%, E:16%, P = 0.004) varied among groups. Multivariable analysis revealed age (HR=1.02), male sex (HR=0.62), and E classification (HR=2.69) as independently associated with 1-year mortality. Competing-risks regression identified D (SHR=0.53) and E classification (SHR=0.45) as inversely associated with myocardial recovery. In patients treated with VA-ECMO for CS, the SCAI classification provided robust risk stratification.

Clinical efficacy of direct or indirect left ventricular unloading during venoarterial extracorporeal membrane oxygenation for primary cardiogenic shock.

OBJECTIVE: Left ventricular (LV) distention is a feared complication in patients receiving venoarterial (VA) extracorporeal membrane oxygenation (ECMO). LV unloading can be achieved indirectly with intra-aortic balloon pump (IABP) or directly with an Impella device (Abiomed, Danvers, Mass). We sought to assess the clinical and hemodynamic effects of IABP and Impella devices on patients supported with VA ECMO. METHODS: We conducted a retrospective review of VA ECMO patients at our institution from January 2015 to June 2020. Patients were categorized as either ECMO alone or ECMO with LV unloading. LV unloading was characterized as either ECMO with IABP or ECMO with Impella. We recorded baseline characteristics, survival, complications, and hemodynamic changes associated with device initiation. RESULTS: During the study, 143 patients received ECMO alone whereas 140 received ECMO with LV unloading (68 ECMO with IABP, 72 ECMO with Impella). ECMO with Impella patients had a higher incidence of bleeding events compared with ECMO alone or ECMO with IABP (52.8% vs 37.1% vs 17.7%; P < .0001). Compared with ECMO alone, ECMO with IABP patients had better survival at 180 days (log rank P = .005) whereas survival in ECMO with Impella patients was not different (log rank P = .66). In a multivariable Cox hazard analysis, age (hazard ratio [HR], 1.02; 95% confidence interval [CI], 1.00-1.03; P = .015), male sex (HR, 0.54; 95% CI, 0.38-0.80; P = .002), baseline lactate (HR, 1.06; 95% CI, 1.02-1.11; P = .004), baseline creatinine (HR, 1.06; 95% CI, 1.00-1.11; P = .032), need for extracorporeal membrane oxygenation-cardiopulmonary resuscitation (HR, 2.09; 95% CI, 1.40-3.39; P = .001), and presence of pre-ECMO IABP (HR, 0.45; 95% CI, 0.25-0.83; P = .010) were associated with reduced mortality. There was no significant difference in hemodynamic changes in the ECMO with IABP versus ECMO with Impella cohorts. CONCLUSIONS: Concomitant support with IABP might help reduce morbidity and improve 180-day survival in patients receiving VA ECMO for cardiogenic shock.

Implantable Peripheral Nerve Stimulation for Peripheral Neuropathic Pain: A Systematic Review of Prospective Studies.

Peripheral nerve stimulation (PNS) has been utilized for over 50 years with accumulating evidence of efficacy in a variety of chronic pain conditions. The level and strength of evidence supporting the use of PNS for peripheral neuropathic pain remains unclear. The purpose of this review is to synthesize data from prospective studies on the efficacy of PNS for neuropathic pain as it pertains to pain intensity, neurological deficits/neuropathy (e.g., weakness, sensory deficits, gait/balance), and other secondary outcomes (quality of life, satisfaction, emotional functioning, and adverse events). In compliance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines, this review identified articles from MEDLINE(R), EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus. Overall, per the Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria, pooled results demonstrate very low quality or low quality of evidence supporting modest to substantial improvement in pain and neurological function after PNS implantation for treatment of peripheral neuropathic pain. PNS for phantom limb pain was the only indication that had moderate level evidence. Future prospective and well-powered studies are warranted to assess the efficacy of PNS for peripheral neuropathic pain.

Perioperative Management of Calciphylaxis: Literature Review and Treatment Recommendations.

