Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitor Improves the Vascular Function of Arteriovenous Fistula in Rats with Hyperglycemia.

Objectives: Few evidence-based medications to improve the primary patency of arteriovenous fistulas in patients with diabetes who require hemodialysis are available. We investigated whether proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) could improve arteriovenous fistula function through pleiotropic effects in a rat model of hyperglycemia. Methods: Ex vivo effects of PCSK9i on the aorta of Sprague-Dawley (SD) rats were investigated using an organ bath system. For in vivo experiments, an abdominal aortocaval (AC) fistula was generated in SD rats (200-250 g) after inducing hyperglycemia through streptozotocin administration (80 mg/kg, intraperitoneal). Alirocumab (50 mg/kg/week, subcutaneous) was administered on the day of fistula surgery and day 7. Echocardiography, blood flow through the aorta-limb, vasomotor reactivity, and serum biochemistry were examined on D14. Furthermore, enzyme-linked immunosorbent assay and immunoblotting were performed. Results: PCSK9i induced aorta relaxation ex vivo through a potassium channel-associated mechanism. PCSK9i significantly improved blood flow and preserved endothelial function without changes in cardiac function and serum lipid levels in rats with hyperglycemia. The levels of lectin-like oxidized low-density lipoprotein receptor-1, superoxide dismutase, cyclooxygenase-2, caspase-1, and interleukin-1ß were significantly reduced in the treatment group. PCSK9i decreased the ratio of phosphorylated to total p38 mitogen-activated protein kinase and extracellular signal-regulated kinase in the aorta of rats with hyperglycemia. Conclusions: Short-term treatment with PCSK9i preserved endothelial function, induced vascular dilatation, and increased blood flow in the AC fistula of rats with hyperglycemia. The pleiotropic mechanisms were associated with the suppression of oxidative stress and tissue inflammation during hyperglycemia.

Radiographical presentations of inadvertent subdural placement of an epidural catheter for successful labor analgesia: A case report.

RATIONALE: Lumbar epidural analgesia is the gold standard for labor pain control. However, misplacement of epidural catheters into the subdural space may inadvertently happen. Unrecognized subdural administration of local anesthetics could result in serious consequences, including high spinal and brainstem blocks. This case report describes a case where subdural epidural catheter placement was recognized early but labor pain was adequately managed by dosage titration of subdural analgesia. PATIENT CONCERNS: This case report describes a 29-year-old primiparous pregnant woman who was admitted to our obstetric unit for labor induction at the gestational age of 38 weeks. An epidural catheter was inserted via the L2-3 intervertebral space using the standard loss of resistance to air technique. DIAGNOSES: The parturient experienced weakness in the lower extremities and numbness in the upper extremities within 15 minutes after administration of 5 mL of 2% v/v lidocaine as a loading dose and systolic blood pressure also dropped by 25%. INTERVENTIONS: The dose regimen (a mixture of 0.1% ropivacaine and 4 µg/mL fentanyl) for patient-controlled analgesia was given with bolus doses of 0.1 mL per demand and lockout intervals of 20 minutes. The analgesic effects were adequately maintained below the T8 dermatome for more than 12 hours without hypotensive episodes or obvious signs of neurological deficits. Computed tomographic myelography was performed by instillation of a nonionic iodinated contrast medium via the epidural catheter on postpartum day 2 for imaging confirmation of catheter placement in the extradural space. LESSONS: Early recognition that epidural catheters for neuraxial analgesia have been inserted into the subdural space is important for the prevention of high spinal blocks. Subdural analgesia could still be achieved by careful clinical assessment and titration of low analgesic doses. This report also presents important and clear serial computed tomographic images of catheter placement in the thoracic-lumbar subdural spaces and the extent of volume spread in the subdural space following administration of contrast medium.

Dual phenotypic characteristics of P-selectin in a mouse model of hemorrhagic shock and hepatectomy.

