Subanesthetic Doses Research Articles

Effects of subanesthetic intravenous ketamine infusion on neuroplasticity-related proteins in male and female Sprague-Dawley rats.

Although ketamine, a multimodal dissociative anesthetic, is frequently used for analgesia and treatment-resistant major depression, molecular mechanisms of ketamine remain unclear. Specifically, differences in the effects of ketamine on neuroplasticity-related proteins in the brains of males and females need further investigation. In the current study, adult male and female Sprague-Dawley rats with an indwelling jugular venous catheter received an intravenous ketamine infusion (0, 10, or 40 mg/kg, 2-h), starting with a 2 mg/kg bolus for ketamine groups. Spontaneous locomotor activity was monitored by infrared photobeams during the infusion. Two hours after the infusion, brain tissue was dissected to obtain the medial prefrontal cortex (mPFC), hippocampus including the CA1, CA3, and dentate gyrus, and amygdala followed by Western blot analyses of a transcription factor (c-Fos), brain-derived neurotrophic factor (BDNF), and phosphorylated extracellular signal-regulated kinase (pERK). The 10 mg/kg ketamine infusion suppressed locomotor activity in male and female rats while the 40 mg/kg infusion stimulated activity only in female rats. In the mPFC, 10 mg/kg ketamine reduced pERK levels in male rats while 40 mg/kg ketamine increased c-Fos levels in male and female rats. Female rats in proestrus/estrus phases showed greater ketamine-induced c-Fos elevation as compared to those in diestrus phase. In the amygdala, 10 and 40 mg/kg ketamine increased c-Fos levels in female, but not male, rats. In the hippocampus, 10 mg/kg ketamine reduced BDNF levels in male, but not female, rats. Taken together, the current data suggest that subanesthetic doses of intravenous ketamine infusions produce differences in neuroplasticity-related proteins in the brains of male and female rats.

Opioid receptor system contributes to the acute and sustained antidepressant-like effects, but not the hyperactivity motor effects of ketamine in mice

In 2000, a subanesthetic dose (0.5 mg/kg i.v.) of the dissociative anesthetic ketamine was reported to have both rapid and robust antidepressant effects in patients diagnosed with major depressive disorder and later, ketamine also was shown to be effective in treatment-resistant depressed patients. However, the mechanisms responsible for ketamine's antidepressant effects remain unclear. In 2018, a clinical study reported that pretreatment with the nonselective opioid antagonist naltrexone attenuated the rapid antidepressant effect of ketamine in depressed patients. The current study investigated the potential role of the opioid receptor system in the acute and sustained antidepressant-like and hyperactive effects of ketamine. Mice were tested in the tail suspension test (TST) and differential-reinforcement-of-low-rate responding (DRL) 72 s task which are behavioral screens for antidepressant-like properties. Additionally, open field locomotor activity also was measured. In all behavioral assays, mice were pretreated with the nonselective opioid receptor antagonist naltrexone or saline prior to ketamine administration. The current study found that ketamine (10 mg/kg) produced acute (30 min) and sustained (24 h) antidepressant-like effects in TST, which were attenuated by pretreatment of 2 mg/kg naltrexone. Ketamine (32 mg/kg) also produced an acute antidepressant-like effect in the DRL 72 s task that was attenuated by pretreatment of 2 mg/kg naltrexone. Finally, ketamine (10 and 32 mg/kg) produced hyperactivity in the open field; however, pretreatment with 2 mg/kg naltrexone failed to block the hyperactivity effects ketamine. These results, along with recent clinical findings, suggest that ketamine's antidepressant effects, but not its hyperactive effects, involve activation of the opioid system.

Determination of Diffusion Kinetics of Ketamine in Brain Tissue: Implications for in vitro Mechanistic Studies of Drug Actions.

