Ketamine metabolism via hepatic CYP450 isoforms contributes to its sustained antidepressant actions.

(R,S)-ketamine (ketamine) has rapid and sustained antidepressant (AD) efficacy at sub-anesthetic doses in depressed patients. A metabolite of ketamine, including (2R,6R)-hydroxynorketamine ((6)-HNKs) has been reported to exert antidepressant actions in rodent model of anxiety/depression. To further understand the specific role of ketamine's metabolism in the AD actions of the drug, we evaluated the effects of inhibiting hepatic cytochrome P450 enzymes on AD responses. We assessed whether pre-treatment with fluconazole (10 and 20 mg/kg, i.p.) 1 hour prior to ketamine or HNKs (10 mg/kg, i.p.) administration would alter behavioral and neurochemical actions of the drugs in male BALB/cJ mice with a highly anxious phenotype. Extracellular microdialysate levels of glutamate and GABA (Gluext, GABAext) were also measured in the medial prefrontal cortex (mPFC). Pre-treatment with fluconazole altered the pharmacokinetic profile of ketamine, by increasing both plasma and brain levels of ketamine and (R,S)-norketamine, while robustly reducing those of (6)-HNKs. At 24 hours post-injection (t24h), fluconazole prevented the sustained AD-like response of ketamine responses in the forced swim test and splash test, as well as the enhanced cortical GABA levels produced by ketamine. A single (2R,6R)-HNK administration resulted in prevention of the effects of fluconazole on the antidepressant-like activity of ketamine in mice. Overall, these findings are consistent with an essential contribution of (6)-HNK to the sustained antidepressant-like effects of ketamine and suggest potential interactions between pharmacological CYPIs and ketamine during antidepressant treatment in patients.

The influence of low-dose s-ketamine on postoperative delirium and cognitive function in older adults undergoing thoracic surgery.

BACKGROUND: Postoperative delirium (POD) and cognitive dysfunction (POCD) are common complications following thoracic surgery, particularly in patients aged 65 years and above. These complications can significantly affect recovery and increase healthcare costs. This study investigates the effects of low-dose S-ketamine on reducing POD and POCD in this patient demographic. METHODS: In this retrospective cohort study, medical records of patients aged ≥ 65 years who underwent elective thoracic surgery from January 2019 to August 2023 were reviewed. Patients were categorized into S-ketamine and Control groups based on intraoperative S-ketamine exposure. POD was assessed using the Confusion Assessment Method (CAM), while cognitive function was evaluated using the Montreal Cognitive Assessment (MoCA) at baseline, 1 week, 1 month, and 6 months post-surgery. Intraoperative and postoperative parameters, including hemodynamic stability, blood loss, pain scores, and ICU stay length, were also recorded. RESULTS: The study comprised 140 participants, with 70 in each group. The S-ketamine group demonstrated a significantly lower incidence of POD at 7 days post-surgery (12.0% vs. 26.7%, P < 0.001), and reduced POCD at 1 month (18.7% vs. 36.0%, P < 0.05) and 6 months (10.7% vs. 21.3%, P < 0.05). The Ketamine group had a significantly higher median MoCA score compared to the Control group both at 1 month (P = 0.021) and 6 months (P = 0.007). Adverse events, such as infection, bleeding, and respiratory failure, showed no significant differences between the groups, suggesting a safe profile for S-ketamine. CONCLUSION: Administering low-dose S-ketamine during thoracic surgery in patients aged 65 years and above significantly reduces the incidence of POD and POCD, highlighting its neuroprotective potential. These findings advocate for the inclusion of S-ketamine in anesthetic protocols to improve postoperative outcomes and reduce healthcare costs in this patient population.

Perioperative esketamine administration for prevention of postpartum depression after the cesarean section: A systematic review and meta-analysis.

