Effects of ultrasound-guided paravertebral block on MMP-9 and postoperative pain in patients undergoing VATS lobectomy: a randomized, controlled clinical trial.

BACKGROUND: Local anesthesia can reduce the response to surgical stress and decrease the consumption of opioids, which may reduce immunosuppression and potentially delay postoperative tumor recurrence. We compared paravertebral block (PVB) combined with general anesthesia (GA) and general anesthesia regarding their effects on postoperative pain and matrix metalloproteinase-9 (MMP-9) after video-assisted thoracoscopic surgery (VATS) lobectomy. METHODS: 54 patients undergoing elective VATS lobectomy at a single tertiary care, teaching hospital located in Qingdao between May 2, 2018 and Sep 28, 2018 were randomised by computer to either paravertebral block combined with general anesthesia or general anesthesia. The primary outcomes were pain scores at rest and on cough at 1, 4, 24, and 48 h after surgery. The secondary outcome were plasma concentrations of MMP-9, complications, and length of postoperative hospital stay. RESULTS: 75 were enrolled to the study, of whom 21 were excluded before surgery. We analyzed lobectomy patients undergoing paravertebral block combined with general anesthesia (n = 25) or general anesthesia (n = 24). Both groups were similar regarding baseline characteristics. Pain scores at rest at 4 h and 24 h, on cough at 4 h were lower in PVB/GA group, compared with GA group (P < 0.05). There were no difference in pain scores at rest at 1 h, 48 h and on cough at 1 h, 24 h, and 48 h between groups. Patients in the PVB/GA group showed a greater decrease in plasma MMP-9 level at T1 and T2 after VATS lobectomy (P < 0.05). Postoperative complications and length of stay did not differ by anesthetic technique. CONCLUSIONS: The paravertebral block/general anesthesia can provide statistically better pain relief and attenuate MMP-9 response to surgery and after VATS lobectomy. This technique may be beneficial for patients to recover rapidly after lung surgery and reduce postoperative tumor recurrence. TRIAL REGISTRATION: Chinese Clinical Trial registration number ChiCTR1800016379. Registered 28 May 2018.

Ropivacaine impairs mitochondrial biogenesis by reducing PGC-1α.

Ropivacaine is one of the commonly used local anesthetics in medical and dental care. However, preclinical and observational studies indicate that ropivacaine could have substantial side effects including neurotoxicity, which has raised concern regarding the safety of this drug. In the present study, we investigated the effects of clinically relevant doses of ropivacaine on mitochondrial biogenesis and function in neuronal cells. Our data indicate that exposure to ropivacaine leads to reduced expression of the major mitochondrial regulator PGC-1α and its downstream transcription factors NRF1 and TFAM. Ropivacaine treatment induces impairment of mitochondrial biogenesis by reducing mitochondrial mass, the ratio of mtDNA to nDNA (mtDNA/nDNA), cytochrome C oxidase activity, and COX-1 expression. Additionally, treatment with ropivacaine causes "loss of mitochondrial function" by impairing the mitochondrial respiratory rate and ATP production. Mechanistically, the reduction of PGC-1α caused by ropivacaine exposure requires inactivation of CREB, while re-introduction of PGC-1α completely rescues ropivacaine-induced mitochondrial abnormalities. In summary, our results provide supporting evidence that mitochondrial impairment is a key event in ropivacaine-mediated neurotoxicity, and the reduction of PGC-1α and its downstream signals are likely the molecular mechanism behind its cellular toxicity.

ACVR1-activating mutation causes neuropathic pain and sensory neuron hyperexcitability in humans.

ABSTRACT: Altered bone morphogenetic protein (BMP) signaling is associated with many musculoskeletal diseases. However, it remains unknown whether BMP dysfunction has direct contribution to debilitating pain reported in many of these disorders. Here, we identified a novel neuropathic pain phenotype in patients with fibrodysplasia ossificans progressiva (FOP), a rare autosomal-dominant musculoskeletal disorder characterized by progressive heterotopic ossification. Ninety-seven percent of these patients carry an R206H gain-of-function point mutation in the BMP type I receptor ACVR1 (ACVR1 R206H ), which causes neofunction to Activin A and constitutively activates signaling through phosphorylated SMAD1/5/8. Although patients with FOP can harbor pathological lesions in the peripheral and central nervous system, their etiology and clinical impact are unclear. Quantitative sensory testing of patients with FOP revealed significant heat and mechanical pain hypersensitivity. Although there was no major effect of ACVR1 R206H on differentiation and maturation of nociceptive sensory neurons (iSNs) derived from FOP induced pluripotent stem cells, both intracellular and extracellular electrophysiology analyses of the ACVR1 R206H iSNs displayed ACVR1-dependent hyperexcitability, a hallmark of neuropathic pain. Consistent with this phenotype, we recorded enhanced responses of ACVR1 R206H iSNs to TRPV1 and TRPA1 agonists. Thus, activated ACVR1 signaling can modulate pain processing in humans and may represent a potential target for pain management in FOP and related BMP pathway diseases.

