The ED50 and ED95 of esketamine for preventing early postoperative pain in patients undergoing laparoscopic cholecystectomy: a prospective, double-blinded trial.

BACKGROUND: This study aims to estimate the safety, efficacy, and median effective dose (ED50) of esketamine for preventing early postoperative pain in patients undergoing laparoscopic cholecystectomy. METHODS: 54 patients undergoing laparoscopic cholecystectomy were prospectively randomized into two groups (group C and group E). Different doses of esketamine were intravenously administered before the skin incision in Group E. The patients in group C received the same dose of saline at the same time. General population characteristics were recorded. The median effective dose (ED50) and 95% effective dose (ED95) were calculated using Dixon's up-and-down method. Hemodynamic parameters were monitored, and pain intensity was assessed using a visual analog scale. We also recorded the condition of anesthesia recovery period and postoperative adverse reactions. RESULTS: The ED50 of esketamine for preventing early postoperative pain was 0.301 mg/kg (95%CI: 0.265-0.342 mg/kg), and the ED95 was 0.379 mg/kg (95%CI: 0.340-0.618 mg/kg), calculated by probability unit regression. Heart rate (HR) was significantly lower in the esketamine group compared to the control at the skin incision (p < 0.05). The total VAS score at resting was significantly lower in the esketamine group compared to the control group during the awakening period (p < 0.05). There was no significant difference between the two groups regarding the incidence of adverse reactions (p > 0.05). CONCLUSIONS: In this study, esketamine can prevent early postoperative pain effectively. The ED50 and ED95 of esketamine for controlling early postoperative pain were 0.301 mg/kg and 0.379 mg/kg, respectively. TRIAL REGISTRATION: ChiCTR2200066663, 13/12/2022.

Predictive value of ELWI combined with sRAGE/esRAGE levels in the prognosis of critically ill patients with acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) is a life-threatening condition. Accurate judgement of the disease progression is essential for controlling the condition in ARDS patients. We investigated whether changes in the level of serum sRAGE/esRAGE could predict the 28-day mortality of ICU patients with ARDS. A total of 83 ARDS patients in the ICU of the Second Affiliated Hospital of Nantong University from January 2021 to June 2022 were consecutively enrolled in this study. Demographic data, primary diagnosis and comorbidities were obtained. Multiple scoring systems, real-time monitoring systems, and biological indicators were determined within 6 h of admission. The clinical parameters for survival status of the ARDS patients were identified by multivariate logistic regression. Receiver operating characteristic (ROC) curve analysis was employed to verify the accuracy of the prognosis of the related parameters. The admission level of sRAGE was significantly higher in the nonsurvival group than in the survival group (p < 0.05), whereas the serum esRAGE level showed the opposite trend. Multivariate logistic regression analysis showed that sRAGE (AUC 0.673, p < 0.05), esRAGE (AUC 0.704, p < 0.05), and ELWI (extravascular lung water index) (AUC 0.717, p < 0.05) were independent risk factors for the prognosis of ARDS. Model B (ELWI + esRAGE) could not be built as a valid linear regression model (ELWI, p = 0.079 > 0.05). Model C (esRAGE + sRAGE) was proven to have no significance because it had a predictive value similar to that of the serum levels of esRAGE (Z = 0.993, p = 0.351) or sRAGE (Z = 1.116, p = 0.265) alone. Subsequently, Model D (sRAGE + esRAGE + ELWI) showed the best 28-day mortality predictive value with a cut-off value of 0.426 (AUC 0.841; p < 0.001), and Model A (sRAGE + ELWI) had a cut-off value of 0.401 (AUC 0.820; p < 0.001), followed by sRAGE (AUC 0.704, p = 0.004), esRAGE (AUC 0.717, p = 0.002), and ELWI (AUC 0.637, p = 0.028). In addition, there was no statistically significant difference between Model A and Model D (Z = 0.966, p = 0.334). The admission level of sRAGE was higher in the nonsurvival group, while the serum esRAGE level showed the opposite trend. Model A and Model D could be used as reliable combined prediction models for predicting the 28-day mortality of ARDS patients.