BACKGROUND: Postpartum Depression (PPD) exerts a substantial negative effect on maternal well-being post-delivery, particularly among Cesarean Section (C/S) recipients. In this study, we aimed to review the efficacy of perioperative esketamine, the S-enantiomer of ketamine, in preventing PPD incidence and depressive symptoms as measured with the Edinburgh Postnatal Depression Scale (EPDS) after C/S. METHODS: A systematic search for relevant articles was conducted in Scopus, PubMed, Web of Sciences, and PsycINFO until April 6, 2024. Meta-analyses were conducted using random-effect models to compare the PPD incidence and EPDS scores via log odds ratio and Hedge's g, respectively, during the first week post-C/S and at 42 days post-C/S in the esketamine and control group. RESULTS: Fourteen studies, including 12 randomized controlled trials and 2 retrospective cohorts, were reviewed. Our meta-analyses found lower PPD incidence during the first week (log odds ratio: -0.956 [95 % confidence interval: -1.420, -0.491]) and at day 42 post-C/S (log odds ratio: -0.989 [95 % confidence interval: -1.707, -0.272]) among patients administered esketamine compared to controls. Additionally, EPDS scores for the esketamine group were significantly lower than controls during the first week (Hedge's g: -0.682 [95 % confidence interval: -1.088, -0.276]) and at day 42 post-C/S (Hedge's g: -0.614 [95 % confidence interval: -1.098, -0.129]). LIMITATIONS: Presence of various concomitant medications and heterogeneous study designs. CONCLUSION: Our review highlights the potential impact of esketamine in PPD prevention, as well as in alleviating depressive symptoms post-C/S, regardless of PPD occurrence, therefore suggesting the benefits of adding esketamine to peri-C/S analgesic regimen.

Subanesthetic S-ketamine does not acutely alter striatal dopamine transporter binding in healthy Sprague Dawley female rats.

Major depressive disorder is one of the most prevalent mental health disorders, posing a global socioeconomic burden. Conventional antidepressant treatments have a slow onset of action, and 30% of patients show no clinically significant treatment response. The recently approved fast-acting antidepressant S-ketamine, an N-methyl-D-aspartate receptor antagonist, provides a new approach for treatment-resistant patients. However, knowledge of S-ketamine's mechanism of action is still being established. Depressed human subjects have lower striatal dopamine transporter (DAT) availability compared to healthy controls. Rodent studies report increased striatal dopamine concentration in response to acute ketamine administration. In vivo [18F]FE-PE2I ([18F]-(E)-N-(3-iodoprop-2-enyl)-2ß-carbofluoroethoxy-3ß-(4'-methyl-phenyl) nortropane) positron emission tomography (PET) imaging of the DAT has not previously been applied to assess the effect of acute subanesthetic S-ketamine administration on DAT availability. We applied translational in vivo [18F]FE-PE2I PET imaging of the DAT in healthy female rats to evaluate whether an acute subanesthetic intraperitoneal dose of 15 mg/kg S-ketamine alters DAT availability. We also performed [3H]GBR-12935 autoradiography on postmortem brain sections. We found no effect of acute S-ketamine administration on striatal DAT binding using [18F]FE-PE2I PET or [3H]GBR-12935 autoradiography. This negative result does not support the hypothesis that DAT changes are associated with S-ketamine's rapid antidepressant effects, but additional studies are warranted.

Perioperative Ketamine and Cancer Recurrence: A Comprehensive Review.

Cancer is a significant global health threat and a leading cause of death worldwide. Effective early-stage interventions, particularly surgery, can potentially cure many solid tumors. However, the risk of postoperative cancer recurrence remains high. Recent research highlights the influence of perioperative anesthetic and analgesic choices on the fate of residual cancer cells, potentially affecting recurrence risks. Among these agents, ketamine-a well-known anesthetic and analgesic-has garnered interest due to its antitumor properties, mainly through inhibiting the N-methyl-D-aspartate (NMDA) receptor found in various cancer tissues. Additionally, ketamine's potential immunomodulatory effects, given the expression of NMDA receptors on immune cells, suggest that it plays a significant role during the perioperative period. This review synthesizes current evidence on ketamine's impact on cancer cell biology, inflammation, immune modulation, and the role of the gut microbiota, proposing ketamine as a promising agent for enhancing oncological outcomes.

The effect of low dose intra-articular S(+) ketamine on osteoarthritis in rats: an experimental study.

BACKGROUND: This study aimed to investigate the analgesic impact of S(+)-ketamine on pain behavior and synovial inflammation in an osteoarthritis (OA) model. METHODS: Animals were grouped as follows: OA-Saline (n = 24) and OA-Ketamine (n = 24), OA induced via intra-articular sodium monoiodoacetate (MIA); a Non-OA group (n = 24) served as the control. On the 7th day post OA induction, animals received either saline or S(+)-ketamine (0.5 mg.kg-1). Behavioral and histopathological assessments were conducted up to day 28. RESULTS: S(+)-ketamine reduced allodynia from day 7 to 28 and hyperalgesia from day 10 to 28. It notably alleviated weight distribution deficits from day 10 until the end of the study. Significant walking improvement was observed on day 14 in S(+)-ketamine-treated rats. Starting on day 14, OA groups showed grip force decline, which was countered by S(+)-ketamine on day 21. However, S(+)-ketamine did not diminish synovial inflammation. CONCLUSION: Low Intra-articular (IA) doses of S(+)-ketamine reduced MIA-induced OA pain but did not reverse synovial histopathological changes. IRB APPROVAL NUMBER: 23115 012030/2009-05.

