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Repeated or prolonged, but not short-term, general anesthesia during the early postnatal period causes long-lasting impairments in memory formation in various species. The mechanisms underlying long-lasting impairment in cognitive function are poorly understood. Here, we show that repeated general anesthesia in postnatal mice induces preferential apoptosis and subsequent loss of parvalbumin-positive inhibitory interneurons in the hippocampus. Each parvalbumin interneuron controls the activity of multiple pyramidal excitatory neurons, thereby regulating neuronal circuits and memory consolidation. Preventing the loss of parvalbumin neurons by deleting a proapoptotic protein, mitochondrial anchored protein ligase (MAPL), selectively in parvalbumin neurons rescued anesthesia-induced deficits in pyramidal cell inhibition and hippocampus-dependent long-term memory. Conversely, partial depletion of parvalbumin neurons in neonates was sufficient to engender long-lasting memory impairment. Thus, loss of parvalbumin interneurons in postnatal mice following repeated general anesthesia critically contributes to memory deficits in adulthood.

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Extracorporeal carbon dioxide removal (ECCO2R) uses mechanical systems to treat hypercapnic respiratory failure. Its utility has been investigated in acute respiratory distress syndrome (ARDS), acute exacerbations of chronic obstructive pulmonary disease (COPD), and status asthmaticus, and as a bridge to lung transplant. In this review, we discuss how it works, why it should help, and current evidence supporting its use.

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Background Postoperative ileus (POI) is among the most common complications affecting patients who undergo major abdominal surgery. Because of the high volume of major surgery and the high incidence of postoperative ileus, failure to code for this complication may have a significant impact on hospital reimbursement and quality measures. Objectives This paper investigates the magnitude of the difference between the prevalence of POI as coded in administrative data versus the prevalence based upon a prospectively applied operational definition of POI in patients undergoing intestinal resection surgery. Methods Data was collected during the course of a prospective study at the University of Iowa Hospitals & Clinics on an investigational digital health device for predicting operationally defined POI. Following the first 24 hours post-surgery, a patient was identified as experiencing POI as operationally defined by the occurrence of vomiting, reversal of diet and/or placement of a nasogastric tube. For all subjects, billing data was also collected. Results A total of 203 adult patients undergoing intestinal resection surgery consented to participate. Of patients who developed POI based on the operational definition, 35% were not coded accordingly to capture appropriate risk adjustment and reimbursement. Conclusions Patients who experienced indicators of POI but who were not coded experienced over two days of additional time in the hospital compared to patients who did not experience POI, representing significant unreimbursed costs. Timing and duration of POI indicators appear to impact coding discrepancies and may suggest means for improving caregiver identification of POI in a patient's medical record.

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Long-lasting cognitive impairment in juveniles undergoing repeated general anesthesia has been observed in numerous preclinical and clinical studies, yet, the underlying mechanisms remain unknown and no preventive treatment is available. We found that daily intranasal insulin administration to juvenile mice for 7 days prior to repeated isoflurane anesthesia rescues deficits in hippocampus-dependent memory and synaptic plasticity in adulthood. Moreover, intranasal insulin prevented anesthesia-induced apoptosis of hippocampal cells, which is thought to underlie cognitive impairment. Inhibition of the mechanistic target of rapamycin complex 1 (mTORC1), a major intracellular effector of insulin receptor, blocked the beneficial effects of intranasal insulin on anesthesia-induced apoptosis. Consistent with this finding, mice lacking mTORC1 downstream translational repressor 4E-BP2 showed no induction of repeated anesthesia-induced apoptosis. Our study demonstrates that intranasal insulin prevents general anesthesia-induced apoptosis of hippocampal cells, and deficits in synaptic plasticity and memory, and suggests that the rescue effect is mediated via mTORC1/4E-BP2 signaling.