Background: Membrane-bound P-selectin induces endothelial adhesion of leucocytes and amplifies organ inflammations during major trauma, while soluble P-selectin (sP-sel) mediates survival rescue properties. This study characterized the differential effects of P-selectin in a "2-hit" model of hemorrhagic shock (HS) and partial hepatectomy (PH). Materials and methods: HS was induced by withdrawing blood (0.3 mL) directly from the mouse femoral arteries. 70% or 50% of liver volumes were resected after inducing HS. Time of survival in P-selectin deficient (Selp -/-) mice treated with and without intraperitoneal injections of recombinant P-sel IgG-Fc fusion proteins (rP-sel-Fc, 1.5 mg/kg) were recorded for up to 72h after injury. In addition, liver regeneration at 72h after HS and 50% PH was assessed in wild-type and Selp -/- mice. Results: Compared to wild-types, Selp -/- mice had significantly higher mortality rates post HS and 70% PH, as none of these animals survived up to 48h postoperatively. The survival curve was restored in Selp -/- mice pre-treated with rP-sel-Fc. In the HS followed by 50% PH experimental arm, liver remnant growth ratios were significantly higher in Selp -/- mice (15.7 ± 3.1 vs 11.7 ± 4.9, P = 0.040). The elevated serum concentrations of alanine aminotransferase post-PH were significantly reduced in Selp -/- mice. Hepatocyte proliferation indices (CYP7a1 and PCNA) expression were enhanced and myeloperoxidase activity in the regenerated remnant liver was reduced in the Selp -/- mice. Conclusion: In critical conditions induced by HS and PH, P-selectin mediates two distinct phenotypic characteristics. Soluble-form circulating P-selectin improves survival in the acute stage of HS and extensive loss of liver parenchyma; membrane-bound P-selectin induces regional pro-inflammatory reactions in the remnant liver after the acute stage of two insults, thereby inhibiting hepatic regeneration. The results of this pre-clinical study may provide molecular mechanistic insight and clinical therapeutic applications of P-selectin in the acute and regenerative phases of traumatic hepatic injury.

Efficacy and safety of an extended-release sebacoyl dinalbuphine ester for laparoscopic cholecystectomy: A randomized controlled trial.

BACKGROUND: A long-acting κreceptor agonist parenteral analgesic may theoretically improve acute pain and reduce incidence of chronic postsurgical pain (CPSP) after laparoscopic cholecystectomy with minimal drug-related side effects of the traditional µreceptor opioids. METHODS: Eighty adult patients undergoing elective laparoscopic cholecystectomy were randomly assigned to receive single intramuscular injection of an extended-release sebacoyl dinalbuphine ester (SDE, Naldebain 150 mg; n = 40) or placebo (n = 40) after anesthesia induction. Standard multimodal analgesia (MMA) was administered for postoperative pain control. The primary endpoint was pain intensity within 7 days after surgery. The secondary endpoints were incidence CPSP at 3 months and adverse reactions up to 7 days after surgery. RESULTS: The highest visual analogue scale (VAS) and area under the curve of VAS 0 to 48 hours after operation were not different between the two groups and a similar proportion of patients requested rescue parenteral analgesics. Average pain intensities were also not different at 72 hours and 7 days after surgery. Incidence of CPSP was 22.5% and 13.1% in patients who received placebo and SDE treatment, respectively (P = .379). Significantly higher incidence of drug-related adverse events, including dizziness, nausea and injection site reactions, were recorded in the SDE group. CONCLUSION: A single dose of extended-release analgesic SDE given intraoperatively did not provide sufficient add-on effect for acute and chronic pain management after laparoscopic cholecystectomies in patients who received standard postoperative MMA. Intramuscular injection of 150 mg SDE in patients with average body mass causes adverse events that could have been overlooked. More clinical studies are warranted to determine the target populations who may benefit from SDE injections for improvement of acute and chronic postsurgical pain management.

Post-extubation use of high-flow nasal oxygenation induces upper airway leak and intrathoracic sepsis after successful Bentall procedure: A case report.

RATIONALE: In recent few years, high-flow nasal oxygenation (HFNO) has been widely used for management of acute hypoxemic respiratory failure and during postextubation periods, including after endotracheal intubation general anesthesia (ETGA). However, HFNO generates positive pressure in the injured airway following removal of endotracheal tube may cause airway leaks. This is the first case report of severe airway leak syndrome following postextubation use of HFNO in surgical patients. PATIENT CONCERNS: This case report describes a 75-year-old female with critical aortic stenosis who underwent an emergency Bentall procedure. HFNO (flow rate of 45 L/min) was applied after weaning from mechanical ventilation and removal of the endotracheal tube. DIAGNOSES: At 6 hours after HFNO application, subcutaneous emphysema in the neck bilaterally and face was noted, and the emphysema extended into the supraclavicular regions. INTERVENTIONS: The HFNO cannula was removed soon after and the patient was re-intubated with an endotracheal tube the following day due to progressive respiratory insufficiency. Unfortunately, the patient general condition deteriorated, as the subcutaneous air collections progressed into deep tissue infections of the neck, mediastinal abscesses, and left-sided empyema. Patient received surgical interventions repeatedly to drain the mediastinal abscess and empiric antimicrobial therapy was given. OUTCOMES: The patient passed away about 2 months later due to uncontrollable sepsis. LESSONS: Air leaks in the upper airway can occur during the use of post-extubation HFNO use, and the resulting subcutaneous emphysema can progress to severe intrathoracic infections in surgical patients who have a sternotomy wound. Therefore, HFNO-induced subcutaneous emphysema should be treated more aggressively in open thoracic or sternotomy surgeries to prevent the development of intrathoracic sepsis.

