High-dose Ketamine Research Articles

High- versus low-dose ketamine for analgesia in older adults in the emergency department

Background and objectivesKetamine is increasingly being utilized in the management of acute pain in the emergency department (ED), including for older adults, a population at increased risk of adverse effects from medications. We aimed to compare the safety and analgesic effects of high-dose (≥0.3mg/kg) to low-dose (<0.3mg/kg) intravenous (IV) ketamine among older ED patients. MethodsMulti-center, retrospective cohort study of adults ≥60years who received IV ketamine for pain between 2018 and 2021. The primary outcome was pain improvement as measured by the Numerical Rating Scale (NRS) pain score within 60min after administration. Secondary outcomes included adverse effects (early discontinuation, nausea, rescue benzodiazepines and intubation) and the need for rescue analgesia. Linear regression was used to assess the association between the change in NRS pain scores and dose after adjusting for baseline pain, requiring an additional dose of ketamine, and receiving an opioid. ResultsA total of 130 older adults received ketamine as an analgesic (37 high-dose, 93 low-dose). Median age was 69.2years, 52 % were women, 40 % had a history of substance use disorder. Prior to ketamine, 76 % received alternate analgesics and 23 % antiemetics. Baseline mean pain score was lower in the high-dose group (6.7 vs. 8.3, difference − 1.7 [95 % CI −2.6 to −0.7], p = 0.013). Change in NRS pain scores were similar between the high-dose and low-dose groups (−2.4 [95 % CI −3.6 to −1.3] vs −1.6 [95 % CI −2.2 to −0.9], p = 0.27). After adjustment for baseline pain score, the high-dose group had a larger reduction in pain scores (−1.3 [95 % CI −2.6 to −0.1], p = 0.042) and percent change of pain (−23.8 % [95 % CI −42.1 % to −5.4 %], p = 0.012). There was no significant difference in rates of rescue analgesia (35.1 % vs. 44.1 %, p = 0.35) or early discontinuation (29.7 % vs. 32.3 %, p = 0.78). Rates of adverse effects were similar. ConclusionHigh-dose and low-dose ketamine reduced pain scores in older adults. High-dose ketamine led to a greater reduction in pain scores, and there was no observed difference in adverse effects or the need for rescue analgesia. One-third needed discontinuation of ketamine in both groups.

Methylphenidate Reversal of Dexmedetomidine-Induced Versus Ketamine-Induced Sedation in Rats.

Dexmedetomidine and ketamine have long elimination half-lives in humans and have no clinically approved reversal agents. Methylphenidate enhances dopaminergic and noradrenergic neurotransmission by inhibiting reuptake transporters for these arousal-promoting neurotransmitters. Previous studies in rats demonstrated that intravenous methylphenidate induces emergence from isoflurane and propofol general anesthesia. These 2 anesthetics are thought to act primarily through enhancement of inhibitory Gamma-aminobutyric acid type A (GABAA) receptors. In this study, we tested the behavioral and neurophysiological effects of methylphenidate in rats after low and high doses of dexmedetomidine (an alpha-2 adrenergic receptor agonist) and ketamine (an N-methyl-D-aspartate [NMDA] receptor antagonist) that induce sedation and unconsciousness, respectively. All experiments used adult male and female Sprague-Dawley rats (n = 32 total) and all drugs were administered intravenously in a crossover, blinded experimental design. Locomotion after sedating doses of dexmedetomidine (10 µg/kg) or ketamine (10 mg/kg) with and without methylphenidate (5 mg/kg) was tested using the open field test (n = 16). Recovery of righting reflex after either high-dose dexmedetomidine (50 µg/kg) or high-dose ketamine (50 mg/kg) with and without methylphenidate (1-5 mg/kg) was assessed in a second cohort of rats (n = 8). Finally, in a third cohort of rats (n = 8), frontal electroencephalography (EEG) was recorded for spectral analysis under both low and high doses of dexmedetomidine and ketamine with and without methylphenidate. Low-dose dexmedetomidine reduced locomotion by 94% in rats. Methylphenidate restored locomotion after low-dose dexmedetomidine (rank difference = 88.5, 95% confidence interval [CI], 70.8-106) and the effect was blocked by coadministration with a dopamine D1 receptor antagonist (rank difference = 86.2, 95% CI, 68.6-104). Low-dose ketamine transiently attenuated mobility by 58% and was not improved with methylphenidate. Methylphenidate did not affect the return of righting reflex latency in rats after high-dose dexmedetomidine nor ketamine. Frontal EEG analysis revealed that methylphenidate reversed spectral changes induced by low-dose dexmedetomidine (F [8,87] = 3.27, P = .003) but produced only transient changes after high-dose dexmedetomidine. Methylphenidate did not induce spectral changes in the EEG after low- or high-dose ketamine. Methylphenidate reversed behavioral and neurophysiological correlates of sedation, but not unconsciousness, induced by dexmedetomidine. In contrast, methylphenidate did not affect sedation, unconsciousness, nor EEG signatures in rats after ketamine. These findings suggest that methylphenidate may be efficacious to reverse dexmedetomidine sedation in humans.

