Effect Of Low-dose Ketamine Infusion Research Articles

Effect of Low-dose Ketamine Infusion on Opioid Consumption in Children Undergoing Open Cardiac Surgery: A Randomized Controlled Double-Blind Study

This study was designed to evaluate the effect of low-dose ketamine infusion on the perioperative consumption of opioids in pediatric open cardiac surgery. A randomized, controlled, double-blinded single-center study was conducted. The study took place in a tertiary care children's hospital. Patients of both sexes aged 2-12 years who underwent cardiac surgery were included. Patients in the ketamine group received a bolus of 0.3 mg/kg of ketamine before skin incision followed by continuous intraoperative infusion of 0.25 mg/kg/h and postoperative infusion of 0.1 mg/kg/h for 24 h. Patients in the control groups received volumes of normal saline either bolus or continuous infusion like that of the ketamine group. The primary outcome was the total dose of fentanyl consumed over the first 24 hours postoperatively. Secondary outcomes were intraoperative fentanyl consumption, time to extubation, modified objective pain score, and incidence of vomiting, pruritus, diplopia, or hallucinations. A total of 80 patients were recruited but the final analysis was done on 35 patients in the ketamine group and 34 in the control group. Fentanyl consumption during surgery and in the first 24 hours postoperatively was significantly lower in the ketamine than the control group. Patients in both the ketamine and control groups had similar times to extubation. Modified objective pain scores were significantly lower in the ketamine group than the control group. None of the patients in either group had diplopia or hallucinations. Low-dose ketamine infusion in children undergoing open cardiac surgery reduced intra- and postoperative opioid consumption and postoperative pain scores. Moreover, ketamine did not cause diplopia or hallucinations.

Right dorsolateral prefrontal cortex volumetric reduction is associated with antidepressant effect of low-dose ketamine infusion: A randomized, double-blind, midazolam-controlled PET-MRI clinical trial

BackgroundEvidence has shown a rapid antidepressant and antisuicidal effects of low-dose ketamine infusion among patients with treatment-resistant depression (TRD) and prominent suicidal ideation (SI). The dorsolateral prefrontal cortex (DLPFC) plays a crucial role in the TRD pathomechanisms. ObjectiveWhether the structural and functional changes of the DLPFC, particularly Brodmann area 46, are associated with the antidepressant and antisuicidal effects of ketamine infusion among such patients is unknown. MethodsWe randomized 48 patients with TRD and SI into groups receiving a single infusion of 0.5 mg/kg ketamine or 0.045 mg/kg midazolam. The Hamilton Depression Rating Scale and the Montgomery–Asberg Depression Rating Scale were used to assess symptoms. Positron emission tomography (PET)–magnetic resonance imaging was conducted prior to infusion and on Day 3 postinfusion. We performed longitudinal voxel-based morphometry (VBM) analysis to evaluate the gray matter (GM) volume changes of the DLPFC. The standardized uptake value ratio (SUVr) of 18F-fluorodeoxyglucose PET images was calculated using the SUV of the cerebellum as a reference region. ResultsThe VBM analysis revealed a small but significant volumetric reduction in the right DLPFC in the ketamine group compared with that in the midazolam group. A greater reduction in depressive symptoms was associated with a smaller decrease in right DLPFC volumes (p = 0.025). However, we found no SUVr changes of the DLPFC between baseline and post-Day 3 ketamine infusion. DiscussionThe optimal modulation of the right DLPFC GM volumes may play an essential role in the antidepressant neuromechanisms of low-dose ketamine.

Cortical inhibition function is associated with baseline suicidal symptoms and post-ketamine suicidal symptom reduction among patients with treatment-resistant depression and strong suicidal ideation

BackgroundWhether cortical excitation and inhibition functions differ between patients with treatment-resistant depression (TRD) and strong suicidal ideation (SI) and healthy subjects and whether 0.5 mg/kg ketamine infusion can modulate cortical excitation and inhibition functions among patients with TRD–SI remain unclear. MethodsA total of 29 patients with TRD–SI and 35 age- and sex-matched healthy controls were assessed using paired-pulse transcranial magnetic stimulation. The patients were randomly assigned to receive either a single 0.5-mg/kg ketamine or 0.045-mg/kg midazolam infusion. Depressive and suicidal symptoms were assessed at baseline and 240 min after infusion. Intracortical facilitation (ICF), short-interval intracortical inhibition (SICI), and long-interval intracortical inhibition (LICI), all of which reflect cortical excitability and inhibition functions, were measured at the same time points. ResultsThe patients with TRD–SI had lower ICF (p < 0.001) estimates (worse cortical excitatory function) and higher SICI (p = 0.032) and LICI (p < 0.001) estimates (worse cortical inhibitory function) compared with the control group. Higher SICI estimates at baseline were associated with greater baseline suicidal symptoms. No differences were found in the SICI, ICF, and LICI estimates at 240 min after the infusion between the two groups. Low-dose ketamine did not alter the cortical excitation and inhibition functions of the patients with TRD–SI. However, decreased SICI estimates (greater cortical inhibition function) were related to the reduction of suicidal symptoms. DiscussionDysfunction of cortical excitation and inhibition may play a crucial role in the pathomechanisms of TRD and suicidal symptoms. However, we found a lack of predictive ability of the baseline cortical excitation and inhibition parameters on the antidepressant and antisuicidal effect of low-dose ketamine infusion.