Effect of S-Ketamine on Postoperative Nausea and Vomiting in Patients Undergoing Video-Assisted Thoracic Surgery: A Randomized Controlled Trial.

Purpose: Postoperative nausea and vomiting (PONV) frequently occur in patients after surgery. In this study, the authors investigated whether perioperative S-ketamine infusion could decrease the incidence of PONV in patients undergoing video-assisted thoracoscopic surgery (VATS) lobectomy. Patients and Methods: This prospective, randomized, double-blinded, controlled study was conducted a total of 420 patients from September 2021 to May 2023 at Xuzhou Central Hospital in China, who underwent elective VATS lobectomy under general anesthesia with tracheal intubation. The patients were randomly assigned to either the S-ketamine group or the control group. The S-ketamine group received a bolus injection of 0.5 mg/kg S-ketamine and an intraoperative continuous infusion of S-ketamine at a rate of 0.25 mg/kg/h. The control group received an equivalent volume of saline. All patients were equipped with patient-controlled intravenous analgesia (PCIA), with a continuous infusion rate of 0.03 mg/kg/h S-ketamine in the S-ketamine group or 0.03 µg/kg/h sufentanil in the control group. The primary outcome was the incidence of PONV. Secondary outcomes included perioperative opioid consumption, hemodynamics, postoperative pain, and adverse events. Results: The incidence of PONV in the S-ketamine group (9.7%) was significantly lower than in the control group (30.5%). Analysis of perioperative opioid usage revealed that remifentanil usage was 40.0% lower in the S-ketamine group compared to the control group (1414.8 µg vs 2358.2 µg), while sufentanil consumption was 75.2% lower (33.1 µg vs 133.6 µg). The S-ketamine group demonstrated better maintenance of hemodynamic stability. Additionally, the visual analogue scale (VAS) scores on postoperative day 1 (POD-1) and postoperative day 3 (POD-3) were significantly lower in the S-ketamine group. Finally, no statistically significant difference in other postoperative adverse reactions was observed between the two groups. Conclusion: The results of this trial indicate that perioperative S-ketamine infusion can effectively reduce the incidence of PONV in patients undergoing VATS lobectomy.

Effects of esketamine on postoperative negative emotions and early cognitive disorders in patients undergoing non-cardiac thoracic surgery: A randomized controlled trial.

STUDY OBJECTIVE: To investigate whether a single dosage of esketamine injection in the anesthesia period could improve postoperative negative emotions and early cognitive function in patients undergoing non-cardiac thoracic surgery. DESIGN: A prospective single center double blinded randomized placebo-controlled trial. SETTING: Perioperative period; operating room, post anesthesia care unit and hospital ward. PATIENTS: 129 adult patients that underwent elective non-cardiac thoracic surgery under general anesthesia. INTERVENTIONS: During the operation, pharmacologic prevention of postoperative negative emotion and early cognitive disorder with 0.2 mg/kg (Low esketamine group) and 0.5 mg/kg esketamine (High esketamine group) vs. placebo. MEASUREMENTS: Emotion and early cognitive performance were assessed on the day before surgery (POD-1), postoperative day 1 (POD1) and day 3 (POD3) using HADS-A, HADS-D, Pain Visual Analogue Scale (VAS), Confusion Assessment Method (CAM), Mini-Mental State Examination (MMSE), and serum biomarkers (S100ß, BDNF, IL-6, acetylcholine, and norepinephrine). MAIN RESULTS: The high esketamine group showed significantly lower HADS-A and HADS-D scores than control group on POD1 and POD3. No significant differences were observed between the low esketamine group and the control group. The esketamine-treated groups showed lower pain VAS scores than the control group at 2 h and on the first day after operation. There were no significant differences among the three groups in CAM and MMSE scores. However, the high esketamine group had lower S100ß and IL-6 levels, and higher BDNF levels postoperatively, while serum acetylcholine and norepinephrine were not significantly different. CONCLUSIONS: A single intraoperative injection of 0.5 mg/kg esketamine can alleviate postoperative anxiety, depression, and pain to some extent. Although cognitive function behavioral evaluation did not show obvious benefits, it can also reduce the production of pro-inflammatory and brain injury-related factors while promoting the generation of brain-derived neurotrophic factor. Registration Trial registry: http://www.chictr.org.cn/; Identifier: ChiCTR2100047067.

Intravenous S-ketamine's analgesic efficacy in third molar surgery. A randomized placebo-controlled double-blind clinical trial.