Exploring ketamine’s reinforcement, cue-induced reinstatement, and nucleus accumbens cFos activation in male and female long evans rats

Ketamine (KET), a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, has rapid onset of antidepressant effects in Treatment-Resistant Depression patients and repeated infusions are required to sustain its antidepressant properties. However, KET is an addictive drug, and so more preclinical and clinical research is needed to assess the safety of recurring treatments in both sexes. Thus, the aim of this study was to investigate the reinforcing properties of various doses of KET (0-, 0.125-, 0.25-, 0.5 mg/kg/infusion) and assess KET’s cue-induced reinstatement and neuronal activation in both sexes of Long Evans rats. Neuronal activation was assessed using the protein expression of the immediate early gene cFos in the nucleus accumbens (Nac), an important brain area implicated in reward, reinforcement and reinstatement to most drug-related cues. Our findings show that KET has reinforcing effects in both male and female rats, albeit exclusively at the highest two doses (0.25 and 0.5 mg/kg/infusion). Furthermore, we noted sex differences, particularly at the highest dose of ketamine, with female rats displaying a higher rate of self-administration. Interestingly, all groups that self-administered KET reinstated to drug-cues. Following drug cue-induced reinstatement test in rats exposed to KET (0.25 mg/kg/infusion) or saline, there was higher cFos protein expression in KET-treated animals compared to saline controls, and higher cFos expression in the core compared to the shell subregions of the Nac. As for reinstatement, there were no notable sex differences reported for cFos expression in the Nac. These findings reveal some sex and dose dependent effects in KET’s reinforcing properties and that KET at all doses induced similar reinstatement in both sexes. This study also demonstrated that cues associated with ketamine induce comparable neuronal activation in the Nac of both male and female rats. This work warrants further research into the potential addictive properties of KET, especially when administered at lower doses which are now being used in the clinic for treating various psychopathologies.

Subcutaneous ketamine reduces suicide risk and improves functioning in depression: A proof-of-concept study

This investigation explores the efficacy of subcutaneous ketamine for mitigating depressive symptoms and suicidal ideation, addressing a crucial need for rapid-onset treatments in severe depression cases. It introduces an innovative approach to administering an NMDA receptor antagonist, significantly advancing psychopharmacological methods for treating suicidal behaviors as distinct entities, even within depressive episodes. The study's objective is to assess the impact of subcutaneous ketamine on diminishing suicidal thoughts and mood symptoms during depressive episodes through a naturalistic, prospective observational design. Conducted at Hospital de Clínicas de Porto Alegre, Brazil, between 2021 and 2023, the study involved 26 patients undergoing a current depressive episode. Of these, 23 completed the acute phase of treatment, and 18 were followed up for 6 months. The treatment regimen commenced with a ketamine dose of 0.5 mg/kg, which was adjusted according to individual responses under psychiatric supervision. The findings revealed substantial decreases in Columbia Suicide Severity Rating Scale scores following multiple ketamine sessions, with most patients achieving remission after approximately eight sessions. A notable reduction in depressive symptoms was also observed. A clear dose-response relationship was established, indicating that higher doses of ketamine were associated with more significant improvements in depressive symptoms, suicidal ideation, and overall functionality. Follow-up assessments suggested that these improvements were sustained over time. The subcutaneous administration of ketamine was generally well-tolerated, with minor and short-lived side effects. The study posits that subcutaneous ketamine may present a promising solution for treating severe depression accompanied by suicidal tendencies, particularly considering its positive influence on patient functionality and well-being. This method could offer a cost-effective and accessible treatment alternative, especially relevant in settings with limited resources. Given its potential in reducing long-term disability and economic viability, the study advocates for its broader application and further validation through larger, controlled trials.Trial Registration: ClinicalTrials.gov NCT05249309.

