Effects Of Ketamine Research Articles

Evaluation of the effect of oral Ketamine compared to placebo on pain reduction in patients with renal colic: a double-blind randomized clinical trial study

Introduction: Renal colic caused by urolithiasis is one of the common causes of severe pain and referral to the emergency room. Using a multimodal method in controlling this type of pain by available anesthetics such as ketamine can help relieve pain, increase satisfaction and reduce hospitalization. Method: This study was conducted as a double-blind clinical trial. 44 patients with renal colic with ASA class 1 were divided into two intervention and control groups. Pethidine (1mg/kg) was administered to both groups. In the intervention group, oral ketamine (0.5 mg/kg) dissolved in 5% dextrose was prescribed, and in the control group, 5% dextrose serum (0.1 ml/kg) was used. Pain intensity was measured by numerical method (NRS) before the treatment and half, one, two and three hours after the intervention. Findings: The median age of the intervention group was 35.2 and the control group was 38.9 (p=0.092). The average amount of pethidine consumed in the intervention group was 94 mg and in the control group was 89 mg, and there was no significant difference between the two groups (p=0.095). In the intervention group, 27.3% and in the control group, 72.7% needed additional pethidine (p=0.000). In hours one, two and three after treatment, the intensity of pain in the intervention group was lower than in the control group, and only in the third hour this difference was statistically significant (p = 0.03). Conclusion: The use of oral ketamine can reduce restlessness without causing side effects and along with pethidine can help relieve the pain of renal colic in the emergency department

Item response theory in early phase clinical trials: Utilization of a reference model to analyze the Montgomery-Åsberg Depression Rating Scale.

In clinical trials, Montgomery-Åsberg Depression Rating Scale (MADRS) questionnaire data are added up to total scores before analysis, assuming equal contribution of each separate question. Item Response Theory (IRT)-based analysis avoids this by using individual question responses to determine the latent variable (ψ), which represents a measure of depression severity. However, utilization of IRT in early phase trials remains difficult, because large datasets are needed to develop IRT models. Therefore, we aimed to evaluate the application and assumptions of a reference IRT model for analysis of an early phase trial. A cross-over, placebo-controlled study investigating the effect of intravenous racemic ketamine on MADRS scores in patients with treatment-resistant major depressive disorder was used as a case study. One hundred forty-seven MADRS responses were measured in 17 patients at five timepoints (predose to 2 weeks after dosing). Two reference IRT models based on different patient populations were selected from literature and used to determine ψ, while testing multiple approaches regarding assumed data distribution. Use of ψ versus total score to determine treatment effect was compared through linear mixed model analysis. Results showed that determined ψ values did not differ significantly between assumed distributions, but were significantly different when changing reference IRT model. Estimated treatment effect size was not significantly affected by chosen approach nor reference population. Finally, increased precision to determine treatment effect was achieved by using IRT versus total scores. This demonstrates the usefulness of reference IRT model application for analysis of questionnaire data in early phase clinical trials.

Effects of a Subanesthetic Ketamine Infusion on Inflammatory and Behavioral Outcomes after Closed Head Injury in Rats.

Traumatic brain injury (TBI) affects millions of people annually, and most cases are classified as mild TBI (mTBI). Ketamine is a potent trauma analgesic and anesthetic with anti-inflammatory properties. However, ketamine's effects on post-mTBI outcomes are not well characterized. For the current study, we used the Closed-Head Impact Model of Engineered Rotational Acceleration (CHIMERA), which replicates the biomechanics of a closed-head impact with resulting free head movement. Adult male Sprague-Dawley rats sustained a single-session, repeated-impacts CHIMERA injury. An hour after the injury, rats received an intravenous ketamine infusion (0, 10, or 20 mg/kg, 2 h period), during which locomotor activity was monitored. Catheter blood samples were collected at 1, 3, 5, and 24 h after the CHIMERA injury for plasma cytokine assays. Behavioral assays were conducted on post-injury days (PID) 1 to 4 and included rotarod, locomotor activity, acoustic startle reflex (ASR), and pre-pulse inhibition (PPI). Brain tissue samples were collected at PID 4 and processed for GFAP (astrocytes), Iba-1 (microglia), and silver staining (axonal injury). Ketamine dose-dependently altered locomotor activity during the infusion and reduced KC/GRO, TNF-α, and IL-1β levels after the infusion. CHIMERA produced a delayed deficit in rotarod performance (PID 3) and significant axonal damage in the optic tract (PID 4), without significant changes in other behavioral or histological measures. Notably, subanesthetic doses of intravenous ketamine infusion after mTBI did not produce adverse effects on behavioral outcomes in PID 1-4 or neuroinflammation on PID 4. A further study is warranted to thoroughly investigate beneficial effects of IV ketamine on mTBI given multi-modal properties of ketamine in traumatic injury and stress.