Background: In most cases, a combination of paracetamol and ibuprofen are the optimal treatment for postoperative pain in third molar surgery. If stronger analgesia is required, opioids are traditionally administered. In day-case, surgery; however, opioids should be avoided. Thus, the anaesthetic agent S-ketamine in analgesic doses might be preferred. Methods: The study was designed as a randomized placebo-controlled double-blind clinical trial. The study enrolled healthy subjects according to the American Society of Anaesthesiologists classification; I or II (ASA), aged 18 to 44 years, with a body weight between 50 and 100 kg. The patients were randomized into three groups where two doses of S-ketamine were compared (high: 0.25 mg/kg or low: 0.125 mg/kg) with placebo (saline). Results: A primary outcome of the study was that VAS at 4 h postoperatively, showed no significant difference between the placebo and high-dose S-ketamine group or in the low-dose group. We found a significant difference between the groups for the first 24 h, with a lower VAS-score in the high-dose S-ketamine group. The time to when 50% had taken their first rescue medication was 12 min later in the high-dose ketamine group. Conclusions: Pre-emptive S-ketamine 0.25 mg/kg gave a global significant reduction of pain by VAS during the first 24 h postoperatively. The time from end of surgery to first rescue medication were longer in the high-dose ketamine group compared to both low-dose ketamine and placebo groups.

Positive effects of low-dose S-ketamine on preventing myocardial injury after thoracoscopic lobectomy in patients aged 70 to 85.

OBJECTIVE: To investigate the effects of low-dose S-ketamine on marker of myocardial injury (BNP, hs-cTnT and HFABP) after thoracoscopic lobectomy in patients aged 70 to 85. METHODS: One hundred patients (four cases excluded) aged 70-85 years, with body mass index 18-24 kg·m-2 and American Society of Anesthesiologists physical status II-III, scheduled for elective lobectomy from April 2022 to April 2023, were selected. The patients were divided into two groups by a random number table method, namely, the low-dose S-ketamine combined with GDFT group (group S) and the control group (group C), with 48 cases in each group. In group S, a low dose of S-ketamine (0.2 mg/kg) was given 1 min before intubation, and the maintenance dose was 0.12 mg·kg-1·h-1. Fluid therapy, guided by cardiac index (CI), changes in stroke volume (△SV), and other dynamic indicators, was used for rehydration during the operation. Group C was given the same amount of normal saline (0.2 mg/kg) 1 min before intubation, and the same rehydration therapy was adopted during the operation. The mean arterial pressure (MAP) and heart rate (HR) of the two groups were observed and recorded immediately after entering the operating room (T0), immediately after intubation (T1), immediately after the beginning of one-lung ventilation (OLV) (T2), immediately after the beginning of surgery (T3), immediately after the end of OLV (T4), and at the end of surgery (T5). The intraoperative fluid intake and output and the use of vasoactive drugs were recorded. The plasma levels of heart-type fatty acid-binding protein (HFABP), high-sensitivity troponin T (hs-cTnT), brain natriuretic peptide (BNP), interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor-α (TNF-α) were recorded 24 h before operation and 24 and 48 h after operation. Visual analogue scale (VAS) pain scores at rest were recorded at 2 (V1), 6 (V2), 12 (V3), 24 (V4), and 48 h (V5) after operation, and the occurrence of myocardial ischemia during hospitalization was noted. RESULTS: Compared with group C, MAP was significantly higher at T1-T5 in group S (P < 0.05), and the plasma concentrations of IL-6, IL-8, TNF-α, BNP, hs-cTnT, and HFABP were significantly lower at 24 and 48 h after operation (P < 0.05). The VAS pain scores at 2, 6, 12, 24, and 48 h after operation, the number of effective patient-controlled intravenous analgesia (PCIA) compressions, and the total number of PCIA compressions within 48 h after operation were significantly decreased (P < 0.05). Compared with group C, The hospitalization days, and the incidence of postoperative myocardial ischemia in group S were lower (P < 0.05). There were no significant intergroup differences in urine volume, extubation time, the incidence of postoperative atrial fibrillation, bleeding volume, colloid infusion volume, total fluid infusion volume, and the incidence of rescue analgesia. CONCLUSIONS: Low-dose S-ketamine can reduce the levels of hs-cTnT, HFABP, and BNP in older patients after pulmonary lobectomy, which has a positive effect on preventing myocardial injury. TRIAL REGISTRATION: This study was registered on CHICTR (registration No. ChiCTR2300074475). Date of registration: 08/08/2023.