HIGH DOSES OF KETAMINE INFLICT MYOCARDIAL INJURY AND CAUSE CHANGES IN THE RELATIVE BODY WEIGHT TO HEART OF ADULT ALBINO WISTAR RATS

Objective: Ketamine is widely used as an anesthetic agent in surgery and emergency medicine. It is also used for procedural sedation, treatment of depression, pain management, and sometimes as a recreational drug. These uses, however, have recommended doses to prevent myocardial injury. This study, therefore, was designed to investigate the level of injury on the myocardium following the administration of high doses of ketamine and to determine the relative body weight to heart weight of the experimental animals. Method: A total of 12 male albino Wistar rats were used and grouped into four including the control group. They were weighed daily and administered 100 mg, 150 mg, and 200 mg/kg/body weight of ketamine intraperitoneally for 2 weeks and weighed again. Experiment was terminated after 14 days and animals were sacrificed and the heart harvested for analysis. Results: Ketamine caused a significant myocardial injury with increase in the doses in different groups by causing inflammation, hypertrophy, vacuolar degenerative changes, atrophy, and extensive hemorrhage around the myocytes. Weight differentiation was noticed in all experimental groups with heart weight contributing to the total body weight by 1.63%, 1.7%, and 1.2% for the 100 mg, 150 mg, and 200 mg/kg/body weight of ketamine groups, respectively. Conclusion: Higher doses of ketamine cause significant myocardial injury as well as differential changes in body weight and heart weight in experimental animals.

The Effects of High-Dose Ketamine on Motor Evoked Potential Monitoring in Patients with Myelopathy: A Case Series

Motor Evoked Potentials (MEPs) allow for real-time monitoring of the corticospinal tracts during spine surgery. MEPs can be difficult to obtain in patients with cervicothoracic myelopathy. We describe 5 myelopathic patients undergoing spine surgery with insufficient MEPs on a standard propofol-based anesthetic. Conversion to high-dose ketamine (20 mcg/kg/min) with other minimally suppressive agents resulted in signal enhancement in a majority (36 of 63) of muscle groups with adequate anesthesia and minimal adverse effects, although with considerable variability in the durability of this effect. High-dose ketamine appears to be a safe and viable option to attempt to augment poor baseline MEP signals.

Ketamine in multiple treatment-resistant depressed inpatients: A naturalistic cohort study

BackgroundKetamine has emerged as an effective treatment option for patients with treatment-resistant depression. However, there is limited evidence of the benefits of ketamine in inpatients with multiple treatment resistance (MTR), who far exceed the formal criteria for treatment resistance and suffer from extensive psychiatric comorbidities. ObjectiveThe aim of this naturalistic study was to provide preliminary evidence for the use of ketamine in the treatment of MTR depression in a naturalistic inpatient setting. MethodsSeventy-seven patients (mean age 45.1 ± 13.8 years) were treated with intravenous or intranasal ketamine (1068 administrations) twice weekly for five weeks, followed by maintenance therapy if clinically indicated. Treatment effects were assessed with the BDI, and side effects were assessed by clinicians. We analyzed dose- and route of application-related changes in depression severity, response and remission rates as well as effects on suicidality and frequency of adverse events. ResultsDepression severity and suicidality decreased in the acute treatment phase and these changes persisted during the maintenance therapy phase. A total of 28.9 % of the patients met the criteria for response, and 15 % met the criteria for remission. The initial treatment response was highly predictive of the outcome at the end of the acute treatment phase. None of the reported side effects required medical intervention. High-dose intravenous ketamine (0.75–1 mg/kg) resulted in the most pronounced clinical effects. LimitationsThis observational, retrospective, and naturalistic study may be subject to bias and did not allow control of external variables. ConclusionsWe outlined a clinically feasible, high-dose ketamine treatment regimen for hospitalized patients with MTR depression.

