Challenges of acute pain management in older patients.

Adequate management of acute pain in the older population is crucial. However, it is inherently complex because of multiple physiological changes that significantly impact both the pharmacokinetics and pharmacodynamics of medications. Current guidelines promote paracetamol as the first-line analgesic for acute pain in older adults, whereas opioids are advised cautiously for moderate to severe acute pain. However, opioids come with a significant array of side effects, which can be more pronounced in older individuals. Ketamine administered via intranasal (IN) and nebulised inhalation in the emergency department for managing acute pain in older patients shows promising potential for improving pain management and reducing opioid reliance Kampan, Thong-on, Sri-on (2024, Age Ageing, 53, afad255). Nebulised ketamine appears superior in terms of adverse event incidence. However, the adoption of IN or nebulised ketamine in older adult acute pain management remains unclear because of the lack of definitive conclusions and clear guidelines. Nevertheless, these modalities can be valuable options for patients where opioid analgesics are contraindicated or when intravenous morphine titration is impractical or contraindicated. Here, we review these concepts, the latest evidence and propose avenues for research.

Effects of a single subanesthetic dose of esketamine on postoperative subthreshold depressive symptoms in patients undergoing unilateral modified radical mastectomy: a randomised, controlled, double-blind trial.

BACKGROUND: Breast cancer is the most common malignant tumor in females worldwide. During disease development, breast cancer patients suffer anxious and depressed, which may lead to worse quality of life or even higher mortality. Esketamine has been regarded as an antidepressant in breast cancer patients with mild or moderate depression. Here, we wonder whether the administration of esketamine could reduce the postoperative depressive symptom score of breast cancer patients who have no preoperative depression. METHODS: A total of 64 patients treated with unilateral modified radical mastectomy were randomly divided into an experimental group (esketamine group, Group E) and a control group (Group C), with 32 cases in each one. After anesthesia induction, Group C received 0.2 ml/kg of normal saline intravenously and Group E was administered 0.2 mg/kg intravenous esketamine. The primary outcome was the Patient Health Questionnaire-9 (PHQ-9) scores. The secondary outcomes included the Visual Analogue Scale (VAS) scores for pain, inflammatory markers, perioperative-related indicators, and the incidence of postoperative delirium, nausea and vomiting. RESULTS: The PHQ-9 score on postoperative day (POD) 1 in Group E declined from the preoperative level, while the score in Group C was higher than before, and the former was far lower than the latter (P = 0.047). There is no statistically significant difference in PHQ-9 scores between Group E and Group C on POD 3, 7, and 30. Moreover, the postoperative leukocyte level of Group E was higher than that of Group C, and the difference was statistically significant (P = 0.030). CONCLUSIONS: A single subanesthetic dose of esketamine can result in lower postoperative score on subthreshold depressive symptoms compared to the Group C on POD 1, without increasing the occurrence of postoperative adverse reactions. TRIAL REGISTRATION: Registration number: Chinese Clinical Trial Registry ChiCTR2200057028. Date of registration: 26/02/2022.

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.

Functional connectivity of the amygdala subregions and the antidepressant effects of repeated ketamine infusions in major depressive disorder.

BACKGROUND: Amygdala subregion-based network dysfunction has been determined to be centrally implicated in major depressive disorder (MDD). Little is known about whether ketamine modulates amygdala subarea-related networks. We aimed to investigate the relationships between changes in the resting-state functional connectivity (RSFC) of amygdala subregions and ketamine treatment and to identify important neuroimaging predictors of treatment outcomes. METHODS: Thirty-nine MDD patients received six doses of ketamine (0.5 mg/kg). Depressive symptoms were assessed, and magnetic resonance imaging (MRI) scans were performed before and after treatment. Forty-five healthy controls underwent one MRI scan. Seed-to-voxel RSFC analyses were performed on the amygdala subregions, including the centromedial amygdala (CMA), laterobasal amygdala (LBA), and superficial amygdala subregions. RESULTS: Abnormal RSFC between the left LBA and the left precuneus in MDD patients is related to the therapeutic efficacy of ketamine. There were significant differences in changes in bilateral CMA RSFC with the left orbital part superior frontal gyrus and in changes in the left LBA with the right middle frontal gyrus between responders and nonresponders following ketamine treatment. Moreover, there was a difference in the RSFC of left LBA and the right superior temporal gyrus/middle temporal gyrus (STG/MTG) between responders and nonresponders at baseline, which could predict the antidepressant effect of ketamine on Day 13. CONCLUSIONS: The mechanism by which ketamine improves depressive symptoms may be related to its regulation of RSFC in the amygdala subregion. The RSFC between the left LBA and right STG/MTG may predict the response to the antidepressant effect of ketamine.