Perioperative ketamine administration to prevent delirium and neurocognitive disorders after surgery: a systematic review and meta-analysis.

Surgery induces high rates of cognitive disorders, persisting for up to 12 months in elderly adults. This review aimed to assess the currently debated preventive effect of perioperative ketamine on postoperative delirium and postoperative neurocognitive disorders (POND). Systematic review and meta-analysis including all randomized controlled trials investigating the effects of perioperative ketamine administration in adult patients compared to placebo or no intervention on postoperative delirium and/or POND between January 2007 and April 2022. Database searches were conducted in PubMed, Medline, Embase, Scopus, and Central. Random effects models were used to pool overall estimates. The GRADE approach was used to assess the quality of the evidence. From 1379 records screened, 14 randomized controlled trials with 1618 patients randomized met our inclusion criteria with a high level of consensus among reviewers, amongst whom 50% were at low-moderate risk of bias. There was no between-group difference in postoperative delirium [8 trials, 1265 patients, odds ratio (OR) 0.93, 95% CI (0.51-1.70), I2 =28%] and POND [5 trials, 494 patients, OR 0.52, 95% CI (0.15-1.80); I2 =78%]. There was no significant between-group difference in postoperative psychological adverse effects, level of pain, hospital length of stay, or mortality. Between-group subgroup analyses showed no difference in delirium or POND incidence according to surgical setting, ketamine dose, mode of administration, combination or not with other drug(s), and assessment timing or definition of cognitive disorders. Perioperative ketamine does not prevent postoperative delirium or POND. Significant study heterogeneity suggests that standardized measures for POND assessment and a specific focus on patients at high risk for POND should be used to improve the comparability of future studies.

Ketamine facilitates appetitive trace conditioning in mice: Further evidence for abnormal stimulus representation in schizophrenia model animals.

Recent studies indicated that positive symptoms of schizophrenia, such as hallucination and delusion, can be modeled using Pavlovian conditioning procedures. Various schizophrenia model animals exhibit abnormally strong associative activations of absent stimuli (i.e., conditioned hallucination) and readily form further associations involving the absent cues (i.e., enhanced mediated conditioning). In the present study using mice, we examined whether the acquisition of appetitive trace conditioning, another Pavlovian task in which animals must form associations between two stimuli that never occur together, is facilitated by injections of ketamine, an N-methyl-D-aspartate-receptor antagonist and a known hallucinogen at low doses in humans and nonhuman animals. Ketamine administration before each conditioning session significantly enhanced the acquisition of 4-s trace conditioning but not delay conditioning. The trace conditioning-specific facilitatory effect of ketamine was replicated in subsequent experiments in which slightly modified procedures were used to enhance the overall levels of conditioned responses. Taken together, the current results demonstrated that low-dose ketamine promotes associative learning between stimuli over a temporal gap, which adds to existing literature illustrating aberrant learning involving absent stimuli in schizophrenia model animals. We discuss potential associative mechanisms through which ketamine promoted trace conditioning with reference to Wagner's (1981) Standard Operating Procedures model. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Bupivacaine, Ketamine And Bupivacaine – Ketamine Epidural Anaesthesia In Bitches Undergoing Ovariohysterectomy