In Case You Haven't Heard…

Federal health authorities have intensified their scrutiny of the drug ketamine for treating mental health disorders as the mind‐altering compound grows in popularity despite the lack of regulatory approval for such use, The Washington Post reported last week. The Food and Drug Administration (FDA) warned in October about the risks of using pharmacy‐made ketamine at home, citing the case of one patient whose breathing slowed to a dangerous level after taking a large dose outside of a health care facility. Then the autopsy of actor Matthew Perry, released Dec. 15, concluded a high dose of ketamine led to his death in October — an event that, while rare, drove home the dark side of the anesthetic that can also be abused recreationally. Meanwhile, the Drug Enforcement Administration continues to craft a rule that would set new limits on how health care professionals can use telemedicine to prescribe tightly regulated drugs like ketamine. Adam Kaplin, who observed the power of ketamine while overseeing clinical trials that led to the approval of Spravato, but also saw the inconvenience and cost that comes with the FDA‐required monitoring, said he is aiming to develop a derivative of ketamine with fewer side effects. The goal, said Kaplin, chief scientific officer of Mira Pharmaceuticals, is to create a drug that the FDA will endorse as safe for patients to take at home.

High-dose Versus Low-dose Oral Ketamine on Control and Relapse of Treatment-resistant Depression: A Randomized, Double-blinded Clinical Trial

Background: Treatment-resistant Depression (TRD) does not respond to conventional treatments. Despite the efforts made to control depression, the outcomes are controversial and inconclusive. New strategies such as ketamine use are accompanied by promising outcomes; however, the best dosage remains a question. Objectives: The current study aimed to compare the effect of 1 and 2 mg/kg of oral ketamine in TRD subjects. Methods: The current randomized clinical trial was conducted on 29 patients suffering from TRD. The patients were randomly assigned into two groups of treatment with low dose (1 mg/kg; n = 17) versus high dose (2 mg/kg; n = 12) oral ketamine twice a week for six weeks. The Hamilton Depression Rating Scale (HDRS) and the Beck Depression Inventory-II (BDI-II) were applied to assess the outcomes of the interventions at baseline, within 2, 4, and 6 weeks after the interventions, and then, within a week, a month, and 2 months after the end of the intervention. Results: Baseline HRDS (P-value = 0.393) and BDI-II (P-value = 0.0.919) were similar in both groups. Neither HDRS (P-value = 0.97) nor BDI-II (P-value = 0.71) had a significant trend of changes when low versus high-dose ketamine uses were compared. The comparison of the frequency of ketamine-related adverse effects revealed a significantly higher incidence of drowsiness (P-value = 0.021) and lightheadedness (P-value = 0.004) in high-dose ketamine. Conclusions: We achieved no conclusive superiority or efficacy of 1 mg/kg over 2 mg/kg of oral ketamine; however, considering the adverse effects, a 1 mg/kg dose is preferred.

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

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

A single dose of ketamine relieves fentanyl-induced-hyperalgesia by reducing inflammation initiated by the TLR4/NF-κB pathway in rat spinal cord neurons.

A large amount of clinical evidence has revealed that ketamine can relieve fentanyl-induced hyperalgesia. However, the underlying mechanism is still unclear. In the current study, a single dose of ketamine (5 mg/kg or 10 mg/kg), TAK-242 (3 mg/kg), or saline was intraperitoneally injected into rats 15 min before four subcutaneous injections of fentanyl. Results revealed that pre-administration of ketamine alleviated fentanyl-induced hyperalgesia according to hind paw-pressure and paw-withdrawal tests. High-dose ketamine can reverse the expression of toll-like receptor-dimer (d-TLR4), phospho- nuclear factor kappa-B (p-NF-κB, p-p65), cyclooxygenase-2 (COX-2), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α) 1 d after fentanyl injection in the spinal cord. Moreover, fentany-linduced-hyperalgesia and changes in the expression of the aforementioned proteins can be attenuated by TAK-242, an inhibitor of TLR4, as well as ketamine. Importantly, TLR4, p-p65, COX-2, and IL-1β were expressed in neurons but not in glial cells in the spinal cord 1 d after fentanyl injection. In conclusion, results suggested that a single dose of ketamine can relieve fentanyl-induced-hyperalgesia via the TLR4/NF-κB pathway in spinal cord neurons.