Role of Flt3l and Rps15 in ketamine anesthesia.

Ketamine is the only intravenous narcotic that has sedative, analgesic, and anesthetic effects. However, the role of Flt3l and ribosomal protein S15 (Rps15) in ketamine anesthesia remains unclear. GSE26364 and GSE93041 were downloaded from gene expression omnibus. Multiple datasets were merged and batched. Differentially expressed genes (DEGs) were screened and weighted gene co-expression network analysis was performed. Construction and analysis of protein-protein interaction network. Gene ontology (GO) and Kyoto Encyclopedia of Gene and Genome were performed. A heat map of gene expression was drawn. TargetScan was used to screen miRNAs regulating DEGs. 882 DEGs were identified. According to the GO analysis, these DEGs were mainly enriched in cell differentiation, extracellular region, and cytoplasm. The Kyoto Encyclopedia of Gene and Genome analysis revealed enrichment in pathways such as the PPAR signaling pathway, TNF signaling pathway, Hippo signaling pathway, and IL-17 signaling pathway. In the Metascape enrichment analysis, GO enrichment categories included leukocyte differentiation, negative regulation of CREB transcription factor activity, and positive regulation of cell cycle. The protein-protein interaction network showed 10 core genes (Rpl7, Rpl18, Rps15, Rpl7l1, Flt3l, Rps16, Eprs, Rps19, Rps28, Rplp2).Gene expression heatmap showed that core genes (Rplp2, Flt3l, Rps15) were highly expressed in samples treated with ketamine anesthesia. Flt3l and Rps15 are highly expressed during ketamine anesthesia, and may be molecular targets.

GM-1020: a novel, orally bioavailable NMDA receptor antagonist with rapid and robust antidepressant-like effects at well-tolerated doses in rodents.

The NMDA receptor (NMDAR) antagonist ketamine has shown great potential as a rapid-acting antidepressant; however, its use is limited by poor oral bioavailability and a side effect profile that necessitates in-clinic dosing. GM-1020 is a novel NMDAR antagonist that was developed to address these limitations of ketamine as a treatment for depression. Here, we present the preclinical characterization of GM-1020 alongside ketamine, for comparison. In vitro, we profiled GM-1020 for binding to NMDAR and functional inhibition using patch-clamp electrophysiology. In vivo, GM-1020 was assessed for antidepressant-like efficacy using the Forced Swim Test (FST) and Chronic Mild Stress (CMS), while motor side effects were assessed in spontaneous locomotor activity and on the rotarod. The pharmacokinetic properties of GM-1020 were profiled across multiple preclinical species. Electroencephalography (EEG) was performed to determine indirect target engagement and provide a potentially translational biomarker. These results demonstrate that GM-1020 is an orally bioavailable NMDAR antagonist with antidepressant-like efficacy at exposures that do not produce unwanted motor effects.

Development of a novel rodent rapid serial visual presentation task reveals dissociable effects of stimulant versus nonstimulant treatments on attentional processes.

