Anti-nociceptive Effects of Dexmedetomidine Infusion Plus Modified Intercostal Nerve Block During Single-port Thoracoscopic Lobectomy: A Double-blind, Randomized Controlled Trial.

BACKGROUND: Multimodal general anesthesia based on modified intercostal nerve block (MINB) has been found as a novel method to achieve an intraoperative opioid-sparing effect. However, there is little information about the effective method to inhibit visceral nociceptive stress during single-port thoracoscopic surgery. OBJECTIVE: To investigate whether a low-dose dexmedetomidine infusion followed by MINB might be an alternative method to blunt visceral stress effectively. STUDY DESIGN: Double-blind, randomized control trial. SETTING: Affiliated hospital from March 2020 through September 2020. METHODS: Fifty-four patients were randomized (1:1), 45 patients were included to receive dexmedetomidine with a 0.4 microgram/kg bolus followed by 0.4 microgram/kg/h infusion (group Dex) or saline placebo (group Con). During the operation, an additional dose of remifentanil 0.05-0.25 microgram/kg/min was used to keep mean arterial pressure (MAP) or heart rate (HR) values around 20% below baseline values. The primary outcome was to evaluate remifentanil consumption. Secondary outcomes included intraoperative hemodynamics, the first time to press an analgesia pump, and adverse effects. RESULTS: Remifentanil consumption during surgery was markedly decreased in the Dex group than in the Con group (0 [0-0] versus 560.0 [337.5-965.0] microgram; P = 0.00). MAP and HR in the Con group during the first 5 minutes after visceral exploration was significantly higher than in the Dex group (P < 0.05). Time to first opioid demand was significantly prolonged (P = 0.04) and postoperative length of stay was shortened slightly in the Dex group (P = 0.05). LIMITATIONS: This study was limited by the measurement of nociception. CONCLUSIONS: This study demonstrates that low-dose dexmedetomidine infusion combined with MINB might be an effective alternative method to blunt visceral stress in patients undergoing single-port thoracoscopic lobectomy. Furthermore, the analgesic effect of MINB was significantly prolonged after dexmedetomidine infusion.

Outcomes of individualized goal-directed therapy based on cerebral oxygen balance in high-risk patients undergoing cardiac surgery: A randomized controlled trial.

STUDY OBJECTIVE: To investigate whether optimizing individualized goal-directed therapy (GDT) based on cerebral oxygen balance in high-risk surgical patients would reduce postoperative morbidity. DESIGN: This was a prospective, randomized, controlled study. SETTING: The study was performed in the First Affiliated Hospital of Anhui Medical University, Hefei, China, from April 2017 to July 2018. PATIENTS: 146 high-risk adult patients undergoing valve replacements or coronary artery bypass surgery with cardiopulmonary bypass (CPB) were enrolled. INTERVENTION: Patients were randomized to an individualized GDT group or usual care group. Individualized GDT was targeted to achieve the following goals: A less than 20% decline in the regional cerebral oxygen saturation (rScO2) level from baseline; a less than 20% decline in the mean arterial pressure (MAP) from baseline, as well as a bispectral index (BIS) of 45-60 before and after CPB and 40-45 during CPB. MEASUREMENTS: The primary outcome was a composite endpoint of 30-day mortality and major postoperative complications. MAIN RESULTS: 128 completed the trial and were included in the modified intention-to-treat analysis. Early morbidity was similar between the GDT (25 [39%] of 65 patients) and usual care groups (33 [53%] of 63 patients) (relative risk 0.73, 95% CI 0.50-1.08; P = 0.15). Secondary analysis showed that 75 (59%) of 128 patients achieved individual targets (irrespective of intervention) and sustained less morbidity (relative risk 3.41, 95% CI 2.19-5.31; P < 0.001). CONCLUSIONS: In high-risk patients undergoing cardiac surgery, individualized GDT therapy did not yield better outcomes, however, the achievement of preoperative individual targets may be associated with less morbidity. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT03103633. Registered on 1 April 2017.

Elamipretide Attenuates Pyroptosis and Perioperative Neurocognitive Disorders in Aged Mice.