Ketamine Induced RCVS (P3-12.008)

<h3>Objective:</h3> To present a case of RCVS induced by ketamine infusions compounded with triptan and NSAID usage. <h3>Background:</h3> A 47 yo female with a history of depression and migraines presented with a persistent headache for 3 days. On the day of presentation, the patient reported the “worst headache of her life”. The headache was “sharp and squeezing”, frontal and retro-orbital in location, radiating to the back of her head, and exasperated by laying flat. The patient reported taking multiple high-dose NSAIDs along with sumatriptan. She had completed a 3-week course of ketamine infusions (75 mg twice weekly for depression) with last infusion 2 days prior to presentation. She was also on a chronic SSRI for depression. Patient denied any alcohol or current recreational drug use, but did report a history of opioid dependency. Initial CT head demonstrated a moderate-sized right frontal lobe subarachnoid and a small subarachnoid in the right posterior parietal lobe. CTA of head and neck demonstrated vasospasm of the left supraclinoid ICA, left M1 segment, and basilar artery. The location, radiographic appearance, and temporal course was consistent with RCVS. CT Angiogram was negative for any luminal irregularity, focal stenosis, or narrowing. MRI brain with contrast redemonstrated the subarachnoid hemorrhage without evidence of a vasculitic process. Lab work-up was negative for ANA, C4, C3, Sjogren’s Antibodies, RF, Anti-DNAs Ab. CRP and ESR were mildly elevated suggesting mild inflammation. <h3>Design/Methods:</h3> N/A <h3>Results:</h3> The etiology of the headache and subarachnoid hemorrhage was suspected to be medication induced RCVS in the setting of concomitant use of sumatriptan, SSRI, and high doses of ketamine. <h3>Conclusions:</h3> Although a rare phenomena, RCVS is a concerning cause of thunderclap headache that should be recognized. RCVS is not a common occurrence with ketamine usage but clinicians should be aware is this possible adverse effect. <b>Disclosure:</b> Dr. Mufti has nothing to disclose. Dr. Canlas has nothing to disclose. Dr. Ritenuti has nothing to disclose.

791: IMPACT OF SEDATION WITH KETAMINE COMPARED TO BENZODIAZEPINES ON DELIRIUM IN THE INTENSIVE CARE UNIT

Introduction: The use of high-dose ketamine infusions for sedation has grown in popularity as an alternative to benzodiazepines in intensive care unit (ICU) patients. Currently, there is a paucity of literature describing the use of high-dose ketamine for sedation. The objectives of this study are to describe high-dose ketamine use in the ICU and its impacts on delirium compared to benzodiazepines. Methods: This is a single-center, retrospective cohort study of patients admitted to an ICU between 5/5/2018 and 12/1/2021. Neurocritical care and cardiovascular surgery patients were excluded. Patients included were mechanically ventilated for ≥ 48 hours and received either ketamine ≥ 1 mg/kg/hr or a benzodiazepine infusion (midazolam or lorazepam) for ≥ 24 hours during their index ICU stay. and baseline demographics, sedative drip information, CAM-ICU scores, hospital and ICU length of stay (LOS), duration of mechanical ventilation, and chloride disturbances were collected The primary outcome was the percentage of eligible ICU days CAM-ICU positive, and secondary outcomes included ICU LOS and duration of mechanical ventilation. Eligible ICU days were defined as days with a Richmond Agitation Sedation Scale score ≥ - 3, and a CAM-ICU positive day was defined as having one positive CAM-ICU score positive. Results: A total of 187 patients were included, with 70 and 117 patients in the ketamine and benzodiazepine groups, respectively. The mean age was 56.9 (14.7), and 64.2% were male. The percentage CAM-ICU positive days in the ICU was 68.1% for ketamine and 51.5% for benzodiazepines (p=0.15). The median ICU LOS in days was 20.1 (11.6, 38.9) for the ketamine arm compared to 15.9 (8.7, 26.0) for the benzodiazepine arm (p=0.069). The median duration of mechanical ventilation in days was 19.5 (7.4, 37.4) compared to 11 (6.1, 22.0) for ketamine and benzodiazepines respectively (p=0.053). Overall, 57.5% of ketamine arm patients and 44.1% of benzodiazepine arm patients died during hospitalization (p=0.17). Conclusions: Compared to benzodiazepine infusions, high-dose ketamine infusions did not result in a significantly different number of CAM-ICU positive ICU days, ICU LOS, or duration of mechanical ventilation.