Ketamine has been in use for over 50 years as a general anesthetic, acting primarily through blockade of N-methyl-D-aspartate receptors in the brain. Recent studies have demonstrated that ketamine also acts as a potent and rapid-acting antidepressant when administered at sub-anesthetic doses. However, the precise mechanism behind this effect remains unclear. We examined the diffusion properties of ketamine in brain tissue to determine their effects in in vitro studies related to the antidepressant action of ketamine. Brain slices from adult mice were exposed to artificial cerebrospinal fluid (aCSF) containing ∼17 μM ketamine HCl for varying amounts of time. The amount of ketamine within each slice was then measured by tandem high-performance liquid chromatography – mass spectrometry to characterize the diffusion of ketamine into brain tissue over time. We successfully modeled the diffusion of ketamine into brain tissue using a mono-exponential function with a time constant of τ = 6.59 min. This curve was then compared to a one-dimensional model of diffusion yielding a diffusion coefficient of approximately 0.12 cm2⋅s–1 for ketamine diffusing into brain tissue. The brain:aCSF partition coefficient for ketamine was determined to be approximately 2.76. Our results suggest that the diffusion properties of ketamine have a significant effect on drug concentrations achieved within brain tissue during in vitro experiments. This information is vital to determine the ketamine concentration necessary for in vitro slice preparation to accurately reflect in vivo doses responsible for its antidepressant actions.

Neonatal administration of a subanaesthetic dose of JM-1232(\u2212) in mice results in no behavioural deficits in adulthood

In animal models, neonatal exposure of general anaesthetics significantly increases apoptosis in the brain, resulting in persistent behavioural deficits later in adulthood. Consequently, there is growing concern about the use of general anaesthetics in obstetric and paediatric practice. JM-1232(−) has been developed as a novel intravenous anaesthetic, but the effects of JM-1232(−) on the developing brain are not understood. Here we show that neonatal administration of JM-1232(−) does not lead to detectable behavioural deficits in adulthood, contrarily to other widely-used intravenous anaesthetics. At postnatal day 6 (P6), mice were injected intraperitoneally with a sedative-equivalent dose of JM-1232(−), propofol, or midazolam. Western blot analysis of forebrain extracts using cleaved poly-(adenosine diphosphate-ribose) polymerase antibody showed that JM-1232(−) is accompanied by slight but measurable apoptosis 6 h after administration, but it was relatively small compared to those of propofol and midazolam. Behavioural studies were performed in adulthood, long after the neonatal anaesthesia, to evaluate the long-term effects on cognitive, social, and affective functions. P6 administration to JM-1232(−) was not accompanied by detectable long-term behavioural deficits in adulthood. However, animals receiving propofol or midazolam had impaired social and/or cognitive functions. These data suggest that JM-1232(−) has prospects for use in obstetric and paediatric practice.

Ketamine disrupts gaze patterns during face viewing in the common marmoset.

Faces are stimuli of critical importance for primates. The common marmoset (Callithrix jacchus) is a promising model for investigations of face processing, as this species possesses oculomotor and face-processing networks resembling those of macaques and humans. Face processing is often disrupted in neuropsychiatric conditions such as schizophrenia (SZ), and thus, it is important to recapitulate underlying circuitry dysfunction preclinically. The N-methyl-d-aspartate (NMDA) noncompetitive antagonist ketamine has been used extensively to model the cognitive symptoms of SZ. Here, we investigated the effects of a subanesthetic dose of ketamine on oculomotor behavior in marmosets during face viewing. Four marmosets received systemic ketamine or saline injections while viewing phase-scrambled or intact videos of conspecifics' faces. To evaluate effects of ketamine on scan paths during face viewing, we identified regions of interest in each face video and classified locations of saccade onsets and landing positions within these areas. A preference for the snout over eye regions was observed following ketamine administration. In addition, regions in which saccades landed could be significantly predicted by saccade onset region in the saline but not the ketamine condition. Effects on saccade control were limited to an increase in saccade peak velocity in all conditions and a reduction in saccade amplitudes during viewing of scrambled videos. Thus, ketamine induced a significant disruption of scan paths during viewing of conspecific faces but limited effects on saccade motor control. These findings support the use of ketamine in marmosets for investigating changes in neural circuits underlying social cognition in neuropsychiatric disorders.NEW & NOTEWORTHY Face processing, an important social cognitive ability, is impaired in neuropsychiatric conditions such as schizophrenia. The highly social common marmoset model presents an opportunity to investigate these impairments. We administered subanesthetic doses of ketamine to marmosets to model the cognitive symptoms of schizophrenia. We observed a disruption of scan paths during viewing of conspecifics' faces. These findings support the use of ketamine in marmosets as a model for investigating social cognition in neuropsychiatric disorders.

N-methyl d-aspartate receptor hypofunction reduces visual contextual integration.