The rapid serial visual presentation (RSVP) task and continuous performance tasks (CPT) are used to assess attentional impairments in patients with psychiatric and neurological conditions. This study developed a novel touchscreen task for rats based on the structure of a human RSVP task and used pharmacological manipulations to investigate their effects on different performance measures. Normal animals were trained to respond to a target image and withhold responding to distractor images presented within a continuous sequence. In a second version of the task, a false-alarm image was included, so performance could be assessed relative to two types of nontarget distractors. The effects of acute administration of stimulant and nonstimulant treatments for ADHD (amphetamine and atomoxetine) were tested in both tasks. Methylphenidate, ketamine, and nicotine were tested in the first task only. Amphetamine made animals more impulsive and decreased overall accuracy but increased accuracy when the target was presented early in the image sequence. Atomoxetine improved accuracy overall with a specific reduction in false-alarm responses and a shift in the attentional curve reflecting improved accuracy for targets later in the image sequence. However, atomoxetine also slowed responding and increased omissions. Ketamine, nicotine, and methylphenidate had no specific effects at the doses tested. These results suggest that stimulant versus nonstimulant treatments have different effects on attention and impulsive behaviour in this rat version of an RSVP task. These results also suggest that RSVP-like tasks have the potential to be used to study attention in rodents.

Effects of adding low-dose esketamine to sufentanil and propofol sedation during cervical conization: a single-centre, randomized controlled trial.

BACKGROUND: Cervical conization is a brief but painful procedure that can be performed under sufficient sedation with propofol and opioids. However, this sedation approach comes with a high risk of sedation-related adverse events (SRAEs). Esketamine, an N-methyl-d-aspartate (NMDA) receptor antagonist, causes less cardiorespiratory depression than opioids. The aim of this study was to assess the efficacy and safety of adding a low dose of esketamine to propofol and sufentanil sedation as an opioid-reduced regimen. METHODS: A total of 122 consecutive patients with ASA I-II, body mass index < 30, and STOP-BANG score < 3 who underwent cervical conization were enrolled and randomly divided into Group S and Group ES. Using a closed-loop target-controlled infusion (TCI) pump with a target bispectral index (BIS) value of 60 ± 5, patients in Group S were sedated with 0.2 mcg·kg-1 sufentanil and propofol, while patients in Group ES were sedated with 0.15 mg·kg-1 esketamine, 0.1 mcg·kg-1 sufentanil and propofol. The primary outcome was the incidence and severity of SRAEs, while the secondary outcomes included effectiveness of sedation, awakening time, psychotomimetic side effects, postoperative pain, postoperative nausea and vomiting, and patient and gynaecologist satisfaction. RESULTS: Data from 120 patients were analysed. The incidence of composite SRAEs was significantly higher in Group S than in Group ES (85.0% vs. 56.7%, P < 0.05). Furthermore, the severity of SRAEs was higher in Group S than in Group ES (P < 0.001). There were no significant differences in the effectiveness of sedation, awakening time, psychotomimetic side effects, postoperative pain, postoperative nausea and vomiting, or patient and gynaecologist satisfaction between the two groups. CONCLUSION: Adding low-dose esketamine to propofol and sufentanil sedation reduces the incidence and severity of SRAEs in patients undergoing cervical conization, with equal sedation efficacy, recovery quality, and no additional psychomimetic side effects. TRIAL REGISTRATION: ChiCTR2000040457 , 28/11/2020.

Continuous ketamine infusion for the management of opioid-induced hyperalgesia following amputation.

We discuss the use of an inpatient multi-day continuous intravenous ketamine infusion for the treatment of opioid-induced hyperalgesia (OIH) and high fentanyl requirements in the case of a patient with a background of fibromyalgia/central sensitisation syndrome who underwent a complicated post-operative course following a right below-knee amputation for high-grade myxoid fibrosarcoma. The patient was successfully tapered off a total fentanyl patch dose of 162 mcg/hour every 72 hours (morphine equivalent dose of 389 mg/day) to short-acting hydromorphone 2 mg orally two times per day as needed (equivalent of 8 mg morphine sustained-release twice per day) during a 2-week admission with only mild withdrawal symptoms. We discuss the pharmacology of ketamine and its possible application in the treatment of OIH.

Sustained antidepressant effect of ketamine through NMDAR trapping in the LHb.

Ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist1, has revolutionized the treatment of depression because of its potent, rapid and sustained antidepressant effects2-4. Although the elimination half-life of ketamine is only 13 min in mice5, its antidepressant activities can last for at least 24 h6-9. This large discrepancy poses an interesting basic biological question and has strong clinical implications. Here we demonstrate that after a single systemic injection, ketamine continues to suppress burst firing and block NMDARs in the lateral habenula (LHb) for up to 24 h. This long inhibition of NMDARs is not due to endocytosis but depends on the use-dependent trapping of ketamine in NMDARs. The rate of untrapping is regulated by neural activity. Harnessing the dynamic equilibrium of ketamine-NMDAR interactions by activating the LHb and opening local NMDARs at different plasma ketamine concentrations, we were able to either shorten or prolong the antidepressant effects of ketamine in vivo. These results provide new insights into the causal mechanisms of the sustained antidepressant effects of ketamine. The ability to modulate the duration of ketamine action based on the biophysical properties of ketamine-NMDAR interactions opens up new opportunities for the therapeutic use of ketamine.

Esketamine Nasal Spray versus Quetiapine for Treatment-Resistant Depression.

BACKGROUND: In treatment-resistant depression, commonly defined as a lack of response to two or more consecutive treatments during the current depressive episode, the percentage of patients with remission is low and the percentage with relapse is high. The efficacy and safety of esketamine nasal spray as compared with extended-release quetiapine augmentation therapy, both in combination with ongoing treatment with a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI), in patients with treatment-resistant depression are unknown. METHODS: In an open-label, single-blind (with raters unaware of group assignments), multicenter, phase 3b, randomized, active-controlled trial, we assigned patients, in a 1:1 ratio, to receive flexible doses (according to the summary of product characteristics) of esketamine nasal spray (esketamine group) or extended-release quetiapine (quetiapine group), both in combination with an SSRI or SNRI. The primary end point was remission, defined as a score of 10 or less on the Montgomery-Åsberg Depression Rating Scale (MADRS), at week 8 (scores range from 0 to 60, with higher scores indicating more severe depression). The key secondary end point was no relapse through week 32 after remission at week 8. All patients were included in the analysis; patients who discontinued the trial treatment were considered as having had an unfavorable outcome (i.e., they were grouped with patients who did not have remission or who had a relapse). Analyses of the primary and key secondary end points were adjusted for age and number of treatment failures. RESULTS: Overall, 336 patients were assigned to the esketamine group and 340 to the quetiapine group. More patients in the esketamine group than in the quetiapine group had remission at week 8 (91 of 336 patients [27.1%] vs. 60 of 340 patients [17.6%]; P = 0.003) and had no relapse through week 32 after remission at week 8 (73 of 336 patients [21.7%] vs. 48 of 340 patients [14.1%]). Over 32 weeks of follow-up, the percentage of patients with remission, the percentage of patients with a treatment response, and the change in the MADRS score from baseline favored esketamine nasal spray. The adverse events were consistent with the established safety profiles of the trial treatments. CONCLUSIONS: In patients with treatment-resistant depression, esketamine nasal spray plus an SSRI or SNRI was superior to extended-release quetiapine plus an SSRI or SNRI with respect to remission at week 8. (Funded by Janssen EMEA; ESCAPE-TRD ClinicalTrials.gov number, NCT04338321.).

Effect of intravenous induction with different doses of Esketamine combined with propofol and sufentanil on intraocular pressure among pediatric strabismus surgery: a randomized clinical trial.