Transcriptional Activation, Deactivation and Rebound Patterns in Cortex, Hippocampus and Amygdala in Response to Ketamine Infusion in Rats.

Ketamine, an N-methyl-D-aspartate (NMDA)-receptor antagonist, is a recently revitalized treatment for pain and depression, yet its actions at the molecular level remain incompletely defined. In this molecular-pharmacological investigation in the rat, we used short- and longer-term infusions of high dose ketamine to stimulate neuronal transcription processes. We hypothesized that a progressively stronger modulation of neuronal gene networks would occur over time in cortical and limbic pathways. A continuous intravenous administration paradigm for ketamine was developed in rat consisting of short (1 h) and long duration (10 h, and 10 h + 24 h recovery) infusions of anesthetic concentrations to activate or inhibit gene transcription in a pharmacokinetically controlled fashion. Transcription was measured by RNA-Seq in three brain regions: frontal cortex, hippocampus, and amygdala. Cellular level gene localization was performed with multiplex fluorescent in situ hybridization. Induction of a shared transcriptional regulatory network occurred within 1 h in all three brain regions consisting of (a) genes involved in stimulus-transcription factor coupling that are induced during altered synaptic activity (immediate early genes, IEGs, such as c-Fos, 9–12 significant genes per brain region, p < 0.01 per gene) and (b) the Nrf2 oxidative stress-antioxidant response pathway downstream from glutamate signaling (Nuclear Factor Erythroid-Derived 2-Like 2) containing 12–25 increasing genes (p < 0.01) per brain region. By 10 h of infusion, the acute results were further reinforced and consisted of more and stronger gene alterations reflecting a sustained and accentuated ketamine modulation of regional excitation and plasticity. At the cellular level, in situ hybridization localized up-regulation of the plasticity-associated gene Bdnf, and the transcription factors Nr4a1 and Fos, in cortical layers III and V. After 24 h recovery, we observed overshoot of transcriptional processes rather than a smooth return to homeostasis suggesting an oscillation of plasticity occurs during the transition to a new phase of neuronal regulation. These data elucidate critical molecular regulatory actions during and downstream of ketamine administration that may contribute to the unique drug actions of this anesthetic agent. These molecular investigations point to pathways linked to therapeutically useful attributes of ketamine.

Long-term ketamine infusion-induced cholestatic liver injury in COVID-19-associated acute respiratory distress syndrome

BackgroundA higher-than-usual resistance to standard sedation regimens in COVID-19 patients suffering from acute respiratory distress syndrome (ARDS) has led to the frequent use of the second-line anaesthetic agent ketamine. Simultaneously, an increased incidence of cholangiopathies in mechanically ventilated patients receiving prolonged infusion of high-dose ketamine has been noted. Therefore, the objective of this study was to investigate a potential dose–response relationship between ketamine and bilirubin levels.MethodsPost hoc analysis of a prospective observational cohort of patients suffering from COVID-19-associated ARDS between March 2020 and August 2021. A time-varying, multivariable adjusted, cumulative weighted exposure mixed-effects model was employed to analyse the exposure–effect relationship between ketamine infusion and total bilirubin levels.ResultsTwo-hundred forty-three critically ill patients were included into the analysis. Ketamine was infused to 170 (70%) patients at a rate of 1.4 [0.9–2.0] mg/kg/h for 9 [4–18] days. The mixed-effects model revealed a positively correlated infusion duration–effect as well as dose–effect relationship between ketamine infusion and rising bilirubin levels (p < 0.0001). In comparison, long-term infusion of propofol and sufentanil, even at high doses, was not associated with increasing bilirubin levels (p = 0.421, p = 0.258). Patients having received ketamine infusion had a multivariable adjusted competing risk hazard of developing a cholestatic liver injury during their ICU stay of 3.2 [95% confidence interval, 1.3–7.8] (p = 0.01).ConclusionsA causally plausible, dose–effect relationship between long-term infusion of ketamine and rising total bilirubin levels, as well as an augmented, ketamine-associated, hazard of cholestatic liver injury in critically ill COVID-19 patients could be shown. High-dose ketamine should be refrained from whenever possible for the long-term analgosedation of mechanically ventilated COVID-19 patients.