Repeated (S)-ketamine administration ameliorates the spatial working memory impairment in mice with chronic pain: role of the gut microbiota-brain axis.

Chronic pain is commonly linked with diminished working memory. This study explores the impact of the anesthetic (S)-ketamine on spatial working memory in a chronic constriction injury (CCI) mouse model, focusing on gut microbiome. We found that multiple doses of (S)-ketamine, unlike a single dose, counteracted the reduced spontaneous alteration percentage (%SA) in the Y-maze spatial working memory test, without affecting mechanical or thermal pain sensitivity. Additionally, repeated (S)-ketamine treatments improved the abnormal composition of the gut microbiome (ß-diversity), as indicated by fecal 16S rRNA analysis, and increased levels of butyrate, a key gut - brain axis mediator. Protein analysis showed that these treatments also corrected the upregulated histone deacetylase 2 (HDAC2) and downregulated brain-derived neurotrophic factor (BDNF) in the hippocampi of CCI mice. Remarkably, fecal microbiota transplantation from mice treated repeatedly with (S)-ketamine to CCI mice restored %SA and hippocampal BDNF levels in CCI mice. Butyrate supplementation alone also improved %SA, BDNF, and HDAC2 levels in CCI mice. Furthermore, the TrkB receptor antagonist ANA-12 negated the beneficial effects of repeated (S)-ketamine on spatial working memory impairment in CCI mice. These results indicate that repeated (S)-ketamine administration ameliorates spatial working memory impairment in CCI mice, mediated by a gut microbiota - brain axis, primarily through the enhancement of hippocampal BDNF - TrkB signaling by butyrate.

Effects of small-dose S-ketamine on anesthesia-induced atelectasis in patients undergoing general anesthesia accessed by lung ultrasound: study protocol for a randomized, double-blinded controlled trial.

BACKGROUND: Atelectasis after anesthesia induction in most patients undergoing general anesthesia may lead to postoperative pulmonary complications (PPCs) and affect postoperative outcomes. However, there is still no existing effective method used for the prevention of perioperative atelectasis. S-ketamine may prevent atelectasis due to airway smooth muscle relaxation and anti-inflammatory effects. Lung ultrasound is a portable and reliable bedside imaging technology for diagnosing anesthesia-induced atelectasis. The primary objective of this study is to assess whether a small dose of S-ketamine can reduce the incidence of atelectasis after intubation, and further investigate the effects of preventing the early formation of perioperative atelectasis and PPCs. METHODS: This is a single-institution, prospective, randomized controlled, parallel grouping, and double-blind study. From October 2020 to March 2022, 100 patients (18-60 years old) scheduled for elective surgery will be recruited from Beijing Tiantan Hospital, Capital Medical University, and randomly assigned to the S-ketamine group (group 1) and the normal saline group (group 2) at a ratio of 1:1. The label-masked agents will be administered 5 min before induction, and all patients will undergo a standardized general anesthesia protocol. Related data will be collected at three time points: after radial artery puncture (T1), 15 min after tracheal intubation (T2), and before extubation (T3). The primary outcome will be the total lung ultrasound scores (LUS) at T2. Secondary outcomes will include LUS in six chest regions at T2, total LUS at T3, arterial blood gas analysis results (PaCO2, PaO2) and PaO2/FiO2 at T2 and T3, and plateau pressure (Pplat) and dynamic lung compliance (Cdyn) at T2 and T3. The incidence of postoperative complications associated with S-ketamine and PPCs at 2 h and 24 h after surgery will be recorded. DISCUSSION: This trial aims to explore whether a simple and feasible application of S-ketamine before the induction of general anesthesia can prevent atelectasis. The results of this study may provide new ideas and direct clinical evidence for the prevention and treatment of perioperative pulmonary complications during anesthesia. TRIAL REGISTRATION: ClinicalTrials.gov NCT04745286. Registered on February 9, 2021.

Traumatic Brain Injury-Induced Fear Generalization in Mice Involves Hippocampal Memory Trace Dysfunction and Is Alleviated by (R,S)-Ketamine.

