Efficacy of remimazolam tosilate versus propofol for total intravenous anaesthesia in urological surgery: A randomised clinical trial.

BACKGROUND: Remimazolam is a novel ultra-short-acting benzodiazepine sedative that acts on the gamma-aminobutyric acid type A receptor (GABAAR). OBJECTIVE: To compare the efficacies of remimazolam (RMZ), and propofol (PROP) combined with remifentanil and cisatracurium for total intravenous anaesthesia (TIVA) in patients undergoing urological surgery. DESIGN: A prospective, single-blind, randomised, noninferiority clinical trial. SETTING: Single centre from 1 January 2022 to 30 March 2022. PATIENTS: A total of 146 adult patients undergoing elective urological surgery. INTERVENTION: Patients were randomly allocated in a 1 : 1 ratio to the PROP or RMZ groups. In the PROP group, anaesthesia was induced with propofol at 100 mg min -1 to reach a bispectral index score (BIS) of 40 to 60. After loss of consciousness (LOC), intravenous fentanyl 3 µg kg -1 was administered, followed by cisatracurium 0.3 mg kg -1 . Patients were intubated 3 min after cisatracurium administration. Anaesthesia was maintained with the combination of propofol (plasma concentration: 2.5 to 4 µg ml -1 ) and remifentanil (plasma concentration: 2.5 to 4 ng ml -1 ). In the RMZ group, anaesthesia was induced with remimazolam tosilate starting at 10 mg kg -1  h -1 to reach a BIS of 40 to 60 and maintained between 0.2 and 2 mg kg -1  h -1 . After LOC, fentanyl and cisatracurium were administered and intubation was performed as in the PROP group. Anaesthesia was maintained with a combination of remimazolam (0.2 to 2 mg kg -1  h -1 ) and remifentanil (plasma concentration: 2.5 to 4 ng ml -1 ). MAIN OUTCOME MEASURES: The primary outcome was the TIVA success rate. The predefined noninferiority margin considered an absolute difference of 6% in the primary outcome between the groups. The secondary outcomes were vital signs, anaesthesia and surgery characteristics, and adverse events. RESULTS: All patients completed the trial. The success rates of TIVA with remimazolam and propofol were 100 and 98.6%, respectively. The incidence of hypotension during anaesthesia was lower in the RMZ group (26%) than in the PROP group (46.6%) ( P  = 0.016). The median [IQR] total consumption of ephedrine during anaesthesia was higher in the PROP group 10 [0 to 12.5] mg than in the RMZ group 0 [0 to 10] mg ( P  = 0.0002). The incidence of injection pain was significantly higher in the PROP group (76.7%) than in the RMZ group (0; P  < 0.001). No significant differences in the controllability of the anaesthesia depth, anaesthesia and surgery characteristics, or vital signs were observed between the groups. CONCLUSION: Remimazolam demonstrated noninferior efficacy to propofol combined with remifentanil and cisatracurium for TIVA in patients undergoing urological surgery. TRIAL REGISTRATION: Chictr.org.cn, identifier: ChiCTR2100050923. CLINICAL REGISTRATION: The study was registered in the Chinese Clinical Trial Registry (ChiCTR2100050923, Principal investigator: Xuehai Guan, Date of registration: 8 November 2021, https://www.chictr.org.cn/showproj.html?proj=133466 ).

Cyclin D1 mediates pain behaviour in a rat model of breast cancer-induced bone pain by a mechanism involving regulation of the proliferation of spinal microglia.