Low-dose nalmefene pretreatment reduces etomidate-induced myoclonus: A randomized, double-blind controlled trial.

BACKGROUND: This study compared the effectiveness of nalmefene and fentanyl in reducing the incidence and severity of etomidate-induced myoclonus. METHODS: One hundred fifty patients were randomized to receive 0.25ug/kg of nalmefene, 1ug/kg of fentanyl, or the same volume of normal saline 3 minutes prior to etomidate-induced anesthesia. The primary observational indexes were the severity level and incidence of etomidate-induced myoclonus, and the secondary observational index included blood pressure, heart rate, and the incidence of adverse effects from anesthesia induction to resuscitation, such as cough, chest wall rigidity, dizziness, nausea, pain after awakening, and intraoperative awareness. RESULTS: The incidence of myoclonus was significantly lower in the nalmefene group (8.0%) than in the fentanyl group (32.0%) (P = .003) and in the normal saline group (72.0%) (P = .000). The severity level of myoclonus in the nalmefene group was significantly lower than the fentanyl group (P = .001) and normal saline group (P = .000). Meanwhile, the incidences of cough and chest wall rigidity during anesthesia induction were significantly lower in the nalmefene group compared with the fentanyl group (P = .003, P = .027). There were no statistically significant differences in heart rate and mean arterial pressure among the 3 gruops (P > .05). There was no difference in the incidence of adverse effects among the 3 groups during recovery from anesthesia (P > .05). CONCLUSION: Intravenous injection of 0.25ug/kg of nalmefene 3 minutes prior to etomidate is more effective in preventing etomidate-induced myoclonus during general anesthesia than 1ug/kg of fentanyl.

Rare and unexpected ventilation difficulties due to tracheal diverticulum: A case report.

RATIONALE: Tracheal diverticulum is a rare airway-related particular occurrence, and the forcible tube insertion may cause tracheal ruptures during tracheotomy. Therefore, fiberoptic bronchoscopy (FOB) should be used routinely on all patients undergoing tracheal intubation or tracheotomy. PATIENT CONCERNS: A 60-year-old male with laryngeal neoplasms was scheduled for partial laryngectomy using a suspension laryngoscope in July 2020. All operations were performed under general anesthesia through orotracheal intubation. Orotracheal intubation was a noninvasive procedure that could effectively control breathing. At the end of the surgery, the percutaneous tracheostomy was performed to maintain airway patency, facilitate spontaneous respiration, and remove the secretions. DIAGNOSES: At this moment, the tracheal diverticulum, located at the right posterolateral region of the trachea, became an unexpected airway-related particular occurrence, which led to tracheal tube placement difficulty, mechanical ventilation difficulty, and high airway pressure. INTERVENTIONS: Subsequently, the tracheal tube was repositioned, with placement again confirmed by the FOB. LESSONS SUBSECTIONS: Tracheal diverticulum is an infrequent cause of tube inserting difficulty for the tracheotomy, and FOB is the first option for patients with catheter placement difficulty and mechanical ventilation difficulty.

Sufentanil, dexmedetomidine combined with surface anesthesia for awake fiberoptic nasotracheal intubation in the patient with severe mouth opening difficulty undergoing wedge resection of the right upper lung: A case report and literature review.

BACKGROUND: Severe mouth opening difficulty may increase the risk of airway management during anesthesia induction, and awake fiberoptic nasotracheal intubation (AFNI) is the first option for patients with orofacial anatomical changes. CASE SUMMARY: A 54-year-old man was scheduled to undergo wedge resection of the right upper lung in August 2021. The patient had a history of enlarged right maxillary lesion resection and partial right maxillary resection surgery in April 2020, which led to orofacial anatomical changes and severe mouth opening difficulty. To avoid difficult airway-related emergency scenarios, the AFNI was successfully performed through intravenous injection of sufentanil and dexmedetomidine combined with lidocaine topical anesthesia under a conscious state without any uncomfortable feeling or complications. CONCLUSIONS: Intravenous injection of sufentanil and dexmedetomidine combined with lidocaine topical anesthesia can be used as an alternative medication scheme to relieve uncomfortable suffering for AFNI in patients with severe mouth opening difficulty.