Comparative study of low-dose ketamine infusion and repetitive transcranial magnetic stimulation in treatment-resistant depression: A posthoc pooled analysis of two randomized, double-blind, placebo-controlled studies

BackgroundThis posthoc analysis compared the antidepressant and antisuicidal effects of low-dose ketamine infusion with those of repetitive transcranial magnetic stimulation (rTMS) on treatment-resistant depression (TRD). MethodsIn the ketamine infusion trial, 48 patients with TRD were randomized to receive a single infusion of 0.5 mg/kg ketamine or normal saline. In the rTMS trial, 105 patients were randomly assigned to intermittent theta-burst stimulation (iTBS), 10-Hz rTMS, or sham stimulation. The 17-item Hamilton Rating Scale for Depression (HDRS) was administered. ResultsThe antidepressant effect was prominent at Day 7 postinfusion in the ketamine group but steadily accumulated with the treatment duration from Day 7 to 14 in the iTBS and 10-Hz rTMS groups, regardless of the level of treatment resistance (all p < .01). Low-dose ketamine infusion and iTBS exerted superior effects on suicidal symptoms (HDRS item 3) than the other three groups (p < .001). The antidepressant effect of iTBS/10-Hz rTMS may persist for up to 3 months; however, the antidepressant effect of a single low-dose ketamine infusion did not persist over a month. DiscussionBoth low-dose ketamine infusion and rTMS/TBS must be included in TRD treatment but may be applied in different clinical situations.

Effects of Low-Dose Ketamine Infusion on Alleviating the Opioid Burden for Patients Undergoing Myomectomy Surgery.

ObjectiveRecent research has focused on the use of N-methyl-D-aspartate (NMDA) receptor antagonists for pain management. Several drugs are known to have this action, including ketamine, which exerts its main analgesic effect through NMDA receptor antagonism. This study aimed to evaluate the effect of low-dose ketamine infusion on opioid exposure for patients undergoing myomectomy surgery under general anaesthesia.MethodsA total of 70 women were included in this prospective double-blind trial study. The patients included in this study were American Society of Anaesthesiologists physical status I–II, aged between 18 and 50 years and scheduled for laparotomy myomectomy surgery. Patients were randomised to receive either a bolus of 0.2 mg kg−1 of ketamine followed by a continuous infusion of 0.2 mg kg−1 hr−1 during the operation or a placebo of normal saline. Both groups also received morphine as needed for pain relief. The primary outcome was the total amount of morphine used during the intraoperative and postoperative periods. Intraoperative and postoperative mean blood pressure, heart rate and postoperative visual analogue scale for pain were assessed.ResultsTotal mean morphine consumption was significantly lower in the ketamine group than in the control group (26±3.5 mg vs. 34.7±3.3 mg, respectively, p<0.05). However, there were no statistical differences between the groups regarding haemodynamics, postoperative pain score and complications.ConclusionThe use of ketamine in low infusion doses intraoperatively during an elective myomectomy procedure produced an opioid-sparing effect by reducing perioperative morphine consumption without significant side effects.

Treatment response to low-dose ketamine infusion for treatment-resistant depression: A gene-based genome-wide association study

BackgroundsEvidence suggested the crucial roles of brain-derived neurotrophic factor (BDNF) and glutamate system functioning in the antidepressant mechanisms of low-dose ketamine infusion in treatment-resistant depression (TRD). Methods65 patients with TRD were genotyped for 684,616 single nucleotide polymorphisms (SNPs). Twelve ketamine-related genes were selected for the gene-based genome-wide association study on the antidepressant effect of ketamine infusion and the resulting serum ketamine and norketamine levels. ResultsSpecific SNPs and whole genes involved in BDNF–TrkB signaling (i.e., rs2049048 in BDNF and rs10217777 in NTRK2) and the glutamatergic and GABAergic systems (i.e., rs16966731 in GRIN2A) were associated with the rapid (within 240 min) and persistent (up to 2 weeks) antidepressant effect of low-dose ketamine infusion and with serum ketamine and norketamine levels. DiscussionOur findings confirmed the predictive roles of BDNF–TrkB signaling and glutamatergic and GABAergic systems in the underlying mechanisms of low-dose ketamine infusion for TRD treatment.

Efficacy of low-dose ketamine infusion in anxious vs nonanxious depression: revisiting the Adjunctive Ketamine Study of Taiwanese Patients with Treatment-Resistant Depression.