Ketamine enhances dopamine D1 receptor expression by modulating microRNAs in a ketamine-induced schizophrenia-like mouse model

The abnormal expression of the dopamine D1 receptor (DRD1) may be associated with schizophrenia. MicroRNAs (miRNAs) can post-transcriptionally regulate DRD1 expression. Here, we established a ketamine-induced schizophrenia-like behavior mouse model and investigated the changes in miR-15a-3p, miR-15b-3p, miR-16-1-3p, and DRD1 in response to ketamine. Administration of high-dose ketamine for seven consecutive days to mice simulated the main symptoms of schizophrenia. The mice exhibited increasing excitability and autonomous activity and reduced learning and memory, including spatial memory. Moreover, ketamine decreased miR-15a-3p, miR-15b-3p, and miR-16-1-3p expression levels in the prefrontal cortex (PFC) and miR-16-1-3p expression in the hippocampus, whereas DRD1 expression increased in these brain regions. In HT22 mouse hippocampal neuronal cells, ketamine induced a dose-dependent increase of endogenous DRD1, which was partially attenuated by a combination of miR-15b-3p and miR-16-1-3p mimics. Indeed, the miR-15b-3p and miR-16-1-3p mimics could significantly inhibit endogenous DRD1expression. We identified +72 to +78 bp (TGCTGCT) of the DRD1 3’UTR as the core regulatory region recognized by the target miRNAs. In summary, we developed a ketamine-induced schizophrenia-like behavior mouse model and found that ketamine inhibited the levels of miR-15a-3p, miR-15b-3p, miR-16-1-3p and increased DRD1 expression in mice.

Excitation of Putative Glutamatergic Neurons in the Rat Parabrachial Nucleus Region Reduces Delta Power during Dexmedetomidine but not Ketamine Anesthesia.

Parabrachial nucleus excitation reduces cortical delta oscillation (0.5 to 4 Hz) power and recovery time associated with anesthetics that enhance γ-aminobutyric acid type A receptor action. The effects of parabrachial nucleus excitation on anesthetics with other molecular targets, such as dexmedetomidine and ketamine, remain unknown. The hypothesis was that parabrachial nucleus excitation would cause arousal during dexmedetomidine and ketamine anesthesia. Designer Receptors Exclusively Activated by Designer Drugs were used to excite calcium/calmodulin-dependent protein kinase 2α-positive neurons in the parabrachial nucleus region of adult male rats without anesthesia (nine rats), with dexmedetomidine (low dose: 0.3 µg · kg-1 · min-1 for 45 min, eight rats; high dose: 4.5 µg · kg-1 · min-1 for 10 min, seven rats), or with ketamine (low dose: 2 mg · kg-1 · min-1 for 30 min, seven rats; high dose: 4 mg · kg-1 · min-1 for 15 min, eight rats). For control experiments (same rats and treatments), the Designer Receptors Exclusively Activated by Designer Drugs were not excited. The electroencephalogram and anesthesia recovery times were recorded and analyzed. Parabrachial nucleus excitation reduced delta power in the prefrontal electroencephalogram with low-dose dexmedetomidine for the 150-min analyzed period, excepting two brief periods (peak median bootstrapped difference [clozapine-N-oxide - saline] during dexmedetomidine infusion = -6.06 [99% CI = -12.36 to -1.48] dB, P = 0.007). However, parabrachial nucleus excitation was less effective at reducing delta power with high-dose dexmedetomidine and low- and high-dose ketamine (peak median bootstrapped differences during high-dose [dexmedetomidine, ketamine] infusions = [-1.93, -0.87] dB, 99% CI = [-4.16 to -0.56, -1.62 to -0.18] dB, P = [0.006, 0.019]; low-dose ketamine had no statistically significant decreases during the infusion). Recovery time differences with parabrachial nucleus excitation were not statistically significant for dexmedetomidine (median difference for [low, high] dose = [1.63, 11.01] min, 95% CI = [-20.06 to 14.14, -20.84 to 23.67] min, P = [0.945, 0.297]) nor low-dose ketamine (median difference = 12.82 [95% CI: -3.20 to 39.58] min, P = 0.109) but were significantly longer for high-dose ketamine (median difference = 11.38 [95% CI: 1.81 to 24.67] min, P = 0.016). These results suggest that the effectiveness of parabrachial nucleus excitation to change the neurophysiologic and behavioral effects of anesthesia depends on the anesthetic's molecular target.