Intraoperative Enteral Nutrition Feeding in Free-Flap Healing after Reconstruction Surgery for Head and Neck Cancers.

OBJECTIVE: To investigate the beneficial outcomes of intraoperative enteral feeding in free-flap regeneration after extended head and neck cancer resection and flap reconstruction surgery. STUDY DESIGN: A pilot randomized, double-blind, placebo-controlled clinical trial. SETTING: Single tertiary care center. METHODS: Patients with advanced head and neck cancers requiring radical tumor resections and free-flap reconstruction were randomly assigned to receive intraoperative enteral nutrition feeding (100 kcal/100 mL at 10-20 mL/h) via a nasogastric tube during free-flap reconstruction (n = 28) or continue fasting (n = 28). The primary outcome was impaired free-flap regeneration that required surgical reintervention within 90 days after the operation. Participants were enrolled between April 2020 and January 2022; the 90-day follow-up ended in April 2022. RESULTS: The incidence of total or partial flap failure was similar between the 2 groups (14.2% or n = 4 in each group), but the rate of wound dehiscence or edge necrosis was significantly reduced in the feeding group (n = 6 vs 0 for fasting vs feeding; absolute risk reduction, 25.0% [95% confidence interval, 6.9-43.0]%; p = 0.022). Hospital stay length was shorter (p = 0.042) and hand grip strength was better preserved (p = 0.025) in the feeding group. Plasma concentrations of interleukin (IL)-6 and IL-8 after the operation increased significantly more in the fasting group. Perioperative adverse events did not differ between the 2 groups. CONCLUSION: Perioperative enteral feeding is a simple, safe, and effective approach to improve perioperative systemic catabolism and proinflammatory reactions, thereby enhancing early wound regeneration after major operations.

Efficacy and Safety of Parenteral Injection of an Extended Release κ-receptor Opioid Sebacoyl Dinalbuphine Ester for Acute and Chronic Pain After Laparoscopic Bariatric Surgery: a Randomized, Placebo-Controlled, Double-Blind Trial.

PURPOSE: µ-receptor opioids are associated with unwanted gastrointestinal side effects and respiratory depression. A long-acting non-µ-receptor parenteral opioid is not currently available for management of acute and chronic postsurgical pain (CPSP). This double-blind clinical trial tested an extended-release κ-receptor agonist, sebacoyl dinalbuphine ester (SDE, Naldebain®) for management of surgical pain after laparoscopic bariatric surgery. MATERIALS AND METHODS: Patients were randomly assigned to receive a single intramuscular injection of SDE (150 mg, n = 30) or vehicle solution (n = 30) at > 12 h before surgery. All patients received standard perioperative multimodal analgesia (MMA). The primary endpoint was the pain intensity in the beginning 7 days after operation. The secondary endpoints were adverse reactions up to 7 days and incidence of CPSP at 3 months after surgery. RESULTS: Compared with placebos, the area under curves of visual analog scale (VAS) for 0-48 h after operation were significantly reduced in SDE group (143.3 ± 65.4 and 105.9 ± 36.3, P = 0.025). There were significantly fewer patients in the SDE group who had moderate-to-severe pain (VAS ≥ 4) (16.7% vs 50%; P = 0.012) at postoperative 48 h. Pain intensities were similar between the two groups at 72 h and 7 days postoperatively. The incidence of CPSP at 3 months was not different. SDE did not increase drug-related systemic adverse events. CONCLUSION: In addition to the standard perioperative MMA, a single-dose injection of long-acting κ-receptor agonist SDE provides significantly better pain management for 48 h following laparoscopic bariatric surgery. A long-acting κ-receptor agonist opioid could improve in-hospital pain management and potentiate early discharge after operation without increasing drug-related systemic complications.