Pyroptosis is a recently characterized inflammatory form of programmed cell death that is thought to be involved in the pathogenesis of perioperative neurocognitive disorders (PND). Elamipretide (SS-31), a mitochondrial-targeted peptide with multiple pharmacological properties, including anti-inflammatory activity, has been demonstrated to protect against many neurological diseases. However, the effect of elamipretide on pyroptosis in PND has not been studied. We established an animal model of PND by performing an exploratory laparotomy on mice under isoflurane anesthesia and examined the effects of elamipretide on cognitive function, synaptic integrity, neuroinflammation, mitochondrial function, and signaling controlling pyroptosis. Our results showed that anesthesia and surgery caused mitochondrial dysfunction and abnormal morphology, activation of canonicalnod-like receptor pyrin domain-containing 3 (NLRP3) inflammasome-caspase-1 dependent pyroptosis, and downregulation of synaptic integrity-related proteins in the hippocampus in aged mice, thus leading to learning and memory deficits in behavioral tests. Remarkably, treatment with the mitochondrial-targeted peptide elamipretide not only had protective effects against mitochondrial dysfunction but also attenuated surgery-induced pyroptosis and cognitive deficits. Our results provide a promising strategy for the treatment of PND involving mitochondrial dysfunction and pyroptosis.

Combination therapy with ropivacaine-loaded liposomes and nutrient deprivation for simultaneous cancer therapy and cancer pain relief.

Autophagy allows cancer cells to respond changes in nutrient status by degrading and recycling non-essential intracellular contents. Inhibition of autophagy combined with nutrient deprivation is an effective strategy to treat cancer. Pain is a primary determinant of poor quality of life in advanced cancer patients, but there is currently no satisfactory treatment. In addition, effective treatment of cancer does not efficiently relieve cancer pain, but may increase pain in many cases. Hence, few studies focus on simultaneous cancer therapy and pain relief, and made this situation even worse. Method: Ropivacaine was loaded into tumor-active targeted liposomes. The cytotoxicity of ropivacaine-based combination therapy in B16 and HeLa cells were tested. Moreover, a mice model of cancer pain which was induced by inoculation of melanoma near the sciatic nerve was constructed to assess the cancer suppression and pain relief effects of ropivacaine-based combination therapy. Results: Ropivacaine and ropivacaine-loaded liposomes (Rop-DPRL) were novelly found to damage autophagic degradation. Replicated administration of Rop-DPRL and calorie restriction (CR) could efficiently repress the development of tumor. In addition, administration of Rop-DPRL could relieve cancer pain with its own analgestic ability in a short duration, while repeated administration of Rop-DPRL and CR resulted in continuous alleviation of cancer pain through reduction of VEGF-A levels in advanced cancer mice. Further, dual inhibition of phosphorylation of STAT3 at Tyr705 and Ser727 by Rop-DPRL and CR contribute to the reduction of VEGF-A. Conclusion: Combination therapy with Rop-DPRL and nutrient deprivation simultaneously suppresses cancer growth and relieves cancer pain.

Enhanced autophagic flux contributes to cardioprotection of remifentanil postconditioning after hypoxia/reoxygenation injury in H9c2 cardiomyocytes.

Remifentanil postconditioning (RPC) has been shown to provide potent cardioprotection against ischemia/reperfusion (I/R) injury, but the underlying mechanism has not been fully elucidated. The current study was designed to investigate whether RPC protects cardiomyocytes against I/R injury through enhancement of autophagic flux. H9c2 cardiomyocytes were exposed to hypoxia/reoxygenation (H/R) to mimic myocardial I/R injury in vitro. Autophagosome formation was evaluated by detecting of light chain 3 (LC3) puncta number and LC3Ⅱ levels using immunofluorescence and western blotting, respectively. Additionally, dual fluorescent staining of LC3 and lysosomal-associated membrane protein 2, a lysosomal marker protein, were used to detect autolysosome formation. Moreover, autophagic flux integrity was tracked using changes in LC3Ⅱ and p62 levels. Lastly, myocardial injury was detected by Hoechst 33342 and propidium iodide staining and MTT assay. The results showed that RPC increased autophagosome formation and promoted autophagosome-lysosome fusion, thereby improving autophagic flux in H9c2 cells. Reversal of these effect by bafilomycin A1 or chloroquine co-administration at reoxygenation onset indicated that RPC improved the impaired autophagic flux following H/R injury. Induction of autophagy was associated with increased cell viability and decreased apoptosis. Autophagy inhibition with bafilomycin A1 or chloroquine and ATG7shRNA significantly abolished RPC-induced cardioprotection. In conclusion, our finding that RPC can protect cardiomyocytes against H/R injury through enhancement of autophagic flux suggests a new mechanism for myocardial protection of opioid postconditioning.