The antidepressant effect of low-dose ketamine infusion on Taiwanese patients with anxious vs nonanxious treatment-resistant depression (ANX-TRD vs NANX-TRD) has remained unknown. In total, 71 patients with TRD were randomized to three groups. Each group had participants who received saline infusions mixed with 0 (a normal saline infusion), 0.2, and 0.5 mg/kg of ketamine. Participants were followed up for 2 weeks. Anxious depression was defined as major depressive disorder with a total score of 7 or more on the 17-item Hamilton Depression Rating Scale Anxiety-Somatization factor. Generalized estimating equation models were used to investigate the effects of treatment (ketamine vs placebo) and depression type (ANX-TRD vs NANX-TRD) in the reduction of depressive symptoms during the follow-up period. Patients with ANX-TRD were less likely to respond to a single low-dose ketamine infusion than those with NANX-TRD. Among patients with NANX-TRD, low-dose ketamine infusion was significantly superior to placebo for reducing depressive symptoms. However, among patients with ANX-TRD, ketamine was not superior to placebo; nonetheless, approximately 30% of the patients responded to ketamine infusion compared to 13% who responded to the placebo. Low-dose ketamine infusion was effective for Taiwanese patients with NANX-TRD but not so effective for those with ANX-TRD. A higher level of anxiety severity accompanying depression was related to greater depression severity. This may confound and reduce the antidepressant effect of ketamine infusion.

Antisuicidal effect, BDNF Val66Met polymorphism, and low-dose ketamine infusion: Reanalysis of adjunctive ketamine study of Taiwanese patients with treatment-resistant depression (AKSTP-TRD)

Background: Growing evidence suggests a rapid antisuicidal effect of low-dose ketamine infusion in Caucasian patients with treatment-resistant depression (TRD). However, the antisuicidal effects of ketamine on Taiwanese patients with TRD remains unknown. Methods: Seventy-one patients with TRD were randomly classified into three treatment groups: 0.5 mg/kg ketamine, 0.2 mg/kg ketamine, or normal saline (placebo) infusion. The Hamilton Depression Rating Scale (HAMD) and Montgomery-Åsberg Depression Rating Scale (MADRS) were applied prior to initiation of test infusions, at 40, 80, 120, and 240 min postinfusion, and sequentially on Days 2, 3, 4, 5, 6, 7, and 14 after ketamine or placebo infusion. Item 3 (suicide) of the HAMD and item 10 (suicidal thoughts) of the MADRS were extracted for generalized estimating equation (GEE) model analyses to investigate the antisuicidal effects of ketamine infusion. Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism was genotyped. Results: The GEE model revealed significant group (p = 0.007) and time (p = 0.004) effects on suicidal symptoms over times (prior to infusion to day 14 postinfusion). The group that received 0.5 mg/kg ketamine infusion exhibited a significantly lower score in item 3 of the HAMD and item 10 of the MADRS compared with the groups that received 0.2 mg/kg ketamine or placebo infusion. Among those carrying any Val allele of BDNF, both 0.5 and 0.2 mg/kg ketamine infusions were effective in reducing suicidal thoughts; however, among those with Met/Met of BDNF, only 0.5 mg/kg ketamine infusion was effective in reducing suicidal thoughts. Discussion: A single low-dose ketamine infusion was effective in reducing suicidal ideation among Taiwanese patients with TRD. BDNF Val66Met polymorphism may play a crucial role in the antisuicidal effects of ketamine infusion.

Antinociceptive effects, metabolism and disposition of ketamine in ponies under target-controlled drug infusion.

Ketamine is widely used as an anesthetic in a variety of drug combinations in human and veterinary medicine. Recently, it gained new interest for use in long-term pain therapy administered in sub-anesthetic doses in humans and animals. The purpose of this study was to develop a physiologically based pharmacokinetic (PBPk) model for ketamine in ponies and to investigate the effect of low-dose ketamine infusion on the amplitude and the duration of the nociceptive withdrawal reflex (NWR). A target-controlled infusion (TCI) of ketamine with a target plasma level of 1 microg/ml S-ketamine over 120 min under isoflurane anesthesia was performed in Shetland ponies. A quantitative electromyographic assessment of the NWR was done before, during and after the TCI. Plasma levels of R-/S-ketamine and R-/S-norketamine were determined by enantioselective capillary electrophoresis. These data and two additional data sets from bolus studies were used to build a PBPk model for ketamine in ponies. The peak-to-peak amplitude and the duration of the NWR decreased significantly during TCI and returned slowly toward baseline values after the end of TCI. The PBPk model provides reliable prediction of plasma and tissue levels of R- and S-ketamine and R- and S-norketamine. Furthermore, biotransformation of ketamine takes place in the liver and in the lung via first-pass metabolism. Plasma concentrations of S-norketamine were higher compared to R-norketamine during TCI at all time points. Analysis of the data suggested identical biotransformation rates from the parent compounds to the principle metabolites (R- and S-norketamine) but different downstream metabolism to further metabolites. The PBPk model can provide predictions of R- and S-ketamine and norketamine concentrations in other clinical settings (e.g. horses).