Effect of positive end-expiratory pressure on pulmonary compliance and pulmonary complications in patients undergoing robot-assisted laparoscopic radical prostatectomy: a randomized control trial.

BACKGROUND: To observe the effects of different positive end-expiratory pressure (PEEP) ventilation strategies on pulmonary compliance and complications in patients undergoing robotic-assisted laparoscopic prostate surgery. METHODS: A total of 120 patients with the American Society of Anesthesiologists Physical Status Class I or II who underwent elective robotic-assisted laparoscopic prostatectomy were enrolled. We randomized the patients divided into divided into three groups of 40 patients each: PEEP0, PEEP5, or PEEP10. Master Anesthetist used volume control ventilation intraoperatively with an intraoperative deep muscle relaxation strategy. Respiratory mechanics indexes were recorded at six time-points: 10 mimuts after anaesthesia induction, immediately after pneumoperitoneum establishment, 30 min, 60 min, 90 min, and at the end of pneumoperitoneum. Arterial blood gas analysis and oxygenation index calculation were performed 10 mimuts after anaesthesia induction, 60 mimuts after pneumoperitoneum, and after tracheal extubation. Postoperative pulmonary complications were also recorded. RESULTS: After pneumoperitoneum, peak inspiratory pressure (Ppeak), plateau pressure (Pplat), mean pressure (Pmean), driving pressure (ΔP), and airway resistance (Raw) increased significantly, and pulmonary compliance (Crs) decreased, persisting during pneumoperitoneum in all groups. Between immediately after pneumoperitoneum establishment, 30 min, 60 min, and 90 min, pulmonary compliance in the 10cmH2OPEEP group was higher than in the 5cmH2OPEEP (P < 0.05) and 0cmH2OPEEP groups(P < 0.05). The driving pressure (ΔP) immediately after pneumoperitoneum establishment, at 30 min, 60 min, and 90 min in the 10cmH2OPEEP group was lower than in the 5cmH2OPEEP (P < 0.05) and 0cmH2OPEEP groups (P < 0.05). Sixty min after pneumoperitoneum and tracheal extubation, the PaCO2 did not differ significantly among the three groups (P > 0.05). The oxygenation index (PaO2/FiO2) was higher in the PEEP5 group than in the PEEP0 and PEEP10 groups 60 min after pneumoperitoneum and after tracheal extubation, with a statistically significant difference (P < 0.05). In postoperative pulmonary complications, the incidence of atelectasis was higher in the PEEP0 group than in the PEEP5 and PEEP10 groups, with a statistically significant difference (p < 0.05). CONCLUSION: The use of PEEP at 5cmH2O during RARP increases lung compliance, improves intraoperative oxygenation index and reduces postoperative atelectasis. TRIAL REGISTRATION: This study was registered in the China Clinical Trials Registry on May 30, 2020 (Registration No. ChiCTR2000033380).

Dexmedetomidine alleviates insulin resistance in hepatocytes by reducing endoplasmic reticulum stress.

PURPOSE: Dexmedetomidine (DEX) stabilizes intraoperative blood glucose levels and reduces insulin resistance (IR), a common perioperative complication. However, the molecular mechanisms underlying these effects remain unclear. Since endoplasmic reticulum stress (ERS) is a mechanism of IR, this study sought to examine whether DEX can effectively alleviate IR by reducing ERS. METHODS: HepG2 and LO2 cells were treated with different concentrations of insulin. The glucose content assay and Cell Counting Kit-8 (CCK-8) were then employed to determine the optimal insulin concentration capable of inducing IR without affecting cell viability. Insulin-resistant hepatocytes were cultured with different concentrations of DEX for 24 h, and the glucose concentration in the supernatant was measured. ERS was assessed by qPCR and western blotting. The latter was also used to quantify the expression of phosphorylated protein kinase B (p-AKT), phosphoenolpyruvate carboxykinase (PEPCK), and glucose 6 phosphatase (G6Pase), which are key proteins involved in the action of insulin. RESULTS: After 48-h of culturing with 10 µg/mL insulin, glucose consumption in hepatocytes was found to be reduced. IR hepatocytes cultured with 10, 100, or 1000 ng/ml DEX for 24 h showed a concentration-dependent increase in glucose consumption. Elevated mRNA and protein levels of ERS markers binding immunoglobulin protein (BIP) and ER protein 29 (ERp29), were reversed by DEX treatment. Moreover, reduced p-AKT and increased PEPCK and G6Pase protein levels in IR hepatocytes were also restored following DEX treatment. CONCLUSION: DEX may alleviate IR in hepatocytes by reducing ERS serving to restore insulin action via the IRS-1/PI3K/AKT pathway.