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BACKGROUND: Extracorporeal carbon dioxide removal (ECCO2R) systems have gained clinical appeal as supplemental therapy in the treatment of acute and chronic respiratory injuries with low tidal volume or non-invasive ventilation. We have developed an ultra-low-flow ECCO2R device (ULFED) capable of operating at blood flows comparable to renal hemodialysis (250 mL/min). Comparable operating conditions allow use of minimally invasive dialysis cannulation strategies with potential for direct integration to existing dialysis circuitry. METHODS: A carbon dioxide (CO2) removal device was fabricated with rotating impellers inside an annular hollow fiber membrane bundle to disrupt blood flow patterns and enhance gas exchange. In vitro gas exchange and hemolysis testing was conducted at hemodialysis blood flows (250 mL/min). RESULTS: In vitro carbon dioxide removal rates up to 75 mL/min were achieved in blood at normocapnia (pCO2 = 45 mmHg). In vitro hemolysis (including cannula and blood pump) was comparable to a Medtronic Minimax oxygenator control loop using a time-of-therapy normalized index of hemolysis (0.19 ± 0.04 g/100 min versus 0.12 ± 0.01 g/100 min, p = 0.169). CONCLUSIONS: In vitro performance suggests a new ultra-low-flow extracorporeal CO2 removal device could be utilized for safe and effective CO2 removal at hemodialysis flow rates using simplified and minimally invasive connection strategies.

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The objective of this work was to conduct pre-clinical feasibility studies to determine if a highly efficient, active-mixing, adult extracorporeal carbon dioxide removal (ECCO2R) system can safely be translated to the pediatric population. The Hemolung Respiratory Assist System (RAS) was tested in vitro and in vivo to evaluate its performance for pediatric veno-venous applications. The Hemolung RAS operates at blood flows of 350-550 ml/min and utilizes an integrated pump-gas exchange cartridge with a membrane surface area of 0.59 m² as the only component of the extracorporeal circuit. Both acute and seven-day chronic in vivo tests were conducted in healthy juvenile sheep using a veno-venous cannulation strategy adapted to the in vivo model. The Hemolung RAS was found to have gas exchange and pumping capabilities relevant to patients weighing 3-25 kg. Seven-day animal studies in juvenile sheep demonstrated that veno-venous extracorporeal support could be used safely and effectively with no significant adverse reactions related to device operation.

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Noninvasive ventilatory support has become the standard of care for patients with chronic obstructive pulmonary disease (COPD) experiencing exacerbations leading to acute hypercapnic respiratory failure. Despite advances in the use of noninvasive ventilation and the associated improvement in survival, as many as 26% of these patients fail noninvasive support and have a higher subsequent risk of mortality than patients treated initially with invasive mechanical ventilation. We report the use of a novel device to avoid invasive mechanical ventilation in two patients who were experiencing acute hypercapnic respiratory failure because of an exacerbation of COPD and were deteriorating, despite support with noninvasive ventilation. This device provided partial extracorporeal carbon dioxide removal at dialysis-like settings through a single 15.5 Fr venovenous cannula inserted percutaneously through the right femoral vein. The primary results were rapid reduction in arterial carbon dioxide and correction of pH. Neither patient required intubation, despite imminent failure of noninvasive ventilation before initiation of extracorporeal support. Both patients were weaned from noninvasive and extracorporeal support within 3 days. We concluded that low-flow extracorporeal carbon dioxide removal, or respiratory dialysis, is a viable option for avoiding intubation and invasive mechanical ventilation in patients with COPD experiencing an exacerbation who are failing noninvasive ventilatory support.

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For patients experiencing acute respiratory failure due to a severe exacerbation of chronic obstructive pulmonary disease (COPD), noninvasive positive pressure ventilation has been shown to significantly reduce mortality and hospital length of stay compared to respiratory support with invasive mechanical ventilation. Despite continued improvements in the administration of noninvasive ventilation (NIV), refractory hypercapnia and hypercapnic acidosis continue to prevent its successful use in many patients. Recent advances in extracorporeal gas exchange technology have led to the development of systems designed to be safer and simpler by focusing on the clinical benefits of partial extracorporeal carbon dioxide removal (ECCO2R), as opposed to full cardiopulmonary support. While the use of ECCO2R has been studied in the treatment of acute respiratory distress syndrome (ARDS), its use for acute hypercapnic respiratory during COPD exacerbations has not been evaluated until recently. This review will focus on literature published over the last year on the use of ECCO2R for removing extra CO2 in patients experiencing an acute exacerbation of COPD.