Calciphylaxis is a serious and rare medical condition that leads to substantial clinical manifestations including pain, creating perioperative and treatment challenges. No standard treatment protocol exists nor are comprehensive guidelines available for perioperative management of patients with calciphylaxis. In this review, we evaluate existing literature (January 2000 to May 2021) with the aim to offer guidance for treating patients with this challenging disease through the perioperative period. Although no therapies are currently considered standard for treating calciphylaxis, multiple interventions are available for improving symptoms. Preoperative and intraoperative management involves monitoring and optimizing patient comorbid conditions and any possible electrolyte imbalances. Postoperative management can be challenging when potential calciphylaxis triggers are indicated, such as warfarin and corticosteroids. In addition, poor wound healing and difficult pain control are common. Therefore, a multifactorial approach to controlling postoperative pain is recommended that includes the use of nerve blocks, renal-sparing opioids, benzodiazepines, and/or ketamine. We present preoperative, intraoperative, and postoperative recommendations for treating calciphylaxis with levels of evidence when appropriate.

In COVID-19 Patients Who Suffer In-Hospital Cardiac Arrest, Cardiopulmonary Resuscitation Outcomes May Be Impacted by Arrest Etiology and Local Pandemic Conditions.

OBJECTIVES: The utility and risks to providers of performing cardiopulmonary resuscitation after in-hospital cardiac arrest in COVID-19 patients have been questioned. Additionally, there are discrepancies in reported COVID-19 in-hospital cardiac arrest survival rates. We describe outcomes after cardiopulmonary resuscitation for in-hospital cardiac arrest in two COVID-19 patient cohorts. DESIGN: Retrospective cohort study. SETTING: New York-Presbyterian Hospital/Columbia University Irving Medical Center in New York, NY. PATIENTS: Those admitted with COVID-19 between March 1, 2020, and May 31, 2020, as well as between March 1, 2021, and May 31, 2021, who received resuscitation after in-hospital cardiac arrest. INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: Among 103 patients with coronavirus disease 2019 who were resuscitated after in-hospital cardiac arrest in spring 2020, most self-identified as Hispanic/Latino or African American, 35 (34.0%) had return of spontaneous circulation for at least 20 minutes, and 15 (14.6%) survived to 30 days post-arrest. Compared with nonsurvivors, 30-day survivors experienced in-hospital cardiac arrest later (day 22 vs day 7; p = 0.008) and were more likely to have had an acute respiratory event preceding in-hospital cardiac arrest (93.3% vs 27.3%; p < 0.001). Among 30-day survivors, 11 (73.3%) survived to hospital discharge, at which point 8 (72.7%) had Cerebral Performance Category scores of 1 or 2. Among 26 COVID-19 patients resuscitated after in-hospital cardiac arrest in spring 2021, 15 (57.7%) had return of spontaneous circulation for at least 20 minutes, 3 (11.5%) survived to 30 days post in-hospital cardiac arrest, and 2 (7.7%) survived to hospital discharge, both with Cerebral Performance Category scores of 2 or less. Those who survived to 30 days post in-hospital cardiac arrest were younger (46.3 vs 67.8; p = 0.03), but otherwise there were no significant differences between groups. CONCLUSIONS: Patients with COVID-19 who received cardiopulmonary resuscitation after in-hospital cardiac arrest had low survival rates. Our findings additionally show return of spontaneous circulation rates in these patients may be impacted by hospital strain and that patients with in-hospital cardiac arrest preceded by acute respiratory events might be more likely to survive to 30 days, suggesting Advanced Cardiac Life Support efforts may be more successful in this subpopulation.

Dorsal Root Ganglion Stimulation for Chronic Groin Pain: A Review.

INTRODUCTION: Chronic neuropathic groin pain develops in a significant number of postsurgical patients; however, multiple etiologies have been identified, and this makes it a challenging condition to treat. While treatment often involves a multimodal approach, advancements in neuromodulation technology, particularly dorsal root ganglion (DRG) stimulation, have benefited patients plagued by chronic pain refractory to standard treatment modalities. Our goal was to provide a definitive source of information for interventional pain physicians regarding groin pain and the use of DRG stimulation for its treatment. MATERIALS AND METHODS: In this narrative review, we provide an overview of groin pain and discuss potential pain generators. We also outline appropriate treatment options with particular interest on DRG stimulation. Lastly, we provide a narrative review of the published literature regarding DRG stimulation for chronic groin pain from a variety of etiologies. CONCLUSION: DRG stimulation has emerged as an alternative neuromodulatory technique for patients with chronic groin pain. While previous studies suggest substantial sustained pain relief with DRG stimulation in this patient population, prospective randomized controlled studies are necessary before formal recommendations can be made.