A comparison of the pharmacokinetics and NMDAR antagonism-associated neurotoxicity of ketamine, (2R,6R)-hydroxynorketamine and MK-801

With the increasing use of ketamine as an off-label treatment for depression and the recent FDA approval of (S)-ketamine for treatment-resistant depression, there is an increased need to understand the long-term safety profile of chronic ketamine administration. Of particular concern is the neurotoxicity previously observed in rat models following acute exposure to high doses of ketamine, broadly referred to as ‘Olney's lesions’. This type of toxicity presents as abnormal neuronal cellular vacuolization, followed by neuronal death and has been associated with ketamine's inhibition of the N-methyl-d-aspartate receptor (NMDAR). In this study, a pharmacological and neuropathological analysis of ketamine, the potent NMDAR antagonist MK-801, and the ketamine metabolite (2R,6R)-hydroxynorketamine [(2R,6R)-HNK)] in rats is described following both single dose and repeat dose drug exposures. Ketamine dosing was studied up to 20 mg/kg intravenously for the single-dose neuropathology study and up to 60 mg/kg intraperitoneally for the multiple-dose neuropathology study. MK-801 dosing was studied up to 0.8 mg/kg subcutaneously for both the single and multiple-dose neuropathology studies, while (2R,6R)-HNK dosing was studied up to 160 mg/kg intravenously in both studies. These studies confirm dose-dependent induction of ‘Olney's lesions’ following both single dose and repeat dosing of MK-801. Ketamine exposure, while showing common behavioral effects, did not induce wide-spread Olney's lesions. Treatment with (2R,6R)-HNK did not produce behavioral effects, toxicity or any evidence of Olney's lesion formation. Based on these results, future NMDAR-antagonist neurotoxicity studies should strongly consider taking pharmacokinetics more thoroughly into account.

Rapid Recovery and Short Duration Anesthesia after Low Dose Ketamine and High Dose Dexmedetomidine in Rhesus Macaques (Macaca mulatta).

Anesthesia in rhesus macaques is required for many procedures. Although ketamine is the backbone of most anesthetic protocols, tolerance to the drug can develop, resulting in the need for higher doses to provide sufficient restraint. Combination with other drugs, such as α-agonists, can be ketamine-sparing, providing for sufficient restraint at lower ketamine doses. In addition, because α-agonists are reversible, recovery from anesthesia has the potential to be much shorter. We hypothesized that use of a low dose of ketamine with a high dose of dexmedetomidine, an α2 receptor selective agonist, in male and female rhesus macaques less than 15 y of age would provide adequate anesthesia for short procedures and that recovery would be faster than in macaques given a higher dose of ketamine (10 mg/kg) alone. We found that the combination, in conjunction with atipamezole for reversal, provided smooth induction of anesthesia and significantly shorter recovery time than did ketamine alone, with no significant effects of sex. The combination of low dose ketamine and high dose dexmedetomidine also provided a 30-min window of anesthesia with analgesia sufficient for mild to moderately painful procedures.

Hypomania associated with high dose ketamine treatment.

For more than 50 years, pharmacotherapy for major depressive disorder (MDD) has narrowly focused on enhancing monoaminergic neurotransmission resulting in more than 30 FDA- approved treatments. In contrast, the glutamatergic, non-competitive N-methyl D-aspartate (NMDA) receptor antagonist ketamine has been "repurposed" as a rapid acting antidepressant1 ; the enantiomer S-ketamine, or esketamine, is now FDA-approved for treatment resistant unipolar depression (TRD).