Viable Allogeneic Mitochondria Transplantation Improves Gas Exchange and Alveolar-Capillary Permeability in Rats with Endotoxin-Induced Acute Lung Injuries.

Background: Acute lung injuries (ALI) cause disruption of the alveolar-capillary barrier and is the leading cause of death in critically ill patients. This study tested the hypothesis that the administration of freshly isolated viable allogeneic mitochondria can prevent alveolar-capillary barrier injuries at the endothelial level, as mitochondrial dysfunction of the pulmonary endothelium is a critical aspect of ALI progression. Methods: ALI was induced by intratracheal lipopolysaccharide instillation (LPS, 1mg/kg) in anesthetized rats. Mitochondria (100 µg) were isolated from the freshly harvested soleus muscles of naïve rats and stained with a green fluorescence MitoTracker™ dyne. A mitochondria or placebo solution was randomly administered into the jugular veins of the rats at 2 h and 4 h after ALI induction. An arterial blood gas analysis was done 20 h later. The animals were then sacrificed and lung tissues were harvested for analysis. Results: An IVIS Spectrum imaging system was used to obtain ex vivo heart-lung block images and track the enhancement of MitoTracker™ fluorescence in the lungs. Mitochondria transplantation significantly improved arterial oxygen contents (PaO2 and SaO2) and reduced CO2 tension in rats with ALI. Animals with mitochondrial transplants had significantly higher ATP concentrations in their lung tissues. Allogeneic mitochondria transplantation preserved alveolar-capillary barrier function, as shown by a reduction in protein levels in the bronchoalveolar lavage fluid and decreased extravasated Evans blue dyne and hemoglobin content in lung tissues. In addition, relaxation responses to acetylcholine and eNOS expression were potentiated in injured pulmonary arteries and inflammatory cells infiltration into lung tissue was reduced following mitochondrial transplantation. Conclusions: Transplantation of viable mitochondria protects the integrity of endothelial lining of the alveolar-capillary barrier, thereby improving gas exchange during the acute stages of endotoxin-induced ALI. However, the long-term effects of mitochondrial transplantation on pulmonary function recovery after ALI requires further investigation.

Mitochondrial Transplantation Attenuates Neural Damage and Improves Locomotor Function After Traumatic Spinal Cord Injury in Rats.

Mitochondrial dysfunction is a hallmark of secondary neuroinflammatory responses and neuronal death in spinal cord injury (SCI). Even though mitochondria-based therapy is an attractive therapeutic option for SCI, the efficacy of transplantation of allogeneic mitochondria in the treatment of SCI remains unclear. Herein, we determined the therapeutic effects of mitochondrial transplantation in the traumatic SCI rats. Compressive SCI was induced by applying an aneurysm clip on the T10 spinal cord of rats. A 100-µg bolus of soleus-derived allogeneic mitochondria labeled with fluorescent tracker was transplanted into the injured spinal cords. The results showed that the transplanted mitochondria were detectable in the injured spinal cord up to 28 days after treatment. The rats which received mitochondrial transplantation exhibited better recovery of locomotor and sensory functions than those who did not. Both the expression of dynamin-related protein 1 and severity of demyelination in the injured cord were reduced in the mitochondrial transplanted groups. Mitochondrial transplantation also alleviated SCI-induced cellular apoptosis and inflammation responses. These findings suggest that transplantation of allogeneic mitochondria at the early stage of SCI reduces mitochondrial fragmentation, neuroapoptosis, neuroinflammation, and generation of oxidative stress, thus leading to improved functional recovery following traumatic SCI.

Prothymosin α Gene Transfer Modulates Myocardial Remodeling after Ischemia-Reperfusion Injury.