Anesthetic management of hip fracture in geriatric patient with respiratory and heart failure using pericapsular nerve group block: A case report.

INTRODUCTION: Hip fracture with severe cardiopulmonary and cerebral dysfunction is a relatively common problem in the elderly population and poses a great challenge to anesthetic management. Pericapsular nerve group (PENG) block combined with nerve blocks of the hip region has recently attracted significant interest from anesthesiologists, and very few reports on its anesthetic management exist. PATIENT CONCERNS: Patient suffered from the right femoral neck fracture, combined with respiratory failure, heart failure, moderate-to-severe pulmonary hypertension, cerebral infarction, atrial fibrillation, and cognitive dysfunction. DIAGNOSIS: Because of right femoral neck fracture, artificial femoral head replacement was scheduled for this patient. INTERVENTIONS: Ultrasound-guided PENG block combined with sacral plexus, thoracic 11 to 12 paravertebral block, and lateral femoral cutaneous block were performed to a high-risk elderly patient. OUTCOMES: The patient successfully received artificial femoral head replacement with our effective anesthesia techniques and no postoperative complication was reported. CONCLUSIONS: Among elderly patients with multiple organ dysfunction undergoing hip surgery, PENG block combined with nerve blocks of the hip region is an ideal anesthesia method. This case demonstrated that these regional analgesia techniques had a stable hemodynamic process, satisfactory anesthetic effect, effective postoperative analgesia, and no effect on postoperative cognitive function. Further studies are needed to determine the appropriate doses of local anesthetics in the elderly with multiple organ system failure to reduce delayed local anesthesia systemic toxicity.

Robotic sleeve lobectomy for centrally located non-small cell lung cancer: A propensity score-weighted comparison with thoracoscopic and open surgery.

OBJECTIVE: To evaluate the surgical and oncologic outcomes of robotic sleeve lobectomy in comparison with video-assisted thoracoscopic surgery (VATS) and open surgery. METHODS: Surgical outcomes in patients with non-small cell lung cancer who underwent sleeve lobectomy via robotic, VATS, and thoracotomy were assessed using the χ2 test, Fisher exact test, and the Kruskal-Wallis rank sum test. Log-rank test and Cox proportional hazards model were used in survival analyses. Propensity score-weighted matching was used to achieve the balance of baseline among the 3 groups. RESULTS: Between 2012 and 2017, 188 patients were included and divided into robotic (n = 49), VATS (n = 73), and open (n = 66) groups. After weighted matching that retained all patients, no statistical difference in 90-day mortality or morbidity among the 3 groups was shown. Patients in the robotic group had less bleeding loss (P < .001), operative time (P < .001), and tube drainage time (P < .001) than the other 2 groups. No positive bronchial margin or conversion presented in the robotic group. In multivariable analyses, surgical technique was independently associated with neither overall survival nor disease-free survival (P > .050). CONCLUSIONS: Robotic sleeve lobectomy is a safe, feasible, and effective procedure. Compared with VATS and open techniques, robotic sleeve lobectomy has a similar oncologic prognosis for patients with centrally located non-small cell lung cancer. Further studies with a larger sample size and long-term follow-up are needed.

Learning curve for robot-assisted lobectomy of lung cancer.