Receptor for activated C kinase 1 mediates the chronic constriction injury-induced neuropathic pain in the rats' peripheral and central nervous system.

Peripheral and central sensitization has been reported as significant features in the course of the occurrence and development of neuropathic pain (NP). Receptor for activated C kinase 1 (RACK1), a scaffold protein, participated in fundamental cellular activities and various neuronal functions. Peripheral and central sensitization are a state that the morphology of neuronal cell bodies as well as the corresponding function change, whether this process can be regulated by RACK1 is still unknown. In this study, the biological effects and mechanisms of RACK1 contributes to the pathogenesis of chronic constriction injury (CCI)-induced neuropathic pain were investigated. By western blot and staining, we found that RACK1 protein changed in dorsal root ganglion (DRG) neurons and spinal cord (SC) neurons except glial cells after CCI. Especially, RACK1 was co-located with IB4-, CGRP-positive neurons, suggesting it was related to integrate nociceptive information from the primary aff ;erents in DRG. The successful establishment of CCI models also directly led to mechanical allodynia and heat hyperalgesia, which could be reversed by intrathecal injection of RACK1 siRNA. Furthermore, intrathecal injection of RACK1 siRNA reduced the expression of RACK1 and accompanying spinal c-fos, which is the transcription factor and marker of neuronal activation. These results suggested that targeting RACK1 be a sensible approach for treating NP.

Interleukin-1 Receptor Associated Kinase 1 Mediates the Maintenance of Neuropathic Pain after Chronic Constriction Injury in Rats.

Neuropathic pain (NP) has complicated pathogenesis as it mainly involves a lesion or dysfunction of the somatosensory nervous system and its clinical treatment remains challenging. Chronic constriction injury (CCI) model is a widely used neuropathic pain model and involved in mechanisms including both nerve inflammatory and injury. Cytokines and their receptors play essential roles in the occurrence and persistence of neuropathic pain, but the underlying mechanisms have not well been understood. Therefore, Interleukin-1 receptor-associated kinase 1 (IRAK1) is chosen to explore the possible mechanisms of NP. In the present study, IRAK1 was found to persistently increase in the dorsal root ganglion (DRG) and spinal cord (SC) during CCI detected by western blot. The staining further confirmed that IRAK1 was mainly co-located in the DRG astrocytes or SC neurons, but less in the DRG microglia or SC astrocytes. Moreover, the region of increased IRAK1 expression was observed in superficial laminae of the spinal dorsal horn, which was the nociceptive neuronal expression domain, suggesting that IRAK1 may mediated CCI-induced pain by nociceptive primary afferent. In addition, intrathecal injection of Toll-like receptor 4 (TLR4) inhibitor or IRAK1 siRNA decreased the expression of IRAK1 accompanied with the alleviation of CCI-induced neuropathic pain. The upregulation of p-NF-κB expression was reversed by IRAK1 siRNA in SC, and intrathecal injection of p-NF-κB inhibitor relieved neuropathic pain. Taking together, targeting IRAK1 may be a potential treatment for chronic neuropathic pain.

Chemokine CXCL10/CXCR3 signaling contributes to neuropathic pain in spinal cord and dorsal root ganglia after chronic constriction injury in rats.