Background: Prothymosin α (ProT), a polypeptide, attenuates inflammation and inhibits transforming growth factor (TGF)-ß signaling in pulmonary tissues. We investigated the potential role of ProT in myocardial ischemia-reperfusion (MyoIR) injury using ProT cDNA transfer. Methods: Serum ProT levels were investigated in cardiogenic shock patients with MyoIR (n = 9). In addition, the myocardium of Sprague-Dawley rats (n = 52) was subjected to 25 min of ischemia followed by an injection of adenoviral vectors (2 × 109 plaque-forming units) carrying ProT or the luciferase gene, 10 min before reperfusion. Echocardiography, serum ProT, and biochemical analyses of organ functions were performed before euthanasia, 14 days after treatment. Immunohistochemistry and immunoblotting of the myocardial tissue were also performed. Results: Serum ProT levels were transiently elevated in the rats and patients early after MyoIR, which was reduced to baseline levels in control rats and patients. ProT gene transfer persistently mobilized ProT serum levels, reduced dilatation, attenuated fibrotic changes, and preserved the left ventricular ejection fraction after MyoIR. Tissue thrombospondin-1 level was abundant, and matrix metalloproteinase-2, collagen I, and collagen IV levels were decreased in the treatment group. While TGF-ß protein level remained stable, ProT transduction mobilized Smad7, which counteracted TGF-ß. ProT reduced tissue microRNA-223 expression, inhibited the associated interleukin-1ß, and preserved RAS p21 protein activator 1 protein abundance. Conclusions: An increase in transient serum ProT levels could be a protective response in the acute stage of MyoIR. ProT gene transfer further preserved ventricular morphology and function through anti-inflammatory and anti-fibrotic effects in the subacute stage after injury.

Transplantation of viable mitochondria improves right ventricular performance and pulmonary artery remodeling in rats with pulmonary arterial hypertension.

OBJECTIVE: Because mitochondrial dysfunction is a key factor in the progression of pulmonary hypertension, this study tested the hypothesis that transplantation of exogenous viable mitochondria can reverse pulmonary artery remodeling and restore right ventricular performance in pulmonary hypertension. METHODS: Pulmonary hypertension was induced by parenteral injection of monocrotaline (60 mg/kg) and creation of a left-to-right shunt aortocaval fistula in rats. Three weeks after creation of fistula, the animals were randomly assigned to receive intravenous delivery of placebo solution or allogeneic mitochondria once weekly for 3 consecutive weeks. Mitochondria (100 µg) were isolated from the freshly harvested soleus muscles of naïve rats. Transthoracic echocardiography was performed at 3 weeks after mitochondrial delivery. RESULTS: Ex vivo heart-lung block images acquired by an IVIS Spectrum (PerkinElmer, Waltham, Mass) imaging system confirmed the enhancement of MitoTracker (Invitrogen, Carlsbad, Calif) fluorescence in the pulmonary arteries. Mitochondria transplantation significantly increased lung tissue adenosine triphosphate concentrations and improved right ventricular performance, as evidenced by a reduction in serum levels of B-type natriuretic peptide and ventricular diameter. Right ventricular mass and wall thickness were restored in the mitochondrial group. In the pulmonary arteries of rats that received mitochondrial treatment, vascular smooth muscle cells expressed higher levels of α-smooth muscle actin and smooth muscle myosin heavy chain II, indicating the maintenance of the nonproliferative, contractile phenotype. The hyper-reactivity of isolated pulmonary arteries to α-adrenergic stimulation was also attenuated after mitochondrial transplantation. CONCLUSIONS: Transplantation of viable mitochondria can restore the contractile phenotype and vasoreactivity of the pulmonary artery, thereby reducing the afterload and right ventricular remodeling in rats with established pulmonary hypertension. The improvement in overall right ventricular performance suggests that mitochondrial transplantation can be a revolutionary clinical therapeutic option for the management of pulmonary hypertension.

Distinct phenotypic expression levels of macrophages in neonatal lungs.

Alveolar macrophages are the front-line defense against environmental pathogens. However, to the best of our knowledge, differences in function and phenotypic expression levels of macrophages between neonatal and adult lungs have not previously been determined. The present study investigated lung tissues and analyzed blood samples to find cell markers of M1 and M2 macrophages in neonatal and adult rats. Pulmonary sepsis was induced by intrapleural instillation of lipopolysaccharide (LPS; 20 mg/kg) and survival time after administration of LPS was measured. In certain neonates, a selective inducible nitric oxide synthase (iNOS) inhibitor, 1400w, was administered prior to induction of pulmonary sepsis. Compared with adults, fetal and neonatal lung tissues had significantly higher levels of iNOS and CD86 (M1 markers), whereas the expression levels of CD206 and arginase-1 (M2 markers) were lower in the neonatal lung. The circulating cells that co-expressed CD68 (monocytes and macrophages) and CD86 in the blood were also significantly higher in neonates than in adults (25.9±6.6 vs. 11.6±2.2%; P=0.007. At basal unstimulated conditions, lung tissue concentrations of nitrite and nitrate (NOx) were significantly lower in the neonates than in adults (112.1±55.9 vs. 340.9±124.9 µM/g; P<0.001). However, NOx was increased following administration of LPS. Administration of 1400w suppressed lung tissue levels of NOx and improved the survival time in neonatal rats treated with LPS. The present study demonstrated that M1 is the primary macrophage phenotype in the neonatal lung and that higher iNOS expression levels do not have a protective effect against pulmonary endotoxins in neonates. Overproduction of NO by iNOS in neonatal alveolar macrophages may result in detrimental effects during pulmonary inflammation.