This research was conducted to analyze the analgesic effects of bupivacaine, ketamine and bupivacaine–ketamine combination on bitches undergoing ovariohysterectomy, and determine a suitable regional anaesthesia. Fifteen (15) apparently healthy bitches, aged 8-12 months and weighing 10 – 15kg were procured within and around Zaria, Kaduna State for this experiment. The animals were grouped into three (3), A, B and C, screened and allowed to acclimatize to the new environment. Premedication was instituted with 0.02 mg/kg atropine sulphate and 1mg/kg Xylazine. Group A was administered an epidural injection of 0.5 % bupivacaine hydrochloride at 1 mg/kg, Group B was administered an epidural injection of 50 mg/ml ketamine hydrochloride at 2 mg/kg and Group C was administered an epidural injection of bupivacaine and ketamine combination at 0.5mg/kg and 1 mg/kg respectively. Analgesic indices determined were time to sphincter relaxation, the onset of action, duration of analgesia and duration of muscle relaxation. A standard ovariohysterectomy procedure was carried out at the onset of analgesia on each experimental animal, lasting an average of 45 minutes. Bitches in the bupivacaine group took a longer time (73 ± 18.0 secs) to sphincter relaxation which was significantly different from the other groups. Ketamine took the shortest amount of time (15 ± 3.0 secs) which was almost immediate. The onset of analgesia was the shortest (3 ± 1.0 mins) in group B with ketamine only. The combination of ketamine and bupivacaine produced a longer duration (121 ± 7.0 mins) of analgesia and significant muscle relaxation (110 ± 20.0 mins). The combination of bupivacaine and ketamine produced superior analgesic effects than those of bupivacaine or ketamine alone used for epidural injection, and sufficient for painful surgeries such as ovariohysterectomy in dogs.

Cellular consequences triggered by ketamine on exposure to human glioblastoma epithelial (LN-229) cells.

Ketamine is generally a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist that interrelates with various other receptors, contributing to a wide range of actions. They are mainly approved as a general anesthetic, but a low dose of ketamine is applied for pain management, depression, and as analgesics. However, there is a significant concern regarding the long-term usage as antidepressants and as an abused drug. The study mainly aims to exhibit the possible long-term side effects of ketamine as an antidepressant and in recreational users. The study explores the in vitro cytotoxicity revealed on LN-229 cells in a dose-dependent manner. According to the cell viability assays, there is a dose-dependent response toward ketamine. Morphological and nuclear integrity was changed on exposure and assessed using Giemsa, Rhodamine phalloidin, 4',6-diamidino-2-phenylindole (DAPI), and Acridine orange staining. The apoptotic cell death marked by nuclear condensation, Lactate dehydrogenase leakage, pro-inflammatory cytokine (interleukin [IL]-β) release, and inhibition of cell migration was observed. The study highlights the importance of nonanesthetic usage of ketamine, which can lead to severe adverse side effects on long-term exposure rather than a single exposure as an anesthetic agent.

Glutamate Chemical Exchange Saturation Transfer (GluCEST) MRI to Evaluate the Rapid Antidepressant Effects of Ketamine in the Hippocampus of Rat Depression Model.

Ketamine is a quick acting antidepressant drug, and an accurate detection method is lacking. Ketamine's effects in a rat depression model have not previously been well explored using glutamate chemical exchange saturation transfer (GluCEST). To investigate the GluCEST changes of chronic unpredictable mild stress (CUMS) rats after receiving either ketamine or saline injection. Randomized animal model trial. 12 CUMS and 6 Sprague-Dawley rats. Divided into three groups: ketamine (N = 6), saline (N = 6), and control (N = 6). 7.0 T/the sequence is GluCEST and 1 H MR spectroscopy (MRS). The CUMS rats were exposed to different stress factors for 8 weeks. The glutamate concentration in the hippocampus was assessed by the GluCEST,1 H MRS, and the high-performance liquid chromatography (HPLC). The t-test, Mann-Whitney U test, and Pearson's correlation. In depression conditions, GluCEST signals were lower in the bilateral hippocampus than in control group. Thirty minutes after ketamine injection, the GluCEST signals in the bilateral hippocampus were higher compared with the saline group (left: 2.99 ± 0.34 [Control] vs. 2.44 ± 0.20 [Saline] vs. 2.85 ± 0.11 [Ketamine]; right: 2.97 ± 0.28 [Control] vs. 2.49 ± 0.25 [Saline] vs. 2.86 ± 0.19 [Ketamine]). In 1 H MRS, significant changes were only observed in the left hippocampus (2.00 ± 0.16 [Control] vs. 1.81 ± 0.09 [Saline] vs. 2.04 ± 0.14 [Ketamine]). Furthermore, HPLC results showed similar trends to those observed in the GluCEST results (left: 2.32 ± 0.22 [Control] vs. 1.96 ± 0.11 [Saline] vs. 2.18 ± 0.11 [Ketamine]; right: 2.35 ± 0.18 [Control] vs. 1.87 ± 0.16 [Saline] vs. 2.09 ± 0.08 [Ketamine]). GluCEST can sensitively evaluate the ketamine's antidepressant effects by detecting the fast increase in glutamate concentration. 1 TECHNICAL EFFICACY STAGE: 1.