BACKGROUND: Robotic lobectomy is widely used for lung cancer treatment. So far, few studies have been performed to systematically analyze the learning curve. Our purpose is to define the learning curve to provide a training guideline of this technique. METHODS: A total of 208 consecutive patients with primary lung cancer who underwent robotic-assisted lobectomy by our surgical team were enrolled in this study. Baseline information and postoperative outcomes were collected. Learning curves were then analyzed using the cumulative sum (CUSUM) method. Patients were divided into three groups according to the cut-off points of the learning curve. Intraoperative characteristics and short-term outcomes were compared among the three groups. RESULTS: CUSUM plots revealed that the docking time, console time and total surgical time in patients were 20, 34 and 32 cases, respectively. Comparison of the surgical time among the 3 phases revealed that the total surgical time (197.03±27.67, 152.61±21.07, 141.35±29.11 min, P<0.001), console time (150.97±26.13, 103.89±18.04, 97.49±24.80 min, P<0.001) and docking time (13.53±2.08, 11.95±1.10, 11.89±1.49 min, P<0.001) were decreased significantly. Estimated blood loss differed among groups (90.63±45.41, 87.63±59.84, 60.29±28.59 mL, P=0.001) and was associated with shorter operative time. There was no conversion or 30-day mortality. No significant differences were observed among other clinic-pathological characteristics among the groups. CONCLUSIONS: For a surgeon, the learning time of robotic lobectomy was in the 32th operation. For a bedside assistant, at least 20 cases were required to achieve the level of optimal docking.

Effect of periaqueductal gray melanocortin 4 receptor in pain facilitation and glial activation in rat model of chronic constriction injury.

OBJECTIVES: Substantial evidence shows that spinal melanocortin 4 receptor (MC4R) may participate in regulation of central sensitization and chronic pain condition induced by peripheral nerve injury. Periaqueductal gray (PAG) is an important component of descending pain facilitatory system and takes part in spinal nociceptive information. This research will choose PAG to discuss the effect of MC4R in pain facilitation induced by chronic constriction injury (CCI) and further discuss its effect in glial activity and inflammatory factor levels in nerve injury. METHODS: Behavior tests (von Frey test and hot-plate test), semi-quantitative reverse transcription polymerase chain reaction (RT-PCR), and immunohistochemistry were used in this research. RESULTS: PAG injection of HS014 (a selective inhibitor of MC4R), not only significantly reduced the established mechanical allodynia and thermal hyperalgesia, but also delayed the development of pain facilitation. Semi-quantitative RT-PCR analysis revealed that MC4R and proopiomelanocortin (POMC) expression in PAG was significantly increased after CCI, but agouti-related protein (AgRP) expression decreased. Immunohistochemistry analysis showed that protein levels of astrocytic marker (GFAP), microglial marker (OX-42), tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6 were significantly increased, but there was little change of the protein levels of IL-10 following CCI. Furthermore, blockade of MC4R decreased immunoreactivity of glia cells and protein levels of pro-inflammatory cytokines, and increased protein levels of anti-inflammatory cytokine IL-10 after CCI. DISCUSSION: This research suggests that activation of MC4R in PAG after peripheral nerve injury participates in pain facilitation by regulating the glial activation and inflammatory cytokines secretion.

Melanocortin 4 receptor antagonists attenuates morphine antinociceptive tolerance, astroglial activation and cytokines expression in the spinal cord of rat.

Chronic use of morphine is accompanied by the development of morphine tolerance, which is one of the major problems associated with opiate treatment. Experimental evidence indicates that melanocortin 4 receptor (MC4R) is involved in development of morphine tolerance. Therefore, we investigated the influence of repeated intrathecal injection of a MC4R antagonist (HS014) on the development of morphine tolerance as measured by hot-plate test. It was also examined whether a single i.t. HS014 administration could counteract the loss of analgesic potency of morphine in morphine tolerant rats. We examined also the influence of i.t. HS014 administration on astrocytes activation and cytokines expression in the spinal cord of rat during morphine tolerance. Morphine treatment (10mg/kg, i.p. twice daily) over 5 days induced tolerance as reflected by a significant reduction of withdrawal latency from 29.67±1.81s to 8.67±1.70s in the hot-plate test. Repeated coadministration of HS014 and morphine, significantly prevented the development of morphine tolerance. A single administration of an MC4R antagonist restored morphine analgesic potency in morphine tolerant rats. Using immunohistochemical staining, we demonstrated the administration of MC4R during the induction of morphine tolerance inhibited the activation of astrocytes; reduced the expression of proinflammatory cytokines interleukin-1ß, IL-6, and tumor necrosis factor-α; upregulated the expression of anti-inflammatory cytokines IL-10 at the L5 lumbar spinal cord. These results suggest that MC4R may be involved in the mechanisms of morphine tolerance and antagonists of this receptor may be a possible new target in the search for strategies preventing the development of morphine tolerance.