Efficacy of perineural dexamethasone with ropivacaine in thoracic paravertebral block for postoperative analgesia in elective thoracotomy: a randomized, double-blind, placebo-controlled trial.

PURPOSE: The purpose of this study was to assess the efficacy of perineural dexamethasone with ropivacaine in multimodal analgesia for thoracic paravertebral block (TPVB) in patients undergoing elective thoracotomy. PATIENTS AND METHODS: Ninety-six patients undergoing thoracotomy were enrolled in this trial and randomized to adjuvant therapy for TPVB: group S (saline), group R (0.5% ropivacaine), or group RD (5 mg dexamethasone and 0.5% ropivacaine). Postoperative analgesia, recovery duration, and chronic pain were recorded. RESULTS: Groups R and RD spent less time in the postanaesthesia care unit, had earlier out-of-bed activity, and had shorter postoperative hospital stays compared with group S. The RD group regained consciousness faster and had lower acute pain scores and used less patient-controlled analgesia during the first 72 h after surgery compared with group S. Postthoracotomy pain was decreased in group RD (19.0%) compared with group S (47.6%) 3 months postoperatively, p = 0.050. CONCLUSION: Perineural dexamethasone with ropivacaine for TPVB improves postoperative analgesia quality, reduces recovery time, and may decrease the incidence of chronic pain after thoracotomy with an opioid-based anesthetic regimen.

Perioperative risk factors and cumulative duration of "triple-low" state associated with worse 30-day mortality of cardiac valvular surgery.

ABSRACT: Hospital stay and mortality in high-risk patients after noncardiac surgery has been associated with a triple low anesthesia. However, the association between anesthesia-related factors and perioperative outcome after cardiac surgery remains unclear.We tested the effect of a novel triple low state: low mean arterial pressure (MAP) <65 mmHg and low bispectral index (BIS) <45 during a low target effect-site concentration (Ce) <1.5 µg ml-1 of propofol anesthesia on postoperative duration of hospitalization and 30-day mortality in cardiac valvular patients. In this prospective observational study, univariable and multivariable logistic regression analyses were used to determine whether perioperative factors, in particular, cumulative duration of triple low state were independently associated with duration of hospitalization and 30-day mortality among patients who underwent elective valvular replacement. 489 patients were included in the final analysis. After adjusting for related covariates, cumulative duration of the triple-low state was not associated with prolonged hospitalization (multivariable odds ratio: 1.007; 95 % confidence interval 0.997-1.017; P = 0.564), but was a significant predictor of 30-day mortality (multivariable odds ratio: 1.016; 95 % confidence interval 1.002-1.031; P = 0.030). Compared to a triple-low duration of <15 min, a duration >60 min increased the 30-day mortality rate by 8 times. After adjusting for patient- and procedure-related characteristics, the cumulative duration of a triple-low state (intraoperative low MAP, low BIS, and low Ce) was associated with poorer 30-day mortality, but not with prolonged duration of hospital stay.The mortality risk was even greater when a cumulative time >60 min.

Sufentanil attenuates impairment of the endothelium-dependent vasodilation induced by hypoxia-reoxygenation in the rat coronary artery.