Low-dose ketamine improves animals' locomotor activity and decreases brain oxidative stress and inflammation in ammonia-induced neurotoxicity.

Ammonium ion (NH4 + ) is the major suspected molecule responsible for neurological complications of hepatic encephalopathy (HE). No specific pharmacological action for NH4 + -induced brain injury exists so far. Excitotoxicity is a well-known phenomenon in the brain of hyperammonemic cases. The hyperactivation of the N-Methyl- d-aspartate (NMDA) receptors by agents such as glutamate, an NH4 + metabolite, could cause excitotoxicity. Excitotoxicity is connected with events such as oxidative stress and neuroinflammation. Hence, utilizing NMDA receptor antagonists could prevent neurological complications of NH4 + neurotoxicity. In the current study, C57BL6/J mice received acetaminophen (APAP; 800 mg/kg, i.p) to induce HE. Hyperammonemic animals were treated with ketamine (0.25, 0.5, and 1 mg/kg, s.c) as an NMDA receptor antagonist. Animals' brain and plasma levels of NH4 + were dramatically high, and animals' locomotor activities were disturbed. Moreover, several markers of oxidative stress were significantly increased in the brain. A significant increase in brain tissue levels of TNF-α, IL-6, and IL-1β was also detected in hyperammonemic animals. It was found that ketamine significantly normalized animals' locomotor activity, improved biomarkers of oxidative stress, and decreased proinflammatory cytokines. The effects of ketamine on oxidative stress biomarkers and inflammation seem to play a key role in its neuroprotective mechanisms in the current study.

Investigation of the effect and availability of ketamine on electroencephalography in cats with temporal lobe epilepsy.

In recent years, electroencephalography (EEG) in veterinary medicine has become important not only in the diagnosis of epilepsy, but also in determining the epileptogenic focus. In cats, sedation and immobilization, usually with medetomidine or dexmedetomidine, are necessary to place the electrodes and to obtain stable scalp EEG recordings. In this study, we hypothesized that, for cats with temporal lobe epilepsy (TLE), ketamine, a sedative/anesthetic and N-methyl-D-aspartate (NMDA) antagonist that activates the limbic system and is also used to treat refractory status epilepticus in dogs, would induce sufficient sedation and immobilization for EEG, as well as induce interictal epileptiform discharges (IEDs) that are more pronounced than those induced with medetomidine. We obtained EEG recordings from TLE cats and healthy cats administered either ketamine or medetomidine alone (study 1) or ketamine after medetomidine sedation (study 2). In study 1, the frequency of IEDs showed no statistically significant difference between ketamine and medetomidine in both TLE and healthy cats. Seizures were observed in 75% (9/12) cats of the TLE group with ketamine alone. When ketamine was administered after sedation with medetomidine (study 2), 3/18 cats in the TLE group developed generalized tonic-clonic seizure and 1/18 cats showed subclinical seizure activity. However, no seizures were observed in all healthy cats in both study 1 and study 2. Slow wave activity at 2-4 Hz was observed in many individuals after ketamine administration regardless studies and groups, and quantitative analysis in study 2 showed a trend toward increased delta band activities in both groups. While there was no significant difference in the count of IEDs between medetomidine and ketamine, ketamine caused seizures in cats with TLE similar to their habitual seizure type and with a higher seizure frequency. Our results suggest that ketamine may activate epileptiform discharges during EEG recordings. However, caution should be used for cats with TLE.