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PURPOSE: The objective of this study was to demonstrate the safety and performance of a unique extracorporeal carbon dioxide removal system (Hemolung, ALung Technologies, Pittsburgh, PA) which incorporates active mixing to improve gas exchange efficiency, reduce exposure of blood to the circuit, and provide partial respiratory support at dialysis-like settings. METHODS: An animal study was conducted using eight domestic crossbred sheep, 6-18 months of age and 49-115 kg in weight. The sheep were sedated and intubated, and a 15.5-Fr dual lumen catheter was inserted into the right jugular vein. The catheter was connected to the extracorporeal circuit primed with heparinized saline, and flow immediately initiated. The animals were then awakened and encouraged to stand. The animals were supported in a stanchion and monitored around the clock. Anticoagulation was maintained with heparin to achieve an aPTT of 46-70 s. RESULTS: Measurements included blood flow rate through the device, carbon dioxide exchange rate, pump speed and sweep gas flow rate. Safety and biocompatibility measurements included but were not limited to plasma-free hemoglobin, hematocrit, white blood cell count, platelet count and fibrinogen. The Hemolung removed clinically significant amounts of carbon dioxide, more than 50 ml/min, at low blood flows of 350-450 ml/min, with minimal adverse effects. CONCLUSIONS: The results of 8-day trials in awake and standing sheep supported by the Hemolung demonstrated that this device can consistently achieve clinically relevant levels of carbon dioxide removal without failure and without significant risk of adverse reactions.

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A study was conducted to measure and compare the levels of hemolysis generated by an intravenous membrane oxygenation device referred to as the Intravenous Membrane Oxygenator (IMO) in previous literature. The device is comprised of several hundred hollow fiber membranes of approximately 40 cm in length that are woven in a fabric and wrapped around a centrally positioned balloon. The balloon, which is similar in shape and volume to an intra-aortic balloon, is rapidly inflated and deflated up to 300 bpm to augment gas exchange. To evaluate the hemolytic nature of this device, an in vitro test system was developed, consisting of two identical test loops, each incorporating a device test section of 1 inch in diameter, a heat exchanger, a Biomedicus pump head, a compliance bag, a venous reservoir bag, and Tygon tubing. Both loops were primed with 1.5 L of a bovine blood solution and run simultaneously at 37 degrees C for 6 hours at 4 L/min. Hematocrit and plasma free hemoglobin concentration were measured every 30 minutes to monitor hemolysis within each loop. This methodology was used to compare the hemolysis of the device at maximal pulsation with that of the control loop with an empty test section, as well as with a pulsing balloon of the same volume without any fibers. The results suggest that the hemolytic nature of the pulsating intravenous oxygenator is consistent with that of an intra-aortic balloon, a clinically used device not associated with any complications due to hemolysis.

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OBJECTIVES: Acute respiratory failure is associated with a mortality of 40% to 50%, despite advanced ventilator support and extracorporeal membrane oxygenation. A respiratory gas exchange catheter (the Hattler Catheter) has been developed as an oxygenator and carbon dioxide removal device for placement in the vena cava and right atrium in the treatment of acute respiratory failure to improve survival. METHODS: Differing from a previously clinically tested intravenous gas exchange device (ie, IVOX), the Hattler Catheter incorporates a small, pulsating balloon surrounded by hollow fibers. The pulsating balloon redirects blood toward the fibers, enhances red cell contact with the membrane, and significantly improves gas exchange so that smaller catheter devices are still efficient on insertion and can be inserted through the jugular or femoral vein. Devices were tested in mock circulatory loops and in short-term (8 hours) and long-term (4 days) experiments in calves to study the effect of various sized balloons and the anatomic location of the device in the venous system as a function of hemodynamics and gas exchange. RESULTS: In vitro performance in water demonstrates an oxygen delivery (Vo(2)) of 140 +/- 8.9 mL. min(-1). m(-2) and a carbon dioxide removal (Vco(2)) of 240 +/- 6.1 mL. min(-1). m(-2). Acute in vivo experiments demonstrate a maximum carbon dioxide consumption of 378 +/- 11.2 mL. min(-1). m(-2). Devices positioned in the right atrium had an average carbon dioxide exchange of 305 mL. min(-1). m(-2), whereas in the inferior vena cava position carbon dioxide exchange was 255 mL. min(-1). m(-2). Devices have been tested long term in calves, with gas exchange rates maintained over this time interval (carbon dioxide consumption, 265 +/- 35 mL. min(-1). m(-2)). Plasma-free hemoglobin levels at the end of 4 days have been 4.8 +/- 3.2 mg/dL. Hemodynamic measurements, including a decrease in cardiac outputs and increased mean pressure decreases across the device become significant only with the larger balloon (40-mL) devices (P <.05, 40-mL vs 13-mL devices). Autopsies show no end-organ damage. The device linearly increases its carbon dioxide output with progressive hypercapnea, predicting its ability to meet tidal volume reduction in the therapy of respiratory failure. CONCLUSIONS: Progress has been made toward developing an intravenous gas exchange catheter to provide temporary pulmonary support for patients in acute respiratory failure.

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