BACKGROUND: It is well-established that maintaining stable intraocular pressure (IOP) within the normal range during ophthalmic surgery is important. Esketamine is a commonly used drug in pediatric general anesthesia due to its good analgesic and sedative effects. However, its application in ophthalmic surgery is limited because it can increase IOP. The effect of esketamine combined with other common anesthetics on IOP has been underinvestigated. This study aimed to investigate the effect of different doses of esketamine combined with propofol and sufentanil on IOP during intravenous induction of general anesthesia for pediatric strabismus surgery. METHODS: A total of 181 children with strabismus undergoing unilateral eye surgery under general anesthesia were recruited. Intravenous induction included the use of sufentanil 0.1 µg/kg, propofol 3 mg/kg, and esketamine. Base on the dosage of esketamine, the patients were randomly allocated into three groups: esketamine low (EL) group with 0.25 mg/kg (n = 62), esketamine high (EH) group with 0.5 mg/kg (n = 60), and normal saline (NS) group (n = 59). Hemodynamic parameters, respiratory parameters, and IOP of the non-surgical eye were recorded and compared among the three groups at different time points: before induction (T0), 1 min after induction but before laryngeal mask insertion (T1), immediately after laryngeal mask insertion (T2), and 2 min after laryngeal mask insertion (T3). RESULTS: There were no significant differences in age, gender, body mass index (BMI), and respiratory parameters among the three groups at T0. The IOP at T1, T2, and T3 was lower than that at T0 in all three groups. The EH group (12.6 ± 1.6 mmHg) had a significantly higher IOP than the EL group (12.0 ± 1.6 mmHg) and the NS group (11.6 ± 1.7 mmHg) at T1. However, no difference was found between the EL and NS groups at any time point. Systolic blood pressure (SBP) and heart rate (HR) at T1, T2, and T3 were lower than at baseline, and SBP and HR were higher at T2 than at T1. Additionally, the EH group had a significantly higher HR at T1 than the other two groups. There was no significant difference in diastolic blood pressure (DBP) among the three groups at any time point. CONCLUSION: Propofol combined with sufentanil significantly decreased IOP during the induction of general anesthesia. Although a dose of 0.5 mg/kg esketamine elevated IOP compared to the low-dose and control groups after induction, the IOP remained lower than baseline. 0.25 mg/kg esketamine combined with propofol and sufentanil had little effect on IOP. Therefore, we advocate that a maximum dose of 0.5 mg/kg esketamine combined with propofol and sufentanil will not elevate IOP compared to baseline in pediatric strabismus surgery. TRIAL REGISTRATION: The registration number is ChiCTR2200066586 at Chictr.org.cn. Registry on 09/12/2022.

Prospective, randomised comparison of two intravenous sedation methods for magnetic resonance imaging in children.

BACKGROUND: Children usually need sedation or even anaesthesia for magnetic resonance imaging (MRI) studies. As there is no universally accepted method for this purpose we undertook a prospective, randomised comparison of propofol and dexmedetomidine in children aged 1 to 10 years. METHODS: After Institutional Board approval and parents' informed consent 64 ASA status I or II children scheduled for MRI scan were enrolled. Patients were premedicated with intravenous (IV) midazolam (0.1 mg kg -1 ) and ketamine (1 mg kg -1 ) and randomised to propofol (P) or dexmedetomidine (D) group. A propofol bolus of 1 mg kg -1 followed by infusion of 4 mg kg -1 h -1 , or dexmedetomidine 1 µg kg -1 followed by 2 µg kg -1 h-1 infusion were used. Heart rate, SpO 2 and non-invasive blood pressure were monitored and recorded at 5 min intervals. Results were compared by means of standard statistical methods. RESULTS: Both dexmedetomidine and propofol after premedication with ketamine and midazolam are suitable for MRI sedation, although propofol use results in shorter recovery time. Less interventions are needed when dexmedetomidine is used.

Comparison of intranasal dexmedetomidine-midazolam, dexmedetomidine-ketamine, and midazolam-ketamine for premedication in paediatric patients: a double-blinded randomized trial.

BACKGROUND: Paediatric patients are a population with a high level of anxiety. The prevention of perioperative stress in a frightened child is important to render the child calm and cooperative for smoother induction. Intranasal premedication is easy and safe, and the drug is rapidly absorbed into the systemic circulation, ensuring early onset of sedation in children and good effectiveness. METHODS: 150 patients in the age group 2-4 years, ASA class I, undergoing elective surgical procedures were enrolled. The patients were randomly divided into 3 groups: a DM group (receiving intranasal dexmedetomidine 1 µg kg -1 and midazolam 0.12 mg kg -1 ), a DK group (receiving intranasal dexmedetomidine 1 µg kg -1 and keta-mine 2 mg kg -1 ), and an MK group (receiving intranasal midazolam 0.12 mg kg -1 and ketamine 2 mg kg -1 ). After 30 minutes of administration of the drugs, the patients were assessed for parent separation anxiety, sedation, ease of IV cannulation, and mask acceptance. RESULTS: The comparison among the 3 groups showed a statistically significant difference for ease of IV cannulation and mask acceptance at 30 minutes, with a P -value of 0.010 with CI of 0.0-0.02, and P -value 0.007 with CI 0.0-0.02, respectively. The parent separation anxiety and sedation score at 30 minutes was statistically insignificant with a P -value of 0.82 with CI of 0.03-0.14 and P -value 0.631 with CI of 0.38-0.58, respectively. CONCLUSIONS: The combination of midazolam and ketamine had a better clinical profile for premedication as compared to other combination drugs used in our study in terms of IV cannulation and acceptance of masks with a comparable decrease in separation anxiety from parents and adequate sedation.