Visual cognition is finely tuned to the elements in a scene but also relies on contextual integration to improve visual detection and discrimination. This integration is impaired in patients with schizophrenia. Studying impairments in contextual integration may lead to biomarkers of schizophrenia, tools to monitor disease progression, and, in animal models, insight into the underlying neural deficits. We developed a nonhuman primate model to test the hypothesis that hypofunction of the N-methyl d-aspartate receptor (NMDAR) impairs contextual integration.Two male rhesus macaques (Macaca mulatta) were trained to indicate which of two patterns on the screen had the highest contrast. One of these patterns appeared in isolation, and the other was surrounded by a high-contrast pattern. In humans, this high-contrast context is known to lead to an underestimation of contrast. This so-called Chubb illusion is thought to result from surround suppression, a key contextual integration mechanism. To test the involvement of NMDAR in this process, we compared animals’ perceptual bias with and without intramuscular injections of a subanesthetic dose of the NMDAR antagonist ketamine.In the absence of ketamine, the animals reported a Chubb illusion - matching reports in healthy humans. Hence, monkeys - just like humans - perform visual contextual integration. This reaffirms the importance of nonhuman primates to help understand visual cognition. Injection of ketamine significantly reduced the strength of the illusion and thus impaired contextual integration. This supports the hypothesis that NMDAR hypofunction plays a causal role in specific behavioral impairments observed in schizophrenia.

Hsa-miR-605 regulates the proinflammatory chemokine CXCL5 in complex regional pain syndrome

Complex regional pain syndrome (CRPS) is a chronic pain condition characterized by inflammation and debilitating pain. CRPS patients with pain refractory to more conventional analgesics can be treated with subanesthetic doses of ketamine. Our previous studies found that poor responders to ketamine had a 22-fold downregulation of the miRNA hsa-miR-605 in blood prior to ketamine treatment. Hence, we sought to investigate the functional significance of miR-605 downregulation and its impact on target gene expression, as investigating target mRNAs of differentially expressed miRNAs can provide important insights on aberrant gene expression that may contribute to disease etiology. Using a bioinformatics prediction, we identified that miR-605 can target the proinflammatory chemokine CXCL5, which plays a role in leukocyte recruitment and activation. We hypothesized that downregulation of miR-605 in poor responders to ketamine could increase CXCL5 expression and thereby contribute to inflammation in these patients. We confirmed that miR-605 regulates CXCL5 by using a miRNA mimic and inhibitor in human primary endothelial cells. Inhibition of miR-605 increased CXCL5 secretion and migration of human monocytic cells, thereby demonstrating a functional impact of miR-605 on chemotaxis. Additionally, CXCL5 mRNA was upregulated in whole blood from poor responders to ketamine, and CXCL5 protein was increased in plasma from CRPS patients. Thus, our studies suggest that miR-605 regulation of CXCL5 can regulate inflammation.

Ketamine prolongs survival in symptomatic SOD1-G93A mice


 Objective. Although riluzole and edaravone are FDA-approved for Amyotrophic Lateral Sclerosis (ALS), these drugs have negligible effect on disease progression and survival. Recent studies reporting neuroprotection from sub-anesthetic doses of ketamine support testing this drug in this rapidly progressing and fatal disease. 
 
 
 
 Methods. We administered ketamine at 0, 10, and 30 mg/kg to SOD1-G93A mice 5 days/week beginning at 90 days of age. We measured body weight, grip strength, and survival in this model of ALS. 
 
 
 
 Results. Although ketamine did not influence disease-related loss of body weight, it did delay grip strength declines in the 30 mg/kg group. Ketamine also prolonged survival in the 30 mg/kg group and dose-dependently increased the latency between 20% loss of body weight and death. 
 
 
 
 Conclusions. These results support further testing of ketamine in preclinical models of ALS to determine optimal dosing. They also support testing in the clinic given the limited efficacy of current ALS treatments and given FDA approval of ketamine for other indications like treatment-resistant depression.