Characterization of self-anticipated pain score prior to elective surgery - a prospective observational study.

BACKGROUND: Current principles of postoperative pain management are primarily based on the types and extent of surgical intervention. This clinical study measured patient's self-anticipated pain score before surgery, and compared the anticipated scores with the actual pain levels and analgesic requirements after surgery. METHODS: This prospective observational study recruited consecutive patients who received elective surgery in the E-Da Hospital, Taiwan from June to August 2018. Patients were asked to subjectively rate their highest anticipated pain level (numeric rating scale, NRS 0-10) for the scheduled surgical interventions during their preoperative anesthesia assessment. After the operation, the actual pain intensity (NRS 0-10) experienced by the patient in the post-anesthesia care unit and the total dose of opioids administered during the perioperative period were recorded. Pain scores ≥4 on NRS were regarded as being unacceptable levels for anticipated or postoperative pain that required more aggressive intervention. RESULTS: A total of 996 patients were included in the study. Most of the patients (86%) received general anesthesia and 73.9% of them had a history of previous operation. Female anticipated significantly higher overall pain intensities than the male patients (adjusted odd ratio 1.523, 95% confidence interval 1.126-2.061; P = 0.006). Patients who took regular benzodiazepine at bedtime (P = 0.037) and those scheduled to receive more invasive surgical procedures were most likely to anticipate for higher pain intensity at the preoperative period (P < 0.05). Higher anticipated pain scores (preoperative NRS ≥ 4) were associated with higher actual postoperative pain levels (P = 0.007) in the PACU and higher total equivalent opioid use (P < 0.001) for acute pain management during the perioperative period. CONCLUSION: This observational study found that patients who are female, use regular benzodiazepines at bedtime and scheduled for more invasive surgeries anticipate significantly higher surgery-related pain. Therefore, appropriate preoperative counseling for analgesic control and the management of exaggerated pain expectation in these patients is necessary to improve the quality of anesthesia delivered and patient's satisfaction.

Prolonged preoperative fasting induces postoperative insulin resistance by ER-stress mediated Glut4 down-regulation in skeletal muscles.

Preoperative fasting aims to prevent pulmonary aspiration and improve bowel preparation, but it may induce profound systemic catabolic responses that lead to protein breakdown and insulin-resistant hyperglycemia after operation. However, the molecular mechanisms of catabolic reaction induced by prolonged preoperative fasting and surgical stress are undetermined. In this study, anesthetized rats were randomly assigned to receive a sham operation or laparotomy cecectomy. Fasting groups were restricted from food and water for 12 h before operation, while the feeding group had free access to food throughout the study period. Twenty-four hours after operation, the animals were sacrificed to collect blood samples and soleus muscles for analysis. Postoperative blood glucose level was significantly increased in the fasting group with elevated serum insulin and C-peptide. Continuous feeding reduced serum myoglobin and lactate dehydrogenase concentrations. Preoperative fasting activated inositol-requiring transmembrane kinase/endoribonuclease (IRE)-1α and c-Jun N-terminal kinase (JNK) mediated endoplasmic reticulum (ER)-stress, and reduced glucose transporter type 4 (Glut4) expression in the soleus muscle. Phospholamban phosphorylation was reduced and intracellular calcium levels were increased in the isolated skeletal muscle cells. Similar results were found in ER stress-induced C1C12 myoblasts. The expression of Glut4 was suppressed in the stressed C1C12, but was potentiated following inhibition of ER stress and chelation of intracellular free calcium. This study provides evidence demonstrating that prolonged preoperative fasting induces ER stress and generates insulin resistance in the skeletal muscle through suppression of Glut4 and inactivation of Ca2+-ATPase, leading to intracellular calcium homeostasis disruption and peripheral insulin resistance.

Rosuvastatin Failed to Improve Arteriovenous Fistula Patency for Hemodialysis in Diabetic Patients - A Randomized Clinical Trial.