Mini-dose esketamine-dexmedetomidine combination to supplement analgesia for patients after scoliosis correction surgery: a double-blind randomised trial.

BACKGROUND: Patients often experience severe pain after scoliosis correction surgery. Esketamine and dexmedetomidine each improves analgesia but can produce side-effects. We therefore tested the hypothesis that a mini-dose esketamine-dexmedetomidine combination safely improves analgesia. METHODS: Two hundred male and female adults having scoliosis correction surgery were randomised to patient-controlled sufentanil analgesia (4 µg kg-1 in normal saline) with either a combined supplement (esketamine 0.25 mg ml-1 and dexmedetomidine 1 µg ml-1) or placebo. The primary outcome was the incidence of moderate-to-severe pain within 72 h, defined as a numeric rating scale (NRS: 0=no pain and 10=worst pain) score ≥4 at any of seven time points. Amongst secondary outcomes, subjective sleep quality was assessed with an NRS score (0=best sleep and 10=worst sleep) for the first five postoperative nights. RESULTS: There were 199 subjects included in the intention-to-treat analysis. Mean infusion rates were 5.5 µg kg-1 h-1 for esketamine and 0.02 µg kg-1 h-1 for dexmedetomidine. The primary outcome incidence was lower with the combined supplement (65.7% [65/99]) than with placebo (86.0% [86/100]; relative risk 0.76; 95% confidence interval: 0.65-0.90; P=0.001). Subjects given the combined supplement had lower pain intensity at rest at five time points (median difference -1 point; P≤0.005), lower pain intensity with movement at six time points (median difference -1 point; P≤0.001), and better subjective sleep quality for the first 5 postoperative nights (median difference -2 to -1 points; P<0.001). Adverse events did not differ between groups. CONCLUSIONS: The mini-dose esketamine-dexmedetomidine combination safely improved analgesia and subjective sleep quality after scoliosis correction surgery. CLINICAL TRIAL REGISTRATION: NCT04791059.

Effects of intra-operative administration of subanesthetic s-ketamine on emergence from sevoflurane anesthesia: a randomized double-blind placebo-controlled study.

BACKGROUND: Ketamine is administered in the perioperative period for its benefits in analgesia, anti-agitation and anti-depression when administered at a small dose. However, it is not clear whether the intra-operative administration of ketamine would affect emergence under sevoflurane anesthesia. To investigate this effect, we designed this trial. METHODS: In this randomized, double-blind, placebo-controlled study, we enrolled 44 female patients aged 18-60 who were scheduled to elective laparoscopic gynecological surgeries. All patients were randomly assigned to saline or s-ketamine group. In s-ketamine group, patients received 0.125 mg/kg s-ketamine 30 min after the start of surgery. In saline group, patients were administered the same volume of saline. Sevoflurane and remifentanil were used to maintain general anesthesia. The primary outcome was emergence time. We also assessed postoperative agitation, cognitive function, and delirium. In addition, we collected and analyzed prefrontal electroencephalogram (EEG) during and after general anesthesia. RESULTS: There were no significant differences in emergence time between s-ketamine group and saline group (10.80 ± 3.77 min vs. 10.00 ± 2.78 min, P = 0.457). Neither postoperative agitation (4 [3, 4] vs. 4 [3, 4], P = 0.835) nor cognitive function (25.84 ± 2.69 vs. 25.55 ± 2.19, P = 0.412) differed between groups. No postoperative delirium was observed in either group. Subanesthetic s-ketamine resulted in active EEG with decreased power of slow (-0.35 ± 1.13 dB vs. -1.63 ± 1.03 dB, P = 0.003), delta (-0.22 ± 1.11 dB vs. -1.32 ± 1.09 dB, P = 0.011) and alpha (-0.31 ± 0.71 dB vs. -1.71 ± 1.34 dB, P = 0.0003) waves and increased power of beta-gamma bands (-0.30 ± 0.89 dB vs. 4.20 ± 2.08 dB, P < 0.0001) during sevoflurane anesthesia, as well as an increased alpha peak frequency (-0.16 ± 0.48 Hz vs. 0.31 ± 0.73 Hz, P = 0.026). EEG patterns did not differ during the recovery period after emergence between groups. CONCLUSION: Ketamine administered during sevoflurane anesthesia had no apparent influence on emergence time in young and middle-aged female patients undergoing laparoscopic surgery. Subanesthetic s-ketamine induced an active prefrontal EEG pattern during sevoflurane anesthesia but did not raise neurological side effects after surgery. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR2100046479 (date: 16/05/2021).