A shea butter-based ketamine ointment: The antidepressant effects of transdermal ketamine in rats

The delayed onset of monoaminergic antidepressants and disadvantages of traditional administration routes created the need for alternative non-invasive delivery methods with rapid onset therapeutic effect. Ketamine attracted attention as a fast-acting glutamatergic antidepressant with ideal physiochemical properties for alternative routes of administration. However, there is no sufficient data for its transdermal use in depression. In this proof-of-concept study, we investigated the antidepressant effects of transdermal ketamine delivered via a novel ointment with skin protective, emulsifying and permeation enhancing properties. A shea butter-based 5% (w/w) ketamine ointment or a drug-free vehicle ointment were applied to the shaved dorsal skin of male Wistar rats for 2 days, twice a day. Behavioral despair, locomotor activity and anxiety-like behavior were respectively assessed in the forced swim test (FST), open field test (OFT), and elevated plus maze (EPM). The pharmacokinetic profile of the ointment was analyzed with high-performance liquid chromatography. Transdermal ketamine ameliorated behavioral despair without altering general locomotor activity and anxiety-like behavior, showing that skin-friendly drug carriers like shea butter may constitute promising alternatives to current routes of delivery for ketamine. Tested transdermal method aims to provide more sustainable drug delivery for long-term treatment schedules. Future studies can investigate its long-term use, side effects and abuse liability.

Optimum Perioperative Analges ia in Radical Nephrectomy, Multimodel Approach with Nalbuphine and Ketamine

Objective: to find perioperative analgesic effectiveness of low dose Ketamine in radical nephrectomy operations and comparing its anodyne potency with Nalbuphine Hcl (Nalbin). Study Design: Quasi-experimental study. Place and Duration of Study: Armed forces institute of urology from Sep 2016 to June 2019. Methodology: The 60 randomly selected surgical patients for radical nephrectomy were divided into two groups in a random manner. The Anaesthetic technique used in both groups (K and N) was standard along with 10 mg injection Nalbin given to both groups at induction. Group-K (n=30) patients had IV Ketamine bolus 0.3 mg /kg followed by 0.1 mg/kg/h infusion at induction till completion of surgery. Group-N (n=30) received a similar volume of saline in bolus as well as an infusion. The pain score (VAS) at different intervals and total Nalbin consumed in 12 hours were recorded for each group. Patient satisfaction and complications were recorded during this period. Results: The effective intraoperative analgesia was achieved with an infusion of low dose Ketamine which continued till completion of surgery as seen in group K which has reduced Nalbin requirement 8.8± 3.5 mg (Group N 25±5 mg). There was a statistically significant reduction in overall pain scores and Nalbin demand (P≤0.05) in the Ketamine group (p≤0.00, 0.036, 0.286, 0.257, 0.253 respectively). Patient satisfaction was better in the Ketamine group but few patients in this group had delayed recovery. Conclusion: Intraoperative low-dose Ketamine infusion provides good postoperative analgesia while reducing the need for opioid analgesics, which must be con

Measuring acute effects of subanesthetic ketamine on cerebrovascular hemodynamics in humans using TD-fNIRS