BACKGROUND: Traumatic brain injury (TBI) is a debilitating neurological disorder caused by an impact to the head by an outside force. TBI results in persistent cognitive impairments, including fear generalization and the inability to distinguish between aversive and neutral stimuli. The mechanisms underlying fear generalization have not been fully elucidated, and there are no targeted therapeutics to alleviate this symptom of TBI. METHODS: To identify the neural ensembles mediating fear generalization, we utilized ArcCreERT2 × enhanced yellow fluorescent protein (EYFP) mice, which allow for activity-dependent labeling and quantification of memory traces. Mice were administered a sham surgery or the controlled cortical impact model of TBI. Mice were then administered a contextual fear discrimination paradigm and memory traces were quantified in numerous brain regions. In a separate group of mice, we tested if (R,S)-ketamine could decrease fear generalization and alter the corresponding memory traces in TBI mice. RESULTS: TBI mice exhibited increased fear generalization when compared with sham mice. This behavioral phenotype was paralleled by altered memory traces in the dentate gyrus, CA3, and amygdala, but not by alterations in inflammation or sleep. In TBI mice, (R,S)-ketamine facilitated fear discrimination, and this behavioral improvement was reflected in dentate gyrus memory trace activity. CONCLUSIONS: These data show that TBI induces fear generalization by altering fear memory traces and that this deficit can be improved with a single injection of (R,S)-ketamine. This work enhances our understanding of the neural basis of TBI-induced fear generalization and reveals potential therapeutic avenues for alleviating this symptom.

Effects of S-ketamine added to patient-controlled analgesia on early postoperative pain and recovery in patients undergoing thoracoscopic lung surgery: A randomized double-blinded controlled trial.

STUDY OBJECTIVE: To investigate whether the addition of S-ketamine to patient-controlled hydromorphone analgesia decreases postoperative moderate-to-severe pain and improves the quality of recovery (QoR) in patients undergoing thoracoscopic lung surgery. DESIGN: Single-center prospective randomized double-blinded controlled trial. SETTING: Tertiary university hospital. PATIENTS: 242 patients undergoing thoracoscopic lung surgery. INTERVENTIONS: Patients were randomized to receive intravenous patient-controlled analgesia (IV-PCA) with hydromorphone alone or hydromorphone combined with S-ketamine (0.5 mg/kg/48 h, 1 mg/kg/48 h, or 2 mg/kg/48 h). MEASUREMENTS: Primary outcome was proportion of patients with moderate-to-severe pain. (numerical rating scale [NRS] pain scores ≥4 when coughing) within 2 days after surgery. Postoperative QoR scores and other prespecified outcomes were also recorded. MAIN RESULTS: Of 242 enrolled patients, 220 were included in the final analysis. The results demonstrated that the incidence of postoperative moderate-to-severe pain was significantly different between the hydromorphone group and combined S-ketamine group (absolute difference, 27.9%; 95% confidence interval [CI], 11.7% to 42.1%; P < 0.001). Patients who received S-ketamine had lower NRS pain scores at rest and when coughing on postoperative day 1 (POD1; median difference 1 and 1, P < 0.001) and postoperative day 2 (POD2; median difference 1 and 1, P < 0.001). The QoR-15 scores were higher in the combined S-ketamine group on POD1 (mean difference 6, P < 0.001) and POD2 (mean difference 6, P < 0.001) than in the hydromorphone group. A higher dose of S-ketamine was associated with deeper sedation. No differences were detected in the other safety outcomes. CONCLUSIONS: Addition of S-ketamine to IV-PCA hydromorphone significantly reduced the incidence of postoperative moderate-to-severe pain and improved the QoR in patients undergoing thoracoscopic lung surgery. TRIAL REGISTRATION: Chinese Clinical Trail Register (identifier: ChiCTR2200058890).

Analgesic Effect of Intraoperative Intravenous S(+)-Ketamine During Total Knee Arthroplasty Surgery: Study Protocol for a Randomized Controlled Clinical Trial.