Ketamine versus ECT for Nonpsychotic Treatment-Resistant Major Depression.

BACKGROUND: Electroconvulsive therapy (ECT) and subanesthetic intravenous ketamine are both currently used for treatment-resistant major depression, but the comparative effectiveness of the two treatments remains uncertain. METHODS: We conducted an open-label, randomized, noninferiority trial involving patients referred to ECT clinics for treatment-resistant major depression. Patients with treatment-resistant major depression without psychosis were recruited and assigned in a 1:1 ratio to receive ketamine or ECT. During an initial 3-week treatment phase, patients received either ECT three times per week or ketamine (0.5 mg per kilogram of body weight over 40 minutes) twice per week. The primary outcome was a response to treatment (i.e., a decrease of ≥50% from baseline in the score on the 16-item Quick Inventory of Depressive Symptomatology-Self-Report; scores range from 0 to 27, with higher scores indicating greater depression). The noninferiority margin was -10 percentage points. Secondary outcomes included scores on memory tests and patient-reported quality of life. After the initial treatment phase, the patients who had a response were followed over a 6-month period. RESULTS: A total of 403 patients underwent randomization at five clinical sites; 200 patients were assigned to the ketamine group and 203 to the ECT group. After 38 patients had withdrawn before initiation of the assigned treatment, ketamine was administered to 195 patients and ECT to 170 patients. A total of 55.4% of the patients in the ketamine group and 41.2% of those in the ECT group had a response (difference, 14.2 percentage points; 95% confidence interval, 3.9 to 24.2; P<0.001 for the noninferiority of ketamine to ECT). ECT appeared to be associated with a decrease in memory recall after 3 weeks of treatment (mean [±SE] decrease in the T-score for delayed recall on the Hopkins Verbal Learning Test-Revised, -0.9±1.1 in the ketamine group vs. -9.7±1.2 in the ECT group; scores range from -300 to 200, with higher scores indicating better function) with gradual recovery during follow-up. Improvement in patient-reported quality-of-life was similar in the two trial groups. ECT was associated with musculoskeletal adverse effects, whereas ketamine was associated with dissociation. CONCLUSIONS: Ketamine was noninferior to ECT as therapy for treatment-resistant major depression without psychosis. (Funded by the Patient-Centered Outcomes Research Institute; ELEKT-D ClinicalTrials.gov number, NCT03113968.).

Randomised, prospective, blinded, clinical trial of opioid-free injectable anaesthesia with or without multimodal analgesia in kittens undergoing ovariohysterectomy.