Sufentanil has been used broadly in cardiac surgery, but the mechanisms by which it modulates coronary vascular tone after ischemia-reperfusion injury are largely unknown. Effects of sufentanil on coronary tone and on the relaxation of rat coronary arteries (CAs) in response to endothelium-dependent (acetylcholine) and endothelium-independent (sodium nitroprusside) relaxing agents in the presence of hypoxia-reoxygenation (H/R) was studied in an in vitro organ chamber setup. Sufentanil (10-7-10-4 mol/L) relaxed rat CA rings in endothelium-dependent and endothelium-independent manners. In endothelium-intact rings, preincubation of H/R-treated CAs with sufentanil (10-5 mol/L) significantly increased the acetylcholine response, but did not augment sodium nitroprusside-induced relaxation. Sufentanil-mediated potentiation of acetylcholine-induced relaxation was not affected by a nitric oxide synthase inhibitor or by intermediate- or small-conductance Ca2+-activated K+ channel blockers. However, potentiation was abolished by iberiotoxin (100 nmol/L), a selective inhibitor of large-conductance Ca2+-activated K+ channels, as well as Rp-cAMPS (30 µmol/L), a cyclic AMP-dependent protein kinase (PKA) inhibitor. Sufentanil induced endothelium-dependent and endothelium-independent relaxation and attenuated H/R-induced impairment of endothelium-dependent vasodilation in the rat CAs. The potentiating effect of sufentanil may involve activation of large-conductance Ca2+-activated K+ channels via cAMP-dependent mechanisms.

Comparison of the Effects of Dexmedetomidine and Propofol on Hemodynamics and Oxygen Balance in Children with Complex Congenital Heart Disease Undergoing Cardiac Surgery.

OBJECTIVE: The aim of this study was to compare the effects of anesthesia by dexmedetomidine and propofol on the hemodynamics and oxygen balance in children with complex congenital heart disease who were undergoing cardiac surgery. METHODS: Fifty-seven children were randomized to receive either a continuous infusion of propofol (6-8 mg/kg/h) or dexmedetomidine (0.5-0.7 µg/kg/h) after anesthesia induction. Hemodynamic data were recorded. Oxygen balance parameters were assessed at baseline after midazolam sedation, before and immediately after skin incisions were made, after sternotomy, 5 minutes after protamine administration, and at the end of surgery. RESULTS: Compared with the dexmedetomidine group, the propofol group exhibited decreases in blood pressure, cardiac output, and cardiac index before skin incision (P < .05) and increases in blood pressure, heart rate, cardiac output, and cardiac index after sternotomy (P < .01). However, very similar trends in oxygen dynamics were obtained in both groups (P > .05), and the cardiac index was not correlated with total oxygen consumption (r = -0.109, P = .066) or the oxygen extraction ratio (r = -0.107, P = .072). CONCLUSIONS: Dexmedetomidine infusion may be superior to propofol anesthesia in children with complex congenital heart disease who are undergoing cardiopulmonary bypass because dexmedetomidine was associated with less variability in heart rate or blood pressure during surgery. However, the oxygen balance was similar when either agent was used.

Effect of aortic root infusion of sufentanil on ischemia-reperfusion injury in patients undergoing mitral valve replacement.

OBJECTIVE: This study investigated the effects of aortic root infusion of sufentanil on myocardial ischemia/reperfusion injury in patients undergoing elective mitral valve replacement (MVR) with cardiopulmonary bypass (CPB). DESIGN: A prospective, randomized, clinical study. SETTING: A university-affiliated teaching hospital. PARTICIPANTS: Fifty-three adult patients undergoing elective MVR with CPB. INTERVENTIONS: Bolus infusions of sufentanil (0.2 µg/kg, n = 24) or normal saline (n = 29) were administered through the aortic root cardioplegia perfusion catheter 5 minutes before aortic unclamping. MEASUREMENTS AND MAIN RESULTS: Plasma concentrations of CK-MB and cTnI and variables including heart rate, mean arterial pressure, central venous pressure, cardiac output, stroke volume, duration of mechanical ventilation, length of ICU stay, length of hospital stay, and 24-hour postoperative inotropic scores were recorded. Plasma concentrations of CK-MB and cTnI were significantly lower 4 and 8 hours after aortic unclamping in the sufentanil postconditioning group compared to control (p<0.05). Inotropic drug use, duration of mechanical ventilation, and length of ICU and hospital stays were reduced significantly in the sufentanil postconditioning group compared to control (p< 0.05). CONCLUSIONS: The present study demonstrated that sufentanil can attenuate myocardial ischemia-reperfusion injury in patients undergoing elective MVR with CPB.

Intracerebroventricular administration of morphine confers remote cardioprotection--role of opioid receptors and calmodulin.