The impact of a standardised ketamine step protocol for cancer neuropathic pain

Context Ketamine at sub-anesthetic doses is a potent analgesia. Its use in cancer pain remains equivocal with protocols varying in patient selection, starting dose, titration, duration of use and adjustment of co-analgesics. Objective To study the impact of a standardised Ketamine Step Protocol on cancer pain in a Palliative Care Unit (PCU). Methodology This is a prospective cohort study of a standardised Ketamine Step Protocol which was developed in a PCU for use in cancer pain. The subcutaneous ketamine infusion was standardised at a starting dose of 75 mg over 24 hours with Haloperidol 5 mg as prophylaxis against psycho-mimetic side effects. Incremental doses of ketamine followed the daily stepwise protocol. Result Of the 48 patients analysed, 41 (85.4%) had neuropathic cancer pain. The median Palliative Performance Scale score (PPSv2) was 40%. Mean Numerical Rating Score (NRS) improved from 6.74 to 2.61 (P < 0.0001) with a mean percentage reduction of 58.05%. The final mean daily ketamine dose needed to achieve stable pain control was 137.50 mg/day (±81.54). 31(62.5%) patients achieved pain control by day 3. The mean Morphine Equivalent Daily Dose (MEDD) reduction was from 130.34 mg to 107.33 mg (P < 0.002) with a percentage reduction of 18.85%. More than half of our patients completed the 5 d protocol with mild to moderate side effects not warranting urgent medical intervention nor termination of the ketamine protocol. Conclusion Use of a standardised Ketamine Step Protocol showed a statistically significant reduction in pain and MEDD in patients with predominantly neuropathic cancer pain. It also demonstrated a safe and effective method for opioid reduction after commencement of parenteral ketamine. Key Message How can a standardised ketamine protocol impact on cancer pain control? Our study shows that: Parenteral ketamine is a potent analgesic which significantly reduced pain in patients with cancer neuropathic pain. This study also demonstrated a safe and effective method for titration of opioids after parenteral ketamine is started. Concurrent use of psychotropics also helps to reduce psycho-mimetic side effects, increasing tolerability to ketamine.

Ketamine's schizophrenia-like effects are prevented by targeting PTP1B

Subanesthetic doses of ketamine induce schizophrenia-like behaviors in mice including hyperlocomotion and deficits in working memory and sensorimotor gating. Here, we examined the effect of in vivo ketamine administration on neuronal properties and endocannabinoid (eCB)-dependent modulation of synaptic transmission onto layer 2/3 pyramidal neurons in brain slices of the prefrontal cortex, a region tied to the schizophrenia-like behavioral phenotypes of ketamine. Since deficits in working memory and sensorimotor gating are tied to activation of the tyrosine phosphatase PTP1B in glutamatergic neurons, we asked whether PTP1B contributes to these effects of ketamine. Ketamine increased membrane resistance and excitability of pyramidal neurons. Systemic pharmacological inhibition of PTP1B by Trodusquemine restored these neuronal properties and prevented each of the three main ketamine-induced behavior deficits. Ketamine also reduced mobilization of eCB by pyramidal neurons, while unexpectedly reducing their inhibitory inputs, and these effects of ketamine were blocked or occluded by PTP1B ablation in glutamatergic neurons. While ablation of PTP1B in glutamatergic neurons prevented ketamine-induced deficits in memory and sensorimotor gating, it failed to prevent hyperlocomotion (a psychosis-like phenotype). Taken together, these results suggest that PTP1B in glutamatergic neurons mediates ketamine-induced deficits in eCB mobilization, memory and sensorimotor gating whereas PTP1B in other cell types contributes to hyperlocomotion. Our study suggests that the PTP1B inhibitor Trodusquemine may represent a new class of fast-acting antipsychotic drugs to treat schizophrenia-like symptoms.

Ketamine disrupts naturalistic coding of working memory in primate lateral prefrontal cortex networks

Ketamine is a dissociative anesthetic drug, which has more recently emerged as a rapid-acting antidepressant. When acutely administered at subanesthetic doses, ketamine causes cognitive deficits like those observed in patients with schizophrenia, including impaired working memory. Although these effects have been linked to ketamine’s action as an N-methyl-D-aspartate receptor antagonist, it is unclear how synaptic alterations translate into changes in brain microcircuit function that ultimately influence cognition. Here, we administered ketamine to rhesus monkeys during a spatial working memory task set in a naturalistic virtual environment. Ketamine induced transient working memory deficits while sparing perceptual and motor skills. Working memory deficits were accompanied by decreased responses of fast spiking inhibitory interneurons and increased responses of broad spiking excitatory neurons in the lateral prefrontal cortex. This translated into a decrease in neuronal tuning and information encoded by neuronal populations about remembered locations. Our results demonstrate that ketamine differentially affects neuronal types in the neocortex; thus, it perturbs the excitation inhibition balance within prefrontal microcircuits and ultimately leads to selective working memory deficits.