OBJECTIVES: This study compared an opioid-free injectable anaesthetic protocol with or without multimodal analgesia in kittens undergoing ovariohysterectomy. METHODS: In this prospective, randomised, blinded, clinical trial, 29 healthy kittens (mean ± SD weight 1.55 ± 0.46 kg; aged 10 weeks to 6 months) were included. Anaesthesia was performed with an intramuscular injection of ketamine (4 mg/kg), dexmedetomidine (40 µg/kg) and midazolam (0.25 mg/kg). In the multimodal group (MMG), cats (n = 14) received meloxicam (0.1 mg/kg SC) and intraperitoneal bupivacaine 0.25% (2 mg/kg), whereas the same volume of saline was administered in the control group (CG; n = 15). Atipamezole (0.4 mg/kg IM) was given 15 mins after ovariohysterectomy. Postoperative pain was assessed using the UNESP-Botucatu multidimensional feline pain assessment scale - short form. Rescue analgesia (buprenorphine 0.02 mg/kg IM in MMG/CG and meloxicam 0.1 mg/kg SC in CG) was administered if pain scores were ⩾4/12. Soft food intake (after 2 and 60 mins) was evaluated at specific time points postoperatively. Statistical analyses were performed with linear models and post-hoc pairwise comparison with Benjamini-Hochberg corrections (P <0.05). RESULTS: The prevalence of rescue analgesia was higher in the CG (n = 15/15) than the MMG (n = 1/14; P <0.001). Pain scores at 1 h, 2 h and 4 h postoperatively were higher in the CG (4.1 ± 2.8, 4.8 ± 3.0 and 5.3 ± 1.2, respectively) than in the MMG (1.6 ± 1.0, 1.1 ± 1.0 and 0.9 ± 0.8, respectively; P <0.001). Food intake (%) at 1 h postoperatively was higher in the MMG after 2 and 60 mins (10.4 ± 9 and 71.9 ± 29, respectively) than in the CG (1.4 ± 2 and 13.9 ± 7, respectively; P <0.001). CONCLUSIONS AND RELEVANCE: This opioid-free protocol using multimodal analgesia produced adequate postoperative pain relief, while almost eliminating the need for rescue analgesia in kittens undergoing ovariohysterectomy. Pain decreased food intake.

Pre-treatment functional connectivity of the cingulate cortex predicts anti-suicidal effects of serial ketamine infusions.

BACKGROUND: Although ketamine can rapidly decrease suicidal ideation (SI), its neurobiological mechanism of action remains unclear. Several areas of the cingulate cortex have been implicated in SI; therefore, we aimed to explore the neural correlates of the anti-suicidal effect of ketamine with cingulate cortex functional connectivity (FC) in depression. METHODS: Forty patients with unipolar or bipolar depression with SI underwent six infusions of ketamine over 2 weeks. Clinical symptoms and resting-state functional magnetic resonance imaging data were obtained at baseline and on day 13. Remitters were defined as those with complete remission of SI on day 13. Four pairs of cingulate cortex subregions were selected: the subgenual anterior cingulate cortex (sgACC), pregenual anterior cingulate cortex (pgACC), anterior mid-cingulate cortex (aMCC), and posterior mid-cingulate cortex (pMCC), and whole-brain FC for each seed region was calculated. RESULTS: Compared with non-remitters, remitters exhibited increased FC of the right pgACC-left middle occipital gyrus (MOG) and right aMCC-bilateral postcentral gyrus at baseline. A high area under the curve (0.91) indicated good accuracy of the combination of the above between-group differential FCs as a predictor of anti-suicidal effect. Moreover, the change of SI after ketamine infusion was positively correlated with altered right pgACC-left MOG FC in remitters (r = 0.66, p = 0.001). CONCLUSIONS: Our findings suggest that the FC of some cingulate cortex subregions can predict the anti-suicidal effect of ketamine and that the anti-suicidal mechanism of action of ketamine may involve alteration of FC between the right pgACC and left MOG.

Why ketamine.

We present the rationale for testing ketamine as an add-on therapy for treating benzodiazepine refractory (established) status epilepticus. In animal studies, ketamine terminates benzodiazepine refractory status epilepticus by interfering with the pathophysiological mechanisms and is a neuroprotectant. Ketamine does not suppress respiration when used for sedation and anesthesia. A Series of reports suggest that ketamine can help terminate refractory and super refractory status epilepticus. We propose to use 1 or 3 mg/Kg ketamine intravenously based on animal-to-human conversion and pharmacokinetic studies. This paper was presented at the 8th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures held in September 2022.