Silencing of spinal Trpv1 attenuates neuropathic pain in rats by inhibiting CAMKII expression and ERK2 phosphorylation.

Accumulating evidence suggests a potential role of transient receptor potential vanilloid 1 (TRPV1) channels in inflammatory and cancer-related pain. However, the role of TRPV1 in the maintenance of neuropathic pain remains elusive. The current study investigated the effects of transient Trpv1 gene silencing using a small interference RNA (siRNA) on neuropathic pain induced by chronic constriction injury (CCI) of the sciatic nerve in rats. Seven days after CCI, the TRPV1 siRNA was intrathecally administered (5 µg/15 µl, once daily for 2 days). TRPV1 and Ca2+/calmodulin-dependent protein kinase II (CAMKII) expression and extracellular signal-regulated kinase (ERK) phosphorylation in the spinal cord were detected using western blotting. The thresholds to mechanical and thermal stimuli were determined before and after intrathecal TRPV1 siRNA administration. TRPV1 and CAMKII expression and ERK2 phosphorylation in the spinal cord were upregulated after CCI. Intrathecal administration of the TRPV1 siRNA not only attenuated behavioural hyperalgesia but also reduced the expression of TRPV1 and CAMKII, as well as ERK2 phosphorylation. Based on these results, silencing of the TRPV1 gene in the spinal cord attenuates the maintenance of neuropathic pain by inhibiting CAMKII/ERK2 activation and suggests that TRPV1 represents a potential target in pain therapy.

Pulsed radiofrequency to the dorsal root ganglion or the sciatic nerve reduces neuropathic pain behavior, decreases peripheral pro-inflammatory cytokines and spinal ß-catenin in chronic constriction injury rats.

BACKGROUND AND OBJECTIVES: Pulsed radiofrequency (PRF) is a minimal neurodestructive interventional pain therapy. However, its analgesic mechanism remains largely unclear. We aimed to investigate the peripheral and spinal mechanisms of PRF applied either adjacent to the ipsilateral L5 dorsal root ganglion (PRF-DRG) or PRF to the sciatic nerve (PRF-SN) in the neuropathic pain behavior induced by chronic constriction injury (CCI) in rats. METHODS: On day 0, CCI or sham surgeries were performed. Rats then received either PRF-DRG, PRF-SN, or sham PRF treatment on day 4. Pain behavioral tests were conducted before surgeries and on days 1, 3, 5, 7, 9, 11, 13, and 14. After the behavioral tests, the rats were sacrificed. The venous blood or sciatic nerve samples were collected for ELISAs and the dorsal horns of the L4-L6 spinal cord were collected for western blot examination. RESULTS: The mechanical allodynia and the thermal hyperalgesia has been relieved by a single PRF-DRG or PRF-SN application. In addition, the analgesic effect of PRF-DRG was superior to PRF-SN on CCI-induced neuropathic pain. Either PRF-DRG or PRF-SN reversed the enhancement of interleukin 1ß (IL-1ß) and tumor necrosis factor alpha (TNF-α) levels in the blood of CCI rats. PRF-DRG or PRF-SN also downregulated spinal ß-catenin expression. CONCLUSIONS: PRF treatment either to DRG or to sciatic nerve reduced neuropathic pain behavior, and reduced peripheral levels of pro-inflammatory cytokines and spinal ß-catenin expression in CCI rats. PRF to DRG has a better analgesic effect than PRF to the nerve.

N-methyl D-aspartate receptor subtype 2B antagonist, Ro 25-6981, attenuates neuropathic pain by inhibiting postsynaptic density 95 expression.