Quantifying neural activity in natural conditions (i.e. conditions comparable to the standard clinical patient experience) during the administration of psychedelics may further our scientific understanding of the effects and mechanisms of action. This data may facilitate the discovery of novel biomarkers enabling more personalized treatments and improved patient outcomes. In this single-blind, placebo-controlled study with a non-randomized design, we use time-domain functional near-infrared spectroscopy (TD-fNIRS) to measure acute brain dynamics after intramuscular subanesthetic ketamine (0.75 mg/kg) and placebo (saline) administration in healthy participants (n = 15, 8 females, 7 males, age 32.4 ± 7.5 years) in a clinical setting. We found that the ketamine administration caused an altered state of consciousness and changes in systemic physiology (e.g. increase in pulse rate and electrodermal activity). Furthermore, ketamine led to a brain-wide reduction in the fractional amplitude of low frequency fluctuations, and a decrease in the global brain connectivity of the prefrontal region. Lastly, we provide preliminary evidence that a combination of neural and physiological metrics may serve as predictors of subjective mystical experiences and reductions in depressive symptomatology. Overall, our study demonstrated the successful application of fNIRS neuroimaging to study the physiological effects of the psychoactive substance ketamine in humans, and can be regarded as an important step toward larger scale clinical fNIRS studies that can quantify the impact of psychedelics on the brain in standard clinical settings.

Effects of low-dose ketamine infusion on vascular endothelial growth factor and matrix metalloproteinase-9 among patients with treatment-resistant depression and suicidal ideation

BackgroundEvidence indicates that vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9) influence the pathophysiology of depression. However, whether low-dose ketamine regulates VEGF and MMP-9 levels and whether changes in VEGF and MMP-9 levels are associated with the antidepressant and antisuicidal effects of ketamine remained unclear. MethodsForty-eight patients with treatment-resistant depression and strong suicidal ideation (TRD-SI) were randomly assigned to a single infusion of 0.5-mg/kg ketamine or 0.045-mg/kg midazolam. The Montgomery–Åsberg Depression Rating Scale (MADRS) and Columbia-Suicide Severity Rating Scale–Ideation Severity Subscale (CSSRS-ISS) were used at baseline and subsequently at several postinfusion timepoints. VEGF and MMP-9 serum levels were analyzed at baseline and on day 3 postinfusion. ResultsAfter adjustment for baseline levels, no significant differences in VEGF (p = .912) and MMP-9 (p = .758) levels were identified on day 3 postinfusion between the study groups. Baseline VEGF levels but not MMP-9 levels were negatively associated with MADRS and CSSRS-ISS scores following infusion. DiscussionA single infusion of low-dose ketamine did not alter the VEGF and MMP-9 levels of the patients with TRD-SI. Higher baseline VEGF levels were associated with greater antidepressant and antisuicidal effects of single low-dose ketamine infusion.

Single subanesthetic dose of ketamine produces delayed impact on brain [18F]FDG PET imaging and metabolic connectivity in rats.

Ketamine, a glutamate NMDA receptor antagonist, is suggested to act very rapidly and durably on the depressive symptoms including treatment-resistant patients but its mechanisms of action remain unclear. There is a requirement for non-invasive biomarkers, such as imaging techniques, which hold promise in monitoring and elucidating its therapeutic impact. We explored the glucose metabolism with [18F]FDG positron emission tomography (PET) in ten male rats in a longitudinal study designed to compare imaging patterns immediately after acute subanaesthetic ketamine injection (i.p. 10 mg/kg) with its sustained effects, 5 days later. Changes in [18F]FDG uptake following ketamine administration were estimated using a voxel-based analysis with SPM12 software, and a region of interest (ROI) analysis. A metabolic connectivity analysis was also conducted to estimate the immediate and delayed effects of ketamine on the inter-individual metabolic covariance between the ROIs. No significant difference was observed in brain glucose metabolism immediately following acute subanaesthetic ketamine injection. However, a significant decrease of glucose uptake appeared 5 days later, reflecting a sustained and delayed effect of ketamine in the frontal and the cingulate cortex. An increase in the raphe, caudate and cerebellum was also measured. Moreover, metabolic connectivity analyses revealed a significant decrease between the hippocampus and the thalamus at day 5 compared to the baseline. This study showed that the differences in metabolic profiles appeared belatedly, 5 days after ketamine administration, particularly in the cortical regions. Finally, this methodology will help to characterize the effects of future molecules for the treatment of treatment resistant depression.

Ketamine counteracts sevoflurane-induced depressive-like behavior and synaptic plasticity impairments through the adenosine A2A receptor/ERK pathway in rats.