GluN2B‐containing NMDA Receptors on Sst‐interneurons act as Initial Cellular Trigger for Antidepressant Actions of Ketamine

A single subanesthetic dose of ketamine exerts rapid antidepressant-like effects via rapid glutamate efflux, activation of mTORC1 signaling, and enhanced synaptic transmission in the medial prefrontal cortex (mPFC); however, the initial cellular trigger for these synaptic and behavioral actions of ketamine still remains unclear. Here, we used electrophysiology, biochemistry, molecular biology and behavioral approaches to determine the baseline sex differences in behavior after GluN2B conditional deletion from Sst-interneurons, and effect of ketamine on chronic unpredictable stress (CUS)-induced behavioral deficits, activation of mTOR signaling cascade and changes in synaptic transmission in male and female GluN2Bfl/fl (WT) and Sst-creGluN2Bfl/fl mice (KO) mice. Acute treatment of ketamine reduces NMDA-induced burst firing of Sst-interneurons ex vivo in mPFC. Deletion of GluN2B from Sst-GABAergic interneurons in the KO produced sexually dimorphic changes in synaptic transmission and behavior. Consistent with the disinhibition hypothesis, ketamine reduces inhibitory, but enhances excitatory transmission of layer V pyramidal neurons of mPFC and reverses CUS-induced behavioral deficits only in WT, but not KO, mice. Preliminary data demonstrate that deletion of GluN2B from Sst-interneurons blocks ketamine-induced activation of mTOR signaling cascade. Our results demonstrate that Sst-interneurons are an initial cellular trigger for synaptic and behavioral actions of ketamine. Consistent with the disinhibition hypothesis, ketamine actions are mediated by GluN2B-NMDARs on Sst-interneurons via disinhibition of pyramidal neurons, activation of mTOR signaling, and enhanced synaptic function in mPFC.

Sustained release ketamine-loaded porous silicon-PLGA microparticles prepared by an optimized supercritical CO2 process.

Ketamine in sub-anaesthetic doses has analgesic properties and an opioid-sparing effect. Intrathecal (i.t.) delivery of analgesics bypasses systemic metabolism and delivers the analgesic agent adjacent to the target receptors in the spinal cord and so small doses are required to achieve effective pain relief. In order to relieve intractable cancer-related pain, sustained-release ketamine formulations are required in combination with a strong opioid because frequent i.t. injection is not practical. In this study, ketamine or ketamine-loaded porous silicon (pSi) were encapsulated into poly(lactic-co-glycolic acid) (PLGA) microparticles by a novel supercritical carbon dioxide (scCO2) method, thereby avoiding the use of organic solvent. Multiple parameters including theoretical drug loading (DL), presence of pSi, size of scCO2 vessel, PLGA type, and use of co-solvent were investigated with a view to obtaining high DL and a sustained-release for an extended period. The most important finding was that the use of a large scCO2 vessel (60mL) resulted in a much higher encapsulation efficiency (EE) compared with a small vessel (12mL). In addition, pre-loading ketamine into pSi slightly improved the level of drug incorporation (i.e. EE and DL). Although the in vitro release was mainly affected by the drug payload, the use of the large scCO2 vessel reduced the burst release and extended the release period for PLGA microparticles with 10% or 20% ketamine loading. Together, our findings provide valuable information for optimization of drug delivery systems prepared with the aid of scCO2.

Novel Glutamatergic Modulators for the Treatment of Mood Disorders: Current Status.