BACKGROUND: Very limited therapeutic strategies exist to prevent the primary failure of arteriovenous (AV) fistulas in patients with diabetes. OBJECTIVES: To investigate whether rosuvastatin could improve the primary patency of AV fistulas in diabetic patients with stage 5 chronic kidney disease (CKD). METHODS: This was a double-blind randomized clinical trial. From July 2012 to September 2018, patients aged between 18 and 65 years with type 2 diabetes and stage 5 CKD were randomized to receive placebo or rosuvastatin (5 mg/day) for 7 days prior to the creation of an AV fistula on the forearm until the 21st day after surgery. Patients were followed up for 180 days after the operation. The primary composite endpoint was the development of fistula immaturity or stenosis. The secondary endpoints were changes in inflammatory markers, oxidative stress, and occurrence of postoperative complications. RESULTS: A total of 60 patients were enrolled in the study. Rosuvastatin resulted in a 20% reduction in total cholesterol from postoperative day 0 to 28 (p = .0006). The overall rate of AV fistula failure (immaturity or stenosis) was 30%, with no significant difference between patients receiving rosuvastatin and those receiving the placebo (33.3% vs. 26.7%, p = .5731). Although not statistically significant, the administration of rosuvastatin might have increased the incidence of postoperative complications (2.99 vs. 2.39 event rate per 1000 patient-days; odds ratio, 1.33; p = .5986). CONCLUSIONS: Rosuvastatin showed no significant beneficial effects on the primary patency of AV fistulas in diabetic patients with stage 5 CKD, but might have been associated with the risk of drug-related complications.

Transplantation of viable mitochondria attenuates neurologic injury after spinal cord ischemia.

OBJECTIVES: Spinal cord ischemia (SCI) is one of the major concerns of postoperative paraplegia during major vascular or aortic surgery. Since mitochondrial dysfunction develops at the early stage of SCI, this study tested the neuronal protective effect of transplantation of viable mitochondria to the ischemic cord in rats. METHODS: SCI was induced by crossclamping of thoracic aorta at T6 level for 25 minutes, followed by release of vascular clip to restore aortic blood flow in the anesthetized rats. Mitochondria (100 µg) were isolated from freshly harvested soleus muscle and delivered via the internal jugular vein before releasing of vascular clip. The motor function was assessed independently up to 7 days after reperfusion. Spinal cords were harvested and analyzed for molecular and histological changes. RESULTS: Whole-body in vivo images acquired by an in vivo imaging system confirmed the enhancement of MitoTracker fluorescence at the regions below crossclamping and in the ischemic cord. Compared with control vehicles, transplantation of mitochondria significantly improved the lower-limb locomotor function of rats subjected to cord ischemia up to 7 days after surgery. Mitochondrial transplantation suppressed the regional endoplasmic reticulum stress in the ischemic cord by attenuating CCAAT-enhancer-binding protein homologous protein expression and restoring binding immunoglobulin protein levels. In accordance, tissue levels of interleukin-6, tumor necrosis factor-α, and caspase-3 were attenuated in the mitochondrial transplanted group. Histologic examination also showed significant increase in numbers of Nissls bodies in the neurons at the ventral horn of ischemic cord following mitochondrial transplantation. CONCLUSIONS: Our study showed that transplantation of freshly isolated mitochondria during the early stage of spinal cord ischemia-reperfusion injury suppressed the oxidative stress in endoplasmic reticulum of the injured cord, thereby reducing neuroapoptosis and improving locomotor function of rats with SCI.

A nationwide survey of intraoperative management for one-lung ventilation in Taiwan: time to accountable for diversity in protective lung ventilation.

BACKGROUND: There is a major paradigm shift for intraoperative mechanical ventilator support by the introduction of lung protective ventilation strategies to reduce postoperative pulmonary complications and improve overall clinical outcomes in non-thoracic surgeries. However, there is currently a lack of standardized practice guideline for lung protection during thoracic surgeries that require one-lung ventilation (OLV). This study aimed to collect the expert opinions of the thoracic anesthesiologists in perioperative care for OLV surgery in Taiwan. METHODS: This prospective cross-sectional study was undertaken in 16 tertiary hospitals in Taiwan from January to February 2019. A structured survey form was distributed across the participating hospitals and the thoracic anesthesiologists were invited to complete the form voluntarily. The survey form consisted of three parts, including the basic information of the institutional anesthesia care standards, ventilatory settings for a proposed patient receiving OLV surgery and expert opinions on OLV. RESULTS: A total of 71 thoracic anesthesiologists responded to the survey. Double-lumen tubes are the most commonly used (93.8%) airway devices for OLV. The most commonly recommended ventilator setting during OLV is a tidal volume of 6-7 ml/kg PBW (67.6%) and a PEEP level of 4-6 cmH2O (73.5%). Dual controlled ventilator modes are used by 44.1% of the anesthesiologists. During OLV, high oxygen fraction (FiO2 > 0.8) is more commonly supplemented to achieve an oxygen saturation higher than 94%. The consensus of anesthesiologists on the indices for lung protection in thoracic surgery is considerably low. Large majority of the anesthesiologists (91.5%) highly recommend that an international clinical practice guideline on the protective lung ventilation strategy for thoracic anesthesia should be established. CONCLUSIONS: This study found that the thoracic anesthesiologists in Taiwan share certain common practices in ventilator support during OLV. However, they are concerned about the lack of fundamental clinical evidences to support the beneficial outcomes of the current lung protective strategies applicable to OLV. Large-scale trials are needed to form an evidence-based clinical practice guideline for thoracic anesthesia.