BACKGROUND: Total knee arthroplasty (TKA) is currently the main treatment for end-stage knee disease. The number of cases of TKA in China increased from 53,880 in 2011 to 374,833 in 2019, representing a 5.9-fold increase. Moderate to severe pain often occurs after TKA, which seriously affects postoperative rehabilitation, patient satisfaction, and overall outcome. Multimodal analgesia is considered the ideal solution. Adequate postoperative analgesia can not only reduce pain, opioid consumption, and, consequently, opioid-related adverse events, but can also reduce the length of hospital stay and costs and improve rehabilitation and patient satisfaction. OBJECTIVE: Effective multimodal pain management in the early postoperative period is essential for anesthesiologists. Additional studies have demonstrated that a low-dose intravenous infusion of ketamine can be administered as an adjuvant drug to alleviate acute postoperative pain. Therefore, we aim to appraise the efficacy and safety of intraoperative intravenous injection of S(+)-ketamine to relieve acute pain after TKA in older patients. METHODS: This is a protocol for a randomized, placebo-controlled trial. A total of 144 participants aged 65 years and older undergoing TKA will be randomly allocated into the S(+)-ketamine and placebo groups in a 1:1 ratio. S(+)-ketamine or the placebo will be intravenously administered at 0.3 mg/kg/h during the operation by anesthesiologists. Blinded evaluation by trained investigators will be completed at 2 hours, 24 hours, and 48 hours after surgery. The primary outcome measure will be the numeric rating scale score at rest and movement at 24 hours after surgery. The secondary outcomes will include the numeric rating scale scores at rest and movement at 2 hours and 48 hours after surgery, the number of patients who require additional analgesics during the first 48 hours after operation, the total consumption of opioids or nonsteroid anti-inflammatory drugs during the first 48 hours after operation, and adverse events at 2, 24, and 48 hours after operation. RESULTS: The protocol was registered at Clinical Trials.gov on February 26, 2022. It was performed in accordance with the approved guidelines and regulations of the participating institutions. Recruitment began in April 2022. Data collection is expected to conclude in September 2024. Study completion is expected in December 2024. CONCLUSIONS: A randomized, controlled, clinical study was designed to observe the analgesic effect of intraoperative intravenous administration of a lower dose of S(+)-ketamine (0.3 mg/kg/h) in older patients after TKA surgery. The protocol will appraise the efficacy and safety of intraoperative intravenous injection of S(+)-ketamine to relieve acute pain after TKA in older patients who may benefit from the administration of S(+)-ketamine. TRIAL REGISTRATION: ClinicalTrials.gov NCT05289050; https://clinicaltrials.gov/ct2/show/NCT05289050. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/53063.

Evaluating the effects of S-ketamine on postoperative delirium in elderly patients following total hip or knee arthroplasty under intraspinal anesthesia: a single-center randomized, double-blind, placebo-controlled, pragmatic study protocol.

Introduction: Postoperative delirium (POD) is an acute, transient brain disorder associated with decreased postoperative quality of life, dementia, neurocognitive changes, and mortality. A small number of trials have explored the role of S-ketamine in the treatment of POD due to its neuroprotective effects. Surprisingly, these trials have failed to yield supportive results. However, heterogeneity in delirium assessment methodologies, sample sizes, and outcome settings as well as deficiencies in S-ketamine use methods make the evidence provided by these studies less persuasive. Given the severe impact of POD on the health of elderly patients and the potential for S-ketamine to prevent it, we believe that designing a large sample size, and rigorous randomized controlled trial for further evaluation is necessary. Methods: This is a single-center, randomized, double-blind, placebo-controlled, pragmatic study. Subjects undergoing total hip or knee arthroplasty will be randomized in a 1:1 ratio to intervention (n = 186) and placebo (n = 186) groups. This trial aims to explore the potential role of S-ketamine in the prevention of POD. Its primary outcome is the incidence of POD within 3 postoperative days. Secondary outcomes include the number of POD episodes, the onset and duration of POD, the severity and subtype of POD, pain scores and opioid consumption, sleep quality, clinical outcomes, and safety outcomes. Discussion: To our knowledge, this is the first pragmatic study that proposes to use S-ketamine to prevent POD. We reviewed a large body of literature to identify potential preoperative confounding variables that may bias associations between the intervention and primary outcome. We will use advanced statistical methods to correct potential confounding variables, improving the test's power and external validity of test results. Of note, the patient population included in this trial will undergo intraspinal anesthesia. Although large, multicenter, randomized controlled studies have found no considerable difference in the effects of regional and general anesthesia on POD, patients receiving intraspinal anesthesia have less exposure to at-risk drugs, such as sevoflurane, propofol, and benzodiazepines, than patients receiving general anesthesia. At-risk drugs have been shown to negatively interfere with the neuroprotective effects of S-ketamine, which may be the reason for the failure of a large number of previous studies. There is currently a lack of randomized controlled studies evaluating S-ketamine for POD prevention, and our trial helps to fill a gap in this area.Trial registration: http://www.chictr.org.cn, identifier ChiCTR2300075796.

Effects of different rates of propofol with or without S-ketamine on ventricular function in healthy cats - a randomized study.