The efficacy of standard antidepressants is limited for many patients with mood disorders such as major depressive disorder (MDD) and bipolar depression, underscoring the urgent need to develop novel therapeutics. Both clinical and preclinical studies have implicated glutamatergic system dysfunction in the pathophysiology of mood disorders. In particular, rapid reductions in depressive symptoms have been observed in response to subanesthetic doses of the glutamatergic modulator racemic (R,S)-ketamine in individuals with mood disorders. These results have prompted investigation into other glutamatergic modulators for depression, both as monotherapy and adjunctively. Several glutamate receptor-modulating agents have been tested in proof-of-concept studies for mood disorders. This manuscript gives a brief overview of the glutamate system and its relevance to rapid antidepressant response and discusses the existing clinical evidence for glutamate receptor-modulating agents, including (1) broad glutamatergic modulators ((R,S)-ketamine, esketamine, (R)-ketamine, (2R,6R)-hydroxynorketamine [HNK], dextromethorphan, Nuedexta [a combination of dextromethorphan and quinidine], deudextromethorphan [AVP-786], axsome [AXS-05], dextromethadone [REL-1017], nitrous oxide, AZD6765, CLE100, AGN-241751); (2) glycine site modulators (D-cycloserine [DCS], NRX-101, rapastinel [GLYX-13], apimostinel [NRX-1074], sarcosine, 4-chlorokynurenine [4-Cl-KYN/AV-101]); (3) subunit (NR2B)-specific N-methyl-D-aspartate (NMDA) receptor antagonists (eliprodil [EVT-101], traxoprodil [CP-101,606], rislenemdaz [MK-0657/CERC-301]); (4) metabotropic glutamate receptor (mGluR) modulators (basimglurant, AZD2066, RG1578, TS-161); and (5) mammalian target of rapamycin complex 1 (mTORC1) activators (NV-5138). Many of these agents are still in the preliminary stages of development. Furthermore, to date, most have demonstrated relatively modest effects compared with (R,S)-ketamine and esketamine, though some have shown more favorable characteristics. Of these novel agents, the most promising, and the ones for which the most evidence exists, appear to be those targeting ionotropic glutamate receptors.

Guanine-Based Purines as an Innovative Target to Treat Major Depressive Disorder.

Guanine-Based Purines as an Innovative Target to Treat Major Depressive Disorder.

Acute cognitive effects of single-dose intravenous ketamine in major depressive and posttraumatic stress disorder

Intravenous (IV) subanesthetic doses of ketamine have been shown to reduce psychiatric distress in both major depressive (MDD) and posttraumatic stress disorder (PTSD). However, the effect of ketamine on cognitive function in these disorders is not well understood. To address this gap, we examined the effect of a single dose of IV ketamine on cognition in individuals with MDD and/or PTSD relative to healthy controls (HC). Psychiatric (n = 29; 15 PTSD, 14 MDD) and sex- age- and IQ matched HC (n = 29) groups were recruited from the community. A single subanesthetic dose of IV ketamine was administered. Mood and cognitive measures were collected prior to, 2 h and 1 day post-ketamine administration. MDD/PTSD individuals evidenced a large-magnitude improvement in severity of depressive symptoms at both 2-hours and 1 day post-ketamine administration (p’s < .001, Cohen d’s = 0.80–1.02). Controlling for baseline performance and years of education, IV ketamine induced declines in attention (ATTN), executive function (EF), and verbal memory (VM) 2 h post-administration, all of which had resolved by 1 day post-ketamine across groups. The magnitude of cognitive decline was significantly larger in MDD/PTSD relative to HC on attention only (p = .012, d = 0.56). Ketamine did not affect working memory (WM) performance. Cognitive function (baseline, change from baseline to post-ketamine) was not associated with antidepressant response to ketamine. Results suggest that while ketamine may have an acute deleterious effect on some cognitive domains in both MDD/PTSD and HC individuals, most notably attention, this reduction is transient and there is no evidence of ketamine-related cognitive dysfunction at 1 day post-administration.

Sedative and analgesic effects of two subanaesthetic doses of ketamine in combination with methadone and a low dose of dexmedetomidine in healthy dogs