AIMS: The involvement of cyclin D1 in the proliferation of microglia, and the generation and maintenance of bone cancer pain (BCP), have not yet been clarified. We investigated the expression of microglia and cyclin D1, and the influences of cyclin D1 on pain threshold. METHODS: Female Sprague Dawley (SD) rats were used to establish a rat model of BCP, and the messenger RNA (mRNA) and protein expression of ionized calcium binding adaptor molecule 1 (IBA1) and cyclin D1 were detected by reverse transcription-polymerase chain reaction (RT-PCR) and western blot, respectively. The proliferation of spinal microglia was detected by immunohistochemistry. The pain behaviour test was assessed by quantification of spontaneous flinches, limb use, and guarding during forced ambulation, mechanical paw withdrawal threshold, and thermal paw withdrawal latency. RESULTS: IBA1 and cyclin D1 in the ipsilateral spinal horn increased in a time-dependent fashion. Spinal microglia proliferated in BCP rats. The microglia inhibitor minocycline attenuated the pain behaviour in BCP rats. The cyclin-dependent kinase inhibitor flavopiridol inhibited the proliferation of spinal microglia, and was associated with an improvement in pain behaviour in BCP rats. CONCLUSION: Our results revealed that the inhibition of spinal microglial proliferation was associated with a decrease in pain behaviour in a rat model of BCP. Cyclin D1 acts as a key regulator of the proliferation of spinal microglia in a rat model of BCP. Disruption of cyclin D1, the restriction-point control of cell cycle, inhibited the proliferation of microglia and attenuated the pain behaviours in BCP rats. Cyclin D1 and the proliferation of spinal microglia may be potential targets for the clinical treatment of BCP.Cite this article: Bone Joint Res 2022;11(11):803-813.

Efficacy of Pre-Treatment with Remimazolam on Prevention of Propofol-Induced Injection Pain in Patients Undergoing Abortion or Curettage: A Prospective, Double-Blinded, Randomized and Placebo-Controlled Clinical Trial.

BACKGROUND: Propofol-induced injection pain (PIP) is a well-known problem in general anesthesia. We hypothesized that pre-treatment with remimazolam prevents PIP in patients undergoing abortion or curettage. MATERIALS AND METHODS: In this prospective, single-center, double-blinded, randomized, placebo-controlled clinical trial, adult patients aged 18 to 60 undergoing abortion or curettage were randomly assigned to three groups. Group Lido received system lidocaine (a bolus of 0.5 mg kg-1, iv). Group Remi received remimazolam (a bolus of 0.1 mg kg-1, iv). Group NS received identical volumes of 0.9% normal saline. Sixty seconds after the injection of lidocaine, remimazolam or saline, patients were injected with propofol at a rate of 12 mL/min until the loss of consciousness. The primary outcome was the incidence of PIP at the time of induction using 4-point scale. Secondary outcomes included propofol-induced injection pain, vital signs, the characteristics of anesthesia and surgery, and adverse events. RESULTS: The incidence of patients with PIP was higher in group NS than that in group Lido and group Remi (75.7, 44.3, and 42.9%, respectively, p < 0.001). The percentages of patients with moderate PIP were higher in group NS than that in group Lido and group Remi (20.0, 2.9, and 1.4%, respectively, p < 0.001). Moreover, the consumption of propofol and the incidence of adverse event (hypoxemia and chin lifting) in group Remi were lower than that in group NS and Lido, and less patients got physical movement and cough in group Remi. The recovery time in group NS was longer than that in group Lido and Remi. CONCLUSION: Our findings indicate that pre-treatment with remimazolam reduced the incidence and intensity of PIP in abortion or curettage patients, equivalent to that of lidocaine without severe adverse effects. TRIAL REGISTRATION: Chinese Clinical Trial Registry (identifier: ChiCTR2100041805).

Role of Spinal Cord Akt-mTOR Signaling Pathways in Postoperative Hyperalgesia Induced by Plantar Incision in Mice.

Poor postoperative pain (POP) control increases perioperative morbidity, prolongs hospitalization days, and causes chronic pain. However, the specific mechanism(s) underlying POP is unclear and the identification of optimal perioperative treatment remains elusive. Akt and mammalian target of rapamycin (mTOR) are expressed in the spinal cord, dorsal root ganglion, and sensory axons. In this study, we explored the role of Akt and mTOR in pain-related behaviors induced by plantar incision in mice. Plantar incision activated spinal Akt and mTOR in a dose-dependent manner. Pre-treatment with Akt inhibitors intrathecally prevented the activation of mTOR dose-dependently. In addition, blocking the Akt-mTOR signaling cascade attenuated pain-related behaviors and spinal Fos protein expression induced by plantar incision. Our observations demonstrate that Akt-mTOR might be a potential therapeutic target for the treatment of POP.