Propofol is used for anesthetic induction in cats and procedural sedation in countries where alfaxalone is not available. Studies have reported propofol-related effects in echocardiography variables in dogs and humans. However, there is a lack of echocardiography studies investigating propofol-related effects on cats. This study aimed to use echocardiography to investigate echocardiographic changes in three protocols using propofol: propofol-slow (2 mg/kg/min, PS); propofol-fast (8 mg/kg/min, PF); propofol-ketamine (S-ketamine 2 mg/kg bolus followed by propofol 2 mg/kg/min; PK) in healthy premedicated (gabapentin-buprenorphine-acepromazine; 200 mg/cat, 0.4, and 0.1 mg/kg, respectively), non-intubated cats. Echocardiographic measurements were obtained at three time points: baseline (before the administration of propofol), end of propofol titration (end-point, T0), and 15 min after T0 (T15). Propofol at a lower rate continued from T0 to T15. Echocardiographic and physiological variables included fractional shortening (FS%), ejection fraction (EF%), HR, BP, and others. Propofol requirements at T0 for PF, PS, and PK groups were 5.0 ± 0.9, 3.8 ± 0.7, and 2.4 ± 0.5 mg/kg, respectively. EF% neither change over time nor between groups. PF and PK showed a reduction in FS% at T0 (47 ± 6 to 34 ± 6 and 42 ± 6 to 36 ± 5, respectively). BP reduced significantly in PF and PS groups (136 ± 26 to 105 ± 13 and 137 ± 22 to 115 ± 15 mmHg, respectively). It is unclear whether changes in echocardiography variables were of clinical relevance related to treatment groups or a result of within-group individual responses.

Comparison of S-ketamine and midazolam for intravenous preoperative sedative and anxiolytic effects in preschool children: study protocol for a randomized controlled clinical trial.

BACKGROUND: Preoperative anxiety management is gaining particular attention in paediatric anaesthesia. Pharmacological and non-pharmacological resorts can be implemented to address this special issue. Despite the various approaches currently used for preoperative sedation in children, the different sedative and anti-anxiety effects between the newly marketed anaesthetic, S-ketamine, and the traditional sedative, midazolam, are still unclear. METHODS: This is a patient- and assessor-blinded randomized controlled clinical trial. Participants (n = 110) will receive S-ketamine (0.5 mg/kg) or midazolam (0.08 mg/kg) intravenously administrated at a ratio of 1:1 in the anaesthesia holding area. The primary outcome of this study is the sedative effect evaluated via the change in the modified Yale preoperative anxiety scale. It will be performed at two timepoints: in the pre-anaesthetic holding area before premedication (baseline, marked as T0) and about 5 min after premedication in the operating room without the existence of their guardians (marked as T1). Our secondary objectives include the parent separation anxiety score, postoperative agitation, caregivers' and anaesthesia care providers' satisfaction, and mask compliance. DISCUSSION: This randomized controlled trial is the first study to compare the anti-anxiety effect of intravenous S-ketamine and midazolam. We will provide a new approach for the clinical management of preoperative anxiety in preschool children posted for elective surgery. TRIAL REGISTRATION: ChiCTR2300069998. Registered on 30 March 2023.

S-Ketamine Improves Slow Wave Sleep and the Associated Changes in Serum Protein Among Gynecological Abdominal Surgery Patients: A Randomized Controlled Trial.

Purpose: This study aims to evaluate the effect of S-ketamine on slow wave sleep (SWS) and the related changes in serum protein in gynecological patients after open abdomen surgery. Methods: This was a randomized controlled trial. One hundred gynecological patients undergoing open abdomen surgery were randomized into an S-ketamine group (group S) or placebo group (0.9% saline; group C). During operation, patients in group S received adjuvant S-ketamine infusion (0.2 mg·kg-1·h-1) while those in group C received 0.9% saline. All patients were connected to patient-controlled intravenous analgesia (PCIA) pump in the end of the surgery and the patients in group S with an additional S-ketamine in PCIA pump. Polysomnogram (PSG) was monitored during the next night after surgery with PCIA pump. Blood samples were collected for proteomic analysis at 6:00 AM after PSG monitoring. The primary outcome was the percentage of SWS (also known as stage 3 non-rapid eye movement sleep, stage N3) on the next night after surgery, and the secondary outcome was subjective sleep quality, pain scores, and the changes in serum proteomics. Results: Complete polysomnogram recordings were obtained from 64 study participants (31 in group C and 33 in group S). The administration of S-ketamine infusion resulted in a significant increase in the percentage of SWS/N3 compared to the control group (group C, median (IQR [range]), 8.9 (6.3, 12.5); group S, median (IQR [range]), 15.6 (12.4, 18.8), P<0.001). However, subjective evaluations of sleep quality revealed no significant variances between the two groups. The protein affected by S-ketamine was primarily associated with posttranslational modification, protein turnover, carbohydrate transport, and metabolism. Conclusion: In patients undergoing open gynecological surgery, S-ketamine enhanced the percentage of objective sleep of SWS during the next night after surgery. Additionally, there were differences observed in serum protein levels between the two groups. Trial Registration: ChiCTR2200055180. Registered on 02/01/2022.