Yoshiki Nakajima

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Background: The pharmacokinetics of prolonged remimazolam infusion in patients undergoing long-term mechanical ventilation remain unclear. This study aimed to evaluate the pharmacokinetics of remimazolam administered continuously for 24 h. Methods: This open-label pharmacokinetic analysis enrolled patients requiring mechanical ventilation into two groups: the surgical group, which received remimazolam during and after surgery, and the medical ICU group, which received remimazolam in the intensive care unit (ICU). Remimazolam was administered at a fixed rate of 0.1 mg/kg/h for ≥ 24 h, and blood samples were collected at regular intervals. Plasma remimazolam concentrations were measured by tandem mass spectrometry. Results: Twenty patients (10 in each group) completed the study. The median duration of remimazolam infusion was 24.0 h in the surgical group and 102.0 h in the medical ICU group. The steady-state plasma concentrations in both the surgical and medical ICU groups exhibited modest intrasubject variability (4.46–32.73%) and moderate intersubject variability (16.45–31.71%), with all values falling within clinically acceptable intermediate ranges. The plasma remimazolam concentration at the end of infusion was 130.7 ng/mL (95% confidence interval [CI] 115.2–146.1) in the surgical group and 134.3 ng/mL (95% CI 98.7–170.0) in the medical ICU group. Noncompartmental analysis showed that the clearance was 54.3 L/h (95% CI 47.6–61.8) and 55.6 L/h (95% CI 42.8–72.1) ( P = 0.856), while the volume of distribution at steady state was 284 L (95% CI 215–376) and 316 L (95% CI 142–707) ( P = 0.780), with no statistically significant differences between the groups. Conclusions: In this preliminary study, both the surgical ICU group (approximately 24 h) and the medical ICU group (beyond 24 h) showed no evidence of time-dependent accumulation of plasma remimazolam, indicating a generally stable pharmacokinetic profile under the examined conditions. Trial registration : In compliance with the Japanese Clinical Trials Act, the study was classified as a Specified Clinical Trial owing to the use of unapproved pharmaceuticals, which were reviewed by a certified review board (CRB) and registered in the Japan Registry of Clinical Trials (jRCTs041200076) on December 15, 2020.

Background The lactate albumin ratio (LAR), a simple prognostic marker used in intensive care units (ICUs), combines lactate and serum albumin levels to predict patient outcomes. Despite its potential, the predictive accuracy of the LAR remains insufficiently explored. This study aimed to assess the usefulness of the LAR in predicting mortality among patients in the ICU. Methods This retrospective study conducted a secondary analysis of prospectively obtained clinical data from the Japanese Intensive Care Patient Database. We included all patients admitted to ICUs between 2015 and 2021, excluding those under the age of 16 years. The main outcome was in-hospital mortality. The LAR predictive value for this outcome was assessed by examining the area under the receiver operating characteristic curve and comparing it against prognostic indicators such as age, lactate, albumin and Sequential Organ Failure Assessment score. LAR shape was assessed using unrestricted spline curves, and the optimal cut-off value was identified from sensitivity and negative likelihood ratio. Subgroup analysis was used to evaluate the predictive accuracy of the LAR across different patient attributes and clinical scenarios. Results Of 2 34 774 cases analysed, in-hospital mortality was 8.8% (20 723 deaths). The LAR had an area under the curve of 0.761 (95%CI 0.757 to 0.765), indicating a fair predictive performance for in-hospital mortality. Unrestricted spline curves demonstrated that LAR can predict mortality through a monotonic positive dose–response relationship with 0.4 as the optimal cut-off value. In subgroup analysis, areas under the curve were significantly higher in subgroups defined by younger age, female sex, unplanned ICU admission, non-surgical patients, non-infectious patients, non-heart failure patients and lack of end-stage renal disease. Conclusions The LAR might be a useful predictor for screening mortality in ICU patients. However, further research to establish appropriate cut-off values for the LAR and identify the optimal target population is warranted.

Endocannabinoid 2-arachidonoylglycerol (2-AG) has been implicated in habituation to stress, and its augmentation reduces stress-induced anxiety-like behavior. Chronic restraint stress (CRS) changes the 2-AG levels in some gross brain areas, such as the forebrain. However, the detailed spatial distribution of 2-AG and its changes by CRS in stress processing-related anatomical structures such as the anterior cingulate cortex (ACC), caudate putamen (CP), nucleus accumbens (NAc), and piriform cortex (PIR) are still unclear. In this study, mice were restrained for 30 min in a 50 mL-centrifuge tube for eight consecutive days, followed by imaging of the coronal brain sections of control and stressed mice using desorption electrospray ionization mass spectrometry imaging (DESI-MSI). The results showed that from the forebrain to the cerebellum, 2-AG levels were highest in the hypothalamus and lowest in the hippocampal region. 2-AG levels were significantly (p < 0.05) upregulated and 2-AG precursors levels were significantly (p < 0.05) downregulated in the ACC, CP, NAc, and PIR of stressed mice compared with control mice. This study provided direct evidence of 2-AG expression and changes, suggesting that 2-AG levels are increased in the ACC CP, NAc, and PIR when individuals are under chronic stress.

In adults, high-dose remifentanil during surgery has been reported to increase postoperative opioid consumption, but this has not been well documented in children. Multimodal analgesia is recommended in the perioperative period for adolescent idiopathic scoliosis (AIS), but no report has examined opioid consumption under epidural analgesia, which is one of the most common types of analgesia. To investigate the association between intraoperative remifentanil dosage and postoperative opioid consumption in AIS in the setting of combined epidural analgesia for postoperative multimodal analgesia. In this retrospective cohort study, patients aged 10-18 years who underwent surgery for scoliosis and epidural analgesia for postoperative pain between July 2012 and April 2019 were included. The primary endpoint was the association between intraoperative cumulative weight-adjusted remifentanil dosage and logarithmic transformation of cumulative weight-adjusted fentanyl consumption in the intensive care unit (ICU). Nonopioid analgesics were investigated as secondary endpoints. An epidural catheter was inserted by the surgeon intraoperatively, and a local anesthetic was administered at the end of the surgery. Multivariate linear regression analysis with adjustment for confounders was performed for all analyses. In total, 142 patients were included, and the median intraoperative remifentanil dosage for all patients was 0.27 (interquartile range, 0.24-0.34) µg/kg/min. No association was observed between cumulative weight-adjusted intraoperative dosage of remifentanil and fentanyl, even after adjusting for potential confounders (slope = −1.25; 95% confidence interval [CI], −4.35 to 1.85; P = 0.43). No association was observed between nonopioid analgesic use and intraoperative remifentanil dosage. No association was noted between remifentanil dosage during surgery for AIS and postoperative opioid consumption with epidural analgesia. However, this study has limitations due to its retrospective design; thus, further prospective studies are warranted.