ProT-α gene transfer attenuates cardiopulmonary remedying and mortality in a flow-induced pulmonary hypertension rat model.

BACKGROUND: ProT is a cell survival gene, which modulates oxidative stress and transforming growth factor (TGF)-ß signaling. We hypothesized that the delivery of the ProT cDNA gene in rats could protect against right heart dysfunction secondary to pulmonary hypertension (PH) induced by left-to-right shunt. METHODS: A 2-hit rat model of flow-induced PH was used, and a single intravenous injection of adenoviral vectors (2 billion plaque-forming unit) carrying ProT or Luc gene was administered. The animals were euthanized 21 days after gene delivery to assess cardiopulmonary function, serum biochemistry, pulmonary artery (PA), and vasomotor reactivity. Immunohistology and immunoblotting of PA tissues were also performed. RESULTS: ProT transduction significantly reduced PA pressure, right ventricle muscle mass, and wall stress, thereby improving the overall survival of the treated rat. Increased production of ProT through gene therapy preserved both the smooth muscle myosin heavy chain-II and α-smooth muscle actin while counteracting the abundance of TGF-ß in PA. Protein abundances of phosphorylated p47-phox, heme oxygenase-1, caspase-3, inducible nitric oxide synthase, cyclo-oxygenase 2, and monocyte chemoattractant protein-1 in PA tissues were reduced. ProT also preserved microRNA-223, thereby suppressing the abundance of PARP-1, which is independent of hypoxia-inducible factor-1α signaling. CONCLUSIONS: ProT gene transduction improved PA function by reducing oxidative stress, attenuating inflammation, and preserving the contractile phenotype of vascular smooth muscle cells. The modification of microRNA-223-associated downstream signaling through ProT transduction may play an important role in mitigating cardiopulmonary remodeling in flow-induced PH.

Characterizing post-extubation negative pressure pulmonary edema in the operating room-a retrospective matched case-control study.

BACKGROUND: Post-extubation negative pressure pulmonary edema (NPPE) is an uncommon but important anesthesia-related emergency presenting with acute respiratory distress and hypoxemia after removal of airway devices. This study investigated the incidence and associated risk factors for post-extubation NPPE during emergence. METHODS: This retrospective, matched case-control study was conducted by reviewing the post-anesthesia records in Tzu Chi General Hospital, Taiwan. Patients reported of having acute hypoxemia (SpO2 < 92%) shortly after the removal of the endotracheal tube or supraglottic airway, associating with radiographic evidence of pulmonary edema and/or pink frothy sputum, were identified as definite NPPE cases. The potential risk factors were compared with the matched controls, who were randomly selected from the same database. RESULTS: A total of 85,561 patients received general anesthesia with airway instrumentation during the 8.5-year study period. A total of 16 patients were identified as definite cases of NPPE. Compared with the matched controls (n = 131), males, active smokers, emergency operation, endotracheal intubation, use of desflurane, and prolonged operation time carried significantly higher risks of developing NPPE (P < 0.05). Multivariate logistic regression analysis illustrated that active smoking (AOR 7.66, 95% CI 1.67-35.3; P = 0.009) and endotracheal intubation (AOR 10.87, 95% CI 1.23-100; P = 0.03) were the two most significant independent variables of post-extubation NPPE. CONCLUSION: We present the first clinical comparative study demonstrating that the overall incidence of NPPE immediately after extubation in the operating room is 0.019%. Our results highlight that active smokers and patients receiving endotracheal intubation general anesthesia are associated with significantly higher risks of developing NPPE following extubation in the operating room.