Ketamine is an ionic glutamic acid N-methyl-d-aspartate receptor (NMDAR) antagonist commonly used in clinical anesthesia, and its rapid and lasting antidepressant effect has stimulated great interest in psychology research. However, the molecular mechanisms underlying its antidepressant action are still undetermined. Sevoflurane exposure early in life might induce developmental neurotoxicity and mood disorders. In this study, we evaluated the effect of ketamine against sevoflurane-induced depressive-like behavior and the underlying molecular mechanisms. Here, we reported that A2AR protein expression was upregulated in rats with depression induced by sevoflurane inhalation, which was reversed by ketamine. Pharmacological experiments showed that A2AR agonists could reverse the antidepressant effect of ketamine, decrease extracellular signal-regulated kinase (ERK) phosphorylation, reduce synaptic plasticity, and induce depressive-like behavior. Our results suggest that ketamine mediates ERK1/2 phosphorylation by downregulating A2AR expression and that p-ERK1/2 increases the production of synaptic-associated proteins, enhancing synaptic plasticity in the hippocampus and thereby ameliorating the depressive-like behavior induced by sevoflurane inhalation in rats. This research provides a framework for reducing anesthesia-induced developmental neurotoxicity and developing new antidepressants.

Antidepressant effects of novel positive allosteric modulators of Trk-receptor mediated signaling – a potential therapeutic concept?

BackgroundMajor depressive disorder (MDD) is defined as a complex mental disorder which is characterized by a pervasive low mood and aversion to activity. Several types of neurotransmitter systems e.g. serotonergic, glutamatergic and noradrenergic systems have been suggested to play an important role in the origination of depression, but neurotrophins such as brain derived neurotrophic factor (BDNF) have also been implicated in the disease process.ObjectivesThe purpose of this study was to examine the effects of a newly developed class of molecules, characterized as positive allosteric modulators of neurotrophin/Trk receptor mediated signaling (Trk-PAM), on neurotransmitter release and depression-like behavior in vivo.MethodsThe effect of and possible interaction of neurotrophin/Trk signaling pathways with serotonergic and glutamatergic systems in the modulation of depression-related responses was studied using newly developed Trk-PAM compounds (ACD855, ACD856 and AC26845), as well as ketamine and fluoxetine in the forced swim test (FST) in rodents. Moreover, in vivo microdialysis in freely moving rats was used to assess changes in neurotransmitter levels in the rat.ResultsThe results from the study show that several different compounds, which all potentiate Trk-receptor mediated signaling, display antidepressant-like activity in the FST. Moreover, the data also indicate that the effects of both fluoxetine and ketamine in the FST, both used in clinical practice, aremediated via BDNF/TrkB signaling, which could have implications for novel therapies in MDD.ConclusionsTrk-PAMs could provide an interesting avenue for the development of novel therapeutics in this area.

Impact of ketamine versus propofol for anesthetic induction on cognitive dysfunction, delirium, and acute kidney injury following cardiac surgery in elderly, high-risk patients.

Evaluate the effects of ketamine versus propofol when used for induction of anesthesia in elderly, high-risk cardiac surgical patients on postoperative complications including cognitive dysfunction, delirium, and acute kidney injury. Prospective, randomized study performed at a tertiary medical center. A total of 52 patients aged ≥70 and older presenting for complex cardiac surgery were randomized to receive either ketamine or propofol for induction of anesthesia. Patients underwent a battery of cognitive testing preoperatively and postoperatively and the incidence of delirium and acute kidney injury were measured. Norepinephrine (NEE) equivalents following induction were assessed for each group. A total of 49 patients were included, 25 in the ketamine group and 24 in the propofol group with 3 patients excluded from the analysis. No difference was found between groups in either postoperative cognitive dysfunction or delirium incidence. Acute kidney injury occurred in 6 (24%) patients in the ketamine group in 12 (50%) patients in the propofol group, but the difference did not meet statistical significance (P = 0.08; Relative Risk = 2.1, 95% CI 0.9-4.7). NEE equivalents were lower in the ketamine group, 9.6 ± 22.2 versus 32.7 ± 46.0, P < 0.03. The use of ketamine versus propofol for induction of anesthesia did not impact the incidence of postoperative cognitive dysfunction or delirium. Twice as many patients in the propofol group developed acute kidney injury, although not reaching statistical significance and warranting further investigation. In elderly, high-risk patients, ketamine was associated with a significantly reduced need for vasopressor support following induction.