Postsynaptic density-95 (PSD-95) is a synaptic scaffolding protein that plays a crucial role in the development of neuropathic pain. However, the underlying mechanism remains unclear. To address the role of PSD-95 in N-methyl-D-aspartate receptor subtype 2B (NR2B) -mediated chronic pain, we investigated the relationship between PSD-95 activation and NR2B function in the spinal cord, by using a rat model of sciatic nerve chronic constriction injury (CCI). We demonstrate that the expression levels of total PSD-95 and cAMP response element binding protein (CREB), as well as phosphorylated NR2B, PSD-95, and CREB, in the spinal dorsal horn, and the interaction of NR2B with PSD-95 were increased in the CCI animals. Intrathecal injection of the selective NR2B antagonist Ro 25-6981 increased paw withdrawal latency, in a thermal pain assessment test. Moreover, repeated treatment with Ro 25-6981 markedly attenuated the thermal hypersensitivity, and inhibited the CCI-induced upregulation of PSD-95 in the spinal dorsal horn. Furthermore, intrathecal injection of the PSD-95 inhibitor strikingly reversed the thermal and mechanical hyperalgesia. Our results suggest that blocking of NR2B signaling in the spinal cord could be used as a therapeutic candidate for treating neuropathic pain.

Dexmedetomidine Attenuates Neuropathic Pain by Inhibiting P2X7R Expression and ERK Phosphorylation in Rats.

α2-Adrenoceptor agonists attenuate hypersensitivity under neuropathic conditions. However, the mechanisms underlying this attenuation remain largely unknown. In the present study, we explored the potential roles of purinergic receptor 7 (P2X7R)/extracellular signal-regulated kinase (ERK) signaling in the anti-nociceptive effect of dexmedetomidine in a rat model of neuropathic pain induced by chronic constriction injury (CCI) of the sciatic nerve. An animal model of CCI was adopted to mimic the clinical neuropathic pain state. Behavioral hypersensitivity to mechanical and thermal stimuli was determined by von Frey filament and Hargreaves' tests, and the spinal P2X7R expression level and ERK phosphorylation were analyzed using western blot analysis and immunohistochemistry. In parallel with the development of mechanical and thermal hyperalgesia, a significant increase in P2X7R expression was noted in the ipsilateral spinal cord on day 7 after CCI. Intrathecal administration of dexmedetomidine (2.5 µg) for 3 days not only attenuated neuropathic pain but also inhibited the CCI-induced P2X7R upregulation and ERK phosphorylation. Intrathecal dexmedetomidine administration did not produce obvious effects on locomotor function. The present study demonstrated that dexmedetomidine attenuates the neuropathic pain induced by CCI of the sciatic nerve in rats by inhibiting spinal P2X7R expression and ERK phosphorylation, indicating the potential therapeutic implications of dexmedetomidine administration for the treatment of neuropathic pain.

Dezocine Antagonizes Morphine Analgesia upon Simultaneous Administration in Rodent Models of Acute Nociception.

BACKGROUND: Dezocine is a powerful analgesic that can be less addictive than morphine, yet how the two drugs interact in vivo is poorly understood. Here we administered dezocine alone or in combination with morphine to different acute nociception paradigms to explore the interactions of the 2 drugs upon co-administration. OBJECTIVE: To evaluate how dezocine interacts with morphine in different acute nociception paradigms. STUDY DESIGN: Laboratory animal study. SETTING: Zhejiang University School of Medicine, Hangzhou, China. METHODS: Healthy mice were treated with saline, dezocine (0.625 - 2.5 µg), or a combination of dezocine with morphine (2.5 µg). Tail withdrawal latency (TWL) was analyzed prior to and 30 minutes after drug administration. Rats were treated with saline, morphine (3 mg/kg), dezocine (3 mg/kg), or a combination of both drugs. The animals were then left uninjured, subjected to plantar incision, or underwent formaldehyde-induced acute inflammation. Nociception was then analyzed in terms of mechanical threshold (MT) to von Frey stimulation and paw withdrawal latency (PWL) to thermal stimulation. Formaldehyde-induced pain score was calculated based on the duration of biting and elevating of the animal's legs. Phosphorylation of extracellular signal-regulated kinase (pERK) was also measured after plantar incision as a molecular index of nociception. RESULTS: Dezocine enhanced TWL but inhibited morphine analgesia in a dose-dependent fashion in mice. Usage of morphine or dezocine alone in uninjured rats increased MT, but co-administering both drugs did not further increase MT. Usage of one drug alone, and both drugs together increased MT and PWL relative to saline at 30 minutes after incision. Usage of one drug alone, but not both drugs together, increased MT and PWL at 120 minutes after incision. Dezocine reduced formaldehyde-induced nociception but co-administering both drugs did not further reduce pain behavior. LIMITATIONS: The results were obtained from animal study; clinical investigations will be needed to clarify their interaction. CONCLUSION: Dezocine antagonizes morphine analgesia on acute nociception upon simultaneous administration.Key words: Dezocine, morphine, acute nociception, analgesia.