The current study aimed to delineate the mechanism of remote preconditioning by intracerebroventricular morphine (RMPC) against myocardial ischemia-reperfusion injury. Male Sprague-Dawley rats were given an intracerebroventricular morphine injection before myocardial ischemia and reperfusion injury. Ischemia-reperfusion injury was achieved by 30min of left coronary artery occlusion followed by 120min of reperfusion. The effects of remote preconditioning by intracerebroventricular morphine preconditioning were also determined upon selective blockade of the δ, κ or µ-opioid receptors, or calmodulin (CaM). The infarct size, as a percentage of the area at risk, was determined by 2,3,5-triphenyltetrazolium staining. Remote preconditioning by intracerebroventricular morphine reduced infarct size in the ischemic/reperfused myocardium, and the effect was abolished by the selective blockade of any one of the three δ, κ and µ opioid receptors or CaM. Furthermore, remote preconditioning by intracerebroventricular morphine increased the expression of CaM in the hippocampus and the plasma level of calcitonin gene-related peptide (CGRP). The results of the present study provide evidence that the cardioprotection of remote preconditioning by intracerebroventricular morphine involves not only all three types of opioid receptors in the central nervous system, but also CaM, which releases CGRP, one of the mediators of remote preconditioning.

Oligomerized grape seed proanthocyanidins ameliorates isoproterenol-induced cardiac remodeling in rats: role of oxidative stress.

The effects of oligomerized grape seed proanthocyanidins (GSP) on haemodynamics, cardiac hypertrophy and fibrosis as well as apoptosis signal-regulating kinase 1 (ASK1) and nuclear factor-κB (NF-κB) cascades in isoproterenol (Iso)-induced cardiac remodelling (CR) rat model were investigated, in addition, the serum SOD activities and MDA content were assayed. Rats were treated with Iso to induce CR and were given distilled water or GSP for 1 week. Control rats received vehicle instead of Iso. Administration of GSP markedly alleviated the elevation of the left ventricle weight (LVW)/body weight (BW), heart weight (HW)/body weight (BW) ratio and cross-sectional area of cardiomyocytes, decreased collagen deposition in the heart, and improved the haemodynamic index. Meanwhile, treatment with GSP significantly ameliorated oxidative stress by improving SOD activities and decreasing MDA formation. Moreover, GSP apparently inhibited the expression ASK1, NF-κB and its targeted gene - COX-2. These findings suggest that administration of GSP has the potential to attenuate Iso-induced CR by repressing oxidative stress and inhibiting the activation of the cellular signaling cascades involving the ASK1 and NF-κB pathways, at least in part, providing a molecular mechanism for the cardioprotective effect of GSP.

[Effects of oligomeric grape seed proanthocyanidins on isoproterenol-induced cardiac remodeling in rats].

The purpose of this study is to evaluate the effect of oligomeric grape seed proanthocyanidins (GSP) on isoproterenol (ISO)-induced cardiac remodeling in rats. ISO was given subcutaneously (5 mg x kg(-1), sc, 7 days) to induce cardiac remodeling in rats. Therapeutic groups were given GSP (50, 100, and 150 mg x kg(-1)) after ISO treatment. After 2 weeks intervention, heart rate (HR), left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP), rate of rise of left ventricular pressure (+/- dp/dt(max)) were examined. The myocardial hypertrophy index was expressed as heart weight/body weight (HW/BW) and left ventricle weight/body weight (LVW/BW), the histological changes were investigated by HE and Van Gieson stain. SOD activity and MDA content in serum, contents of hydroxyproline (Hyp) in the left ventricular tissue were assayed by xanthinoxidase method, thiobarbituric acid (TBA) method and alkaline hydrolysis method, respectively. After the onset of ISO-treatment, GSP therapy potently improved cardiac function, inhibited myocardial hypertrophy, improved cardiac pathology change, decreased the myocardial cross-section area (CSA), collagen volume fraction (CVF) and perivascular circumferential collagen area (PVCA), reduced the content of Hyp in the left ventricular tissue, inhibited the decrease of SOD activity and increase of MDA content in serum. GSP possess protective effect against ISO induced cardiac remodeling in rats, this may be related to reducing the oxidative stress and improving antioxidant capacity.