ObjectiveTo evaluate the sedative, analgesic and recovery characteristics of two subanaesthetic ketamine doses in combination with dexmedetomidine and methadone for intramuscular sedation in healthy Beagles. Study designRandomized, blinded, crossover, experimental study. AnimalsSix healthy adult Beagles. MethodsDogs were randomly given three treatments: dexmedetomidine (3 μg kg–1) and methadone (0.3 mg kg–1) combined with ketamine at 1 and 2 mg kg–1 (K1 and K2, respectively) or saline (K0), intramuscularly. Sedation score, response to tail clamping and rectal temperature were recorded at baseline, 5, 15, 25, 35, and 45 minutes posttreatment. Pulse rate (PR), respiratory rate, oxygen haemoglobin saturation and noninvasive blood pressure were also recorded at baseline and every 5 minutes until 45 minutes posttreatment. Onset and duration of recumbency, response to venous catheterization and recovery quality were also assessed. Sedation and physiological variables were compared between treatments and within treatments compared to baseline (analysis of variance). Nonparametric data were analysed with the Friedman and Cochran’s Q tests; p < 0.050. ResultsIncreased sedation was found at 15 (K0 and K1), 25 (all treatments) and 35 (K1) minutes compared with baseline. Sedation score, onset (3–12 minutes) and duration of recumbency (29–51 minutes) were similar between treatments. Recovery quality was considered acceptable in all cases. Response to tail clamping was inconsistent within treatments with no differences between them. None of the dogs responded to venous catheterization. There were no differences between treatments in physiological variables, except for PR which was higher in K2 than in K0. Oxygen supplementation was required in five and three dogs administered saline and ketamine, respectively. Conclusions and clinical relevanceThe addition of 1 or 2 mg kg–1 of ketamine to methadone and dexmedetomidine combination did not enhance sedation or antinociception in healthy dogs. Recovery quality was unaffected.

Effect of Ketamine on Human Neurochemistry in Posterior Cingulate Cortex: A Pilot Magnetic Resonance Spectroscopy Study at 3 Tesla.

Ketamine is a powerful glutamatergic long-lasting antidepressant, efficient in intractable major depression. Whereas ketamine’s immediate psychomimetic side-effects were linked to glutamate changes, proton MRS (1H-MRS) showed an association between the ratio of glutamate and glutamine and delayed antidepressant effect emerging ∼2 h after ketamine administration. While most 1H-MRS studies focused on anterior cingulate, recent functional MRI connectivity studies revealed an association between ketamine’s antidepressant effect and disturbed connectivity patterns to the posterior cingulate cortex (PCC), and related PCC dysfunction to rumination and memory impairment involved in depressive pathophysiology. The current study utilized the state-of-the-art single-voxel 3T sLASER 1H-MRS methodology optimized for reproducible measurements. Ketamine’s effects on neurochemicals were assessed before and ∼3 h after intravenous ketamine challenge in PCC. Concentrations of 11 neurochemicals, including glutamate (CRLB ∼ 4%) and glutamine (CRLB ∼ 13%), were reliably quantified with the LCModel in 12 healthy young men with between-session coefficients of variation (SD/mean) <8%. Also, ratios of glutamate/glutamine and glutamate/aspartate were assessed as markers of synaptic function and activated glucose metabolism, respectively. Pairwise comparison of metabolite profiles at baseline and 193 ± 4 min after ketamine challenge yielded no differences. Minimal detectable concentration differences estimated with post hoc power analysis (power = 80%, alpha = 0.05) were below 0.5 μmol/g, namely 0.39 μmol/g (∼4%) for glutamate, 0.28 μmol/g (∼10%) for Gln, ∼14% for glutamate/glutamine and ∼8% for glutamate/aspartate. Despite the high sensitivity to detect between-session differences in glutamate and glutamine concentrations, our study did not detect delayed glutamatergic responses to subanesthetic ketamine doses in PCC.

Sedation and anesthesia of pediatric patient for External beam radiotherapy (XRT)

BACKGROUND: External beam radiation delivers a beam of high-energy x-rays to a patient's tumor site, Ιn order to destroy the cancer cells. External beam radiation gets its name from the fact that the beams come from an external source (a machine called a linear accelerator) and are aimed at the site of the tumor.AIM: was to obtain the most recent guideline in sedation and anesthesia of pediatric patient for External beam radiotherapy (XRT). Providing sedation anesthesia techniques during the performance of diagnostic and therapeutic procedures οn children decreases anxiety, discomfort, and pain and may improve child wellbeing. Immobilization is a pre-requisite for accurate radiotherapy. SUBJECTS and METHODS: This is a review article, the search was performed in MEDLINE , Embase , Pubmed, and CINHAL. RESULTS: Anesthetic drugs can be used in sub-anesthetic doses to cause sedation but, because they are potent, the difference between sedative and anesthetic doses is too small and airway skills are required too often for non-anesthetists to use them.C0NCLUSION: Sedation and anesthesia of pediatric patients have serious associated risks, as hypoventilation, apnea airway obstruction and cardiopulmonary impairment or depression. These risks should be avoided, diagnosed rapidly and treated appropriately. Medical practitioners responsible for the sedation process should know the nature of the sedatives and their side-effects. They should be able to detect and manage complications.This study was approved by the institutional ethical committee.