Sedation Quality of Low – Dose Ketamine Combined with Dexmedetomidine versus Propofol in Phacoemulsification under Local Anesthesia: A Triple-Blinded Randomized Clinical Trial

Purpose: To compare the hemodynamic effects of low-dose ketamine combined with dexmedetomidine versus propofol in phacoemulsification under local anesthesia. Place and Duration of Study: School of Medicine, Isfahan University of Medical Sciences during 2020-2021. Methods: Sixty patients admitted for cataract surgery were included. Those with history of systemic diseases, insufficient pupil dilation, sensitivity to drugs and uncooperative patients were excluded. Participants were randomly allocated to two groups; group which was administered ketamine with dexmedetomidine (Ketodex) and group which was given ketamine with propofol (Ketofel). Effect on blood pressure, pulse and sedation was recorded. Results: Mean age was 65 ± 9.9 years. Sixty-five were females. Ketodex increased the risk of hemodynamic disorders compared to Ketofel (P = 0.04). The risk of nausea and vomiting was higher in the Ketodex group although not significant. The effect of drug course on heart rate, blood pressure and sedation was significant in both groups (P &lt; 0.05). Neither at baseline, nor in the 1st and 5th minutes of surgery, was the mean arterial pressure (MAP) was significantly different between the two groups. From 10th minute of surgery until the end of surgery and from the beginning of recovery until the 30th minute of recovery, the MAP and pulse rate were higher in Ketofol group. Sedation effect during surgery was higher in the Ketodex group compared to the Ketofol group, and the difference was statistically significant at minutes 10, 20 and 30 of surgery. Conclusion: There is higher effect of sedation and fewer side effects of ketamine-dexmedetomidine combination compared to the ketamine-propofol combination.

The IMpact of PerioperAtive KeTamine on Enhanced Recovery after Abdominal Surgery (IMPAKT ERAS): protocol for a pragmatic, randomized, double-blinded, placebo-controlled trial

BackgroundMultimodal analgesic strategies that reduce perioperative opioid consumption are well-supported in Enhanced Recovery After Surgery (ERAS) literature. However, the optimal analgesic regimen has not been established, as the contributions of each individual agent to the overall analgesic efficacy with opioid reduction remains unknown. Perioperative ketamine infusions can decrease opioid consumption and opioid-related side effects. However, as opioid requirements are drastically minimized within ERAS models, the differential effects of ketamine within an ERAS pathway remain unknown. We aim to pragmatically investigate through a learning healthcare system infrastructure how the addition of a perioperative ketamine infusion to mature ERAS pathways affects functional recovery.MethodsThe IMPAKT ERAS trial (IMpact of PerioperAtive KeTamine on Enhanced Recovery after Abdominal Surgery) is a single center, pragmatic, randomized, blinded, placebo-controlled trial. 1544 patients undergoing major abdominal surgery will be randomly allocated to receive intraoperative and postoperative (up to 48 h) ketamine versus placebo infusions as part of a perioperative multimodal analgesic regimen. The primary outcome is length of stay, defined as surgical start time until hospital discharge. Secondary outcomes will include a variety of in-hospital clinical end points derived from the electronic health record.DiscussionWe aimed to launch a large-scale, pragmatic trial that would easily integrate into routine clinical workflow. Implementation of a modified consent process was critical to preserving our pragmatic design, permitting an efficient, low-cost model without reliance on external study personnel. Therefore, we partnered with leaders of our Investigational Review Board to develop a novel, modified consent process and shortened written consent form that would meet all standard elements of informed consent, yet also allow clinical providers the ability to recruit and enroll patients during their clinical workflow. Our trial design has created a platform for subsequent pragmatic studies at our institution.Trial registrationNCT04625283, Pre-results.