Inflammatory cytokines and chemokines play essential roles in the occurrence and persistence of neuropathic pain (NP). Chronic constriction injury (CCI) enhances the activation of p-ERK, which is involved in neuropathic pain. Although the chemokine CXCL10 and its receptor CXCR3 are implicated in the pathophysiology of itch, it is largely unexplored for neuropathic pain. In this study, we determined the role of the CXCL10-CXCR3 axis in NP using a well-established CCI model. CCI significantly induced mechanical allodynia and thermal hyperalgesia. Following the pain course, a significant increase of CXCL10 and CXCR3 in both dorsal root ganglion (DRG) neurons and spinal cord (SC) neurons was detected in rats. Furthermore, intrathecal injection of CXCR3 inhibitor AMG487 was found to attenuate pain hypersensitivity in a dose-dependent manner in CCI. The expression of p-ERK was also depressed after intrathecal injection of AMG487 associated with a significant laxation of hyperalgesia, which demonstrated that the interaction of CXCL10/CXCR3 possibly took part in neuropathic pain by regulating p-ERK signaling in the SC. Overall, these findings demonstrate that the CXCL10/CXCR3 signaling pathway is critical in CCI.

Translocation Associated Membrane Protein 1 Contributes to Chronic Constriction Injury-Induced Neuropathic Pain in the Dorsal Root Ganglion and Spinal Cord in Rats.

Neuropathic pain is a severe debilitating state caused by injury or dysfunction of somatosensory nervous system, and the clinical treatment is still challenging. Translocation associated membrane protein 1 (TRAM1), an adapter protein, participates in a variety of transduction pathways and mediates the biological functions such as cell proliferation, activation, and differentiation. However, whether TRAM1 is involved in the pathogenesis of neuropathic pain is still unclear. In our study, we reported the role of TRAM1 in the maintenance of neuropathic pain induced by chronic constriction injury (CCI) on rats. By western blot and staining, we found that TRAM1 increased in the dorsal root ganglion (DRG) neurons and spinal cord (SC) neurons after CCI. Being similar to IB4-, CGRP-positive expressed area, TRAM1 also expressed in the superficial laminae of the spinal cord dorsal horn (SCDH), suggesting it was related to the innervations of the primary afferents. Moreover, intrathecal injection of TRAM1 siRNA or Toll-like receptor 4 (TLR4) inhibitor induced low expression of TRAM1 in SC, which alleviated the pain response induced by CCI. The upregulation of p-NF-κB expression was reversed by TRAM1 siRNA in SC and DRG, and intrathecal injection of p-NF-κB inhibitor relieved neuropathic pain. All the data indicated that TRAM1 could take part in CCI-induced pain and might be a potential treatment for chronic neuropathic pain.

TCF4 Mediates the Maintenance of Neuropathic Pain Through Wnt/ß-Catenin Signaling Following Peripheral Nerve Injury in Rats.

Neuropathic pain is elicited after a serious disorder of the nervous system and is along with the neural damage. It is usually chronic and challenging to treat. Transcription factor 4 (TCF4) is a key transcription factor of Wnt signaling system. Recent studies have shown that TCF4 interacts with ß-catenin in the Wnt signaling pathway and coactivates downstream target genes in diverse systems. However, it is not well elucidated in the pathogenesis of neuropathic pain. In the present study, we investigated the role of TCF4 in the maintenance of neuropathic pain after chronic constriction injury (CCI) in rats. CCI induced persistent TCF4 upregulation in the dorsal root ganglion and spinal cord. Interestingly, TCF4 was mainly colocalized with neurons in the injured dorsal root ganglion and spinal cord on CCI day 7. Moreover, the expression patterns of ß-catenin and glycogen synthase kinase-3ß (GSK-3ß) were parallel with that of TCF4 in vivo studies. Intrathecal injection of Wnt/ß-catenin pathway inhibitor IWR-1-endo and TCF4 small interfering RNA (siRNA) significantly attenuated CCI-induced mechanical allodynia and heat hyperalgesia. The results suggest that TCF4 in the dorsal root ganglion and spinal cord is involved in the maintenance of CCI-induced neuropathic pain. Targeting TCF4 or Wnt/ß-catenin signaling may be a potential treatment for chronic neuropathic pain.