A systematic review of ketamine for the treatment of depression among older adults

<h3>Introduction</h3> Depression is the second most prevalent mental health disorder among older adults after anxiety disorders. It effects 7% of the general older population globally 5.6% of US older adults. Suicide rates also increase between ages of 60-90 in both men and women around the world. A large body of literature shows increased association of late life depression with increased morbidity and mortality in this age group. Evidence for depression as a risk factor for physical and cognitive decline that results in lower quality of life and function among older adults underlines the importance of early recognition and prompt treatment of this serious condition. The most common modalities currently used for treatment of late life depression include pharmacotherapy, psychotherapy and electroconvulsive therapy (ECT). Pharmacotherapy mostly consists of antidepressants targeting the monoaminergic system. Ketamine has recently emerged as a novel, rapid acting option for treatment resistant depression in adults. Ketamine is a N-methyl-D-aspartate (NMDA) receptor antagonist, which has been used primarily as an anesthetic since the 1960s. In 1990s preclinical studies demonstrated the role of NMDA receptor antagonists in treatment of depression, which was later confirmed in a pilot clinical study. Berman et al administered subanaesthetic doses of Ketamine (0.5mg/kg) vs. placebo to 7 study participants which resulted in robust decreases in Hamilton Depression Rating Scale scores within 4 hours of the infusion in all participants. The effect was sustained for 3 days followed by diminution of the scores and relapse of symptoms. This rapid onset anti-depressant effect of ketamine compared to conventional antidepressants attracted considerable interest and these findings have since been reliably replicated in multiple different studies, using different protocols and routes of administration of ketamine. This systematic review evaluates randomized controlled trials completed in the older adult population with depression to appraise the efficacy and tolerability of ketamine specifically in this population. <h3>Methods</h3> The authors followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) On November 09, 2019 the authors conducted a comprehensive search of multiple databases: PubMed (through November 09, 2019), MEDLINE (Ovid ALL 1946 to November 08, 2019), Embase (Ovid 1974 to 2019 November 08), PsycINFO (Ovid 1806 to October Week 4 2019), Web of Science Core Collection (through November 09, 2019), and Cochrane Central Register of Controlled Trials (Issue 11 of 12, November 2019). The search strategy was filtered for human studies in PubMed, MEDLINE, and Embase using controlled vocabulary terms in the search strategy. On December 13, 2019 an updated search was completed. The search repeated the controlled vocabulary terms and free text terms. <h3>Results</h3> A total of 1699 citations were deduplicated to 1005 and uploaded to Covidence for screening by two separate screeners. Two studies were found to meet the inclusion criteria for this review. The first study showed a significant reduction in depression symptoms with use of repeated subcutaneous ketamine administration among older adults with depression. The second study failed to achieve significance on its primary outcome measure but did show a decrease in MADRS scores with intranasal ketamine. This study also showed a higher response and remission rates in esketamine group when compared to the placebo group. Both the studies showed relapse in symptoms after a week of last treatment, but the benefits were better sustained with repeated treatments. The adverse effects from ketamine generally lasted only lasted a few hours and abated spontaneously without any additional intervention. No cognitive adverse effects were noted in either trial from the use of ketamine. <h3>Conclusions</h3> The current evidence for use of ketamine among older adults with depression indicates some benefits with one positive and one negative trial. Although one of the trails did not achieve significance on primary outcome measure, it still showed benefit of ketamine in reducing depressive symptoms. Both studies show longer sustenance of antidepressant effects at higher doses and with repeated treatments. One of the studies showed better ketamine efficacy in younger old subjects (65 to 74 years) when compared to older old (³75 years) subjects. Ketamine was well tolerated in both studies with adverse-effects being mild and transient. Additionally, there were no negative cognitive effects of ketamine noted among any of the study participants. Based on the limited current evidence, it is our opinion that ketamine shows some benefit in relieving depressive symptoms in older adults. However, there is dearth of randomized controlled trials and we need more well designed studies to arrive at a reliable conclusion regarding ketamine's benefit in treating depression among older adults. <h3>Funding</h3> None