Anesthetic Management of a Patient With an Implantable Hypoglossal Nerve Stimulator: A Case Report.

Obstructive sleep apnea (OSA) is a common condition, particularly in obese men and in those with an increased neck circumference. Management with a continuous positive airway pressure (CPAP) machine has been the mainstay of treatment over many years; although, it is not acceptable to all. Recently, innovative medical devices, such as hypoglossal nerve stimulators, have emerged and are now being increasingly utilized. We present a case report of a patient undergoing rotator cuff repair on the same side as the implanted device and our recommendations on the anesthetic management.

Evaluation of distal radial artery cross-sectional internal diameter in neonates and infants by ultrasound and adequate selection of an intra-arterial catheter size.

BACKGROUND: Radial artery catheterization in neonates, infants, and young children is a common and useful invasive procedure that brings technical placement challenges and potential complications due to the small diameter size of the radial artery in these patients. The aim of this study is to determine appropriate catheter sizes in infants up to 6 months of age. MATERIALS AND METHODS: A total of fifty infants undergoing general anesthesia or hospitalized in the neonatal intensive care unit were included. Images of the radial artery diameter were obtained from the infant's wrist using Philips EPIQ Diagnostic Ultrasound System CVX Release 4.0. All images obtained were distal in the forearm, medial to the border of the styloid process of the radius, at the point of maximal impulse of the radial artery, and with the wrist at a 45-degree angle position. We recorded postmenstrual age, chronological age, gender, weight, location, comorbidities, medications, weight, and vital signs of each individual. RESULTS: In this single cohort study of 50 children whose ages ranged from 0 to 6 months chronological age, their radial artery diameters were averaged proportionally to their weight and age. Use of a 22G catheter would result in 100% occlusion of the diameter of the artery in most study subjects. Use of a 24G catheter would result in a range of 75%-99% occlusion depending on weight, postmenstrual age, and chronological age of the infants. CONCLUSIONS: In view of these findings, we recommend using US to measure the diameter of the radial artery and choose the most appropriate catheter size before proceeding with US-guidance for radial artery cannulation in infants. This will prevent inappropriate sizing of the catheter and the thrombotic complications this can incur.

Deviation from Clinical Routines Can Reveal Sources of Device Design Vulnerability.

The ability to adequately ventilate a patient is critical and sometimes a challenge in the emergency, intensive care, and anesthesiology settings. Commonly, initial ventilation is achieved through the use of a face mask in conjunction with a bag that is manually squeezed by the clinician to generate positive pressure and flow of air or oxygen through the patient's airway. Large or small erroneous openings in the breathing circuit can lead to leaks that compromise ventilation ability. Standard procedure in anesthesiology is to check the circuit apparatus and oxygen delivery system prior to every case. Because the face mask itself is not a piece of equipment that is associated with a source of leak, some common anesthesia machine designs are constructed such that the circuit is tested without the mask component. We present an example of a leak that resulted from complete failure of the face mask due to a tiny tear in its cuff by the patient's sharp teeth edges. This subsequently prevented formation of a seal between the face mask and the patient's face and rendered the device incapable of generating the positive pressure it is designed to deliver. This instance depicts the broader lesson that deviation from clinical routines can reveal unappreciated sources of vulnerability in device design.

Even the Simplest Devices May Malfunction: Split Septum Design Revisited.

Split septum medical devices are used in tubing for intravenous (IV) fluid administration-an extremely common clinical task. These tubing caps contain a needleless, valveless system that allows fluid to flow directly through the lumen of the catheter but prevents backflow of fluid or blood when the tubing extension is not connected. We experienced complete failure of a needle-free connector extension set with a Luer-access split septum device in multiple patients due to the split septum remaining fused and essentially unsplit despite being connected on both ends. This led to an adverse event in a patient due to repeated unnecessary IV insertion attempts. This case shows how even the simplest of devices can malfunction and highlights the need for vigilance in clinical practice.