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Drug Design, Development and Therapy 2024Sepsis is recognized as a multiorgan and systemic damage caused by dysregulated host response to infection. Its acute systemic inflammatory response highly resembles...
BACKGROUND
Sepsis is recognized as a multiorgan and systemic damage caused by dysregulated host response to infection. Its acute systemic inflammatory response highly resembles that of lipopolysaccharide (LPS)-induced endotoxemia. Propofol and dexmedetomidine are two commonly used sedatives for mechanical ventilation in critically ill patients and have been reported to alleviate cognitive impairment in many diseases. In this study, we aimed to explore and compare the effects of propofol and dexmedetomidine on the encephalopathy induced by endotoxemia and to investigate whether ferroptosis is involved, finally providing experimental evidence for multi-drug combination in septic sedation.
METHODS
A total of 218 C57BL/6J male mice (20-25 g, 6-8 weeks) were used. Morris water maze (MWM) tests were performed to evaluate whether propofol and dexmedetomidine attenuated LPS-induced cognitive deficits. Brain injury was evaluated using Nissl and Fluoro-Jade C (FJC) staining. Neuroinflammation was assessed by dihydroethidium (DHE) and DCFH-DA staining and by measuring the levels of three cytokines. The number of Iba1 and GFAP cells was used to detect the activation of microglia and astrocytes. To explore the involvement of ferroptosis, the levels of and ; the content of iron, malondialdehyde (MDA), and glutathione (GSH); and the expression of ferroptosis-related proteins were investigated.
CONCLUSION
The single use of propofol and dexmedetomidine mitigated LPS-induced cognitive impairment, while the combination showed poor performance. In alleviating endotoxemic neural loss and degeneration, the united sedative group exhibited the most potent capability. Both propofol and dexmedetomidine inhibited neuroinflammation, while propofol's effect was slightly weaker. All sedative groups reduced the neural apoptosis, inhibited the activation of microglia and astrocytes, and relieved neurologic ferroptosis. The combined group was most prominent in combating genetic and biochemical alterations of ferroptosis. Fpn1 may be at the core of endotoxemia-related ferroptosis activation.
Topics: Dexmedetomidine; Animals; Propofol; Ferroptosis; Mice; Male; Endotoxemia; Mice, Inbred C57BL; Lipopolysaccharides; Dose-Response Relationship, Drug; Brain Diseases; Hypnotics and Sedatives
PubMed: 38681208
DOI: 10.2147/DDDT.S458013 -
British Journal of Anaesthesia Aug 2023Anaesthetic-induced unresponsiveness and non-rapid eye movement (NREM) sleep share common neural pathways and neurophysiological features. We hypothesised that these... (Clinical Trial)
Clinical Trial
BACKGROUND
Anaesthetic-induced unresponsiveness and non-rapid eye movement (NREM) sleep share common neural pathways and neurophysiological features. We hypothesised that these states bear resemblance also at the experiential level.
METHODS
We compared, in a within-subject design, the prevalence and content of experiences in reports obtained after anaesthetic-induced unresponsiveness and NREM sleep. Healthy males (N=39) received dexmedetomidine (n=20) or propofol (n=19) in stepwise doses to induce unresponsiveness. Those rousable were interviewed and left unstimulated, and the procedure was repeated. Finally, the anaesthetic dose was increased 50%, and the participants were interviewed after recovery. The same participants (N=37) were also later interviewed after NREM sleep awakenings.
RESULTS
Most subjects were rousable, with no difference between anaesthetic agents (P=0.480). Lower drug plasma concentrations were associated with being rousable for both dexmedetomidine (P=0.007) and propofol (P=0.002) but not with recall of experiences in either drug group (dexmedetomidine: P=0.543; propofol: P=0.460). Of the 76 and 73 interviews performed after anaesthetic-induced unresponsiveness and NREM sleep, 69.7% and 64.4% included experiences, respectively. Recall did not differ between anaesthetic-induced unresponsiveness and NREM sleep (P=0.581), or between dexmedetomidine and propofol in any of the three awakening rounds (P>0.05). Disconnected dream-like experiences (62.3% vs 51.1%; P=0.418) and memory incorporation of the research setting (88.7% vs 78.7%; P=0.204) were equally often present in anaesthesia and sleep interviews, respectively, whereas awareness, signifying connected consciousness, was rarely reported in either state.
CONCLUSIONS
Anaesthetic-induced unresponsiveness and NREM sleep are characterised by disconnected conscious experiences with corresponding recall frequencies and content.
CLINICAL TRIAL REGISTRATION
Clinical trial registration. This study was part of a larger study registered at ClinicalTrials.gov (NCT01889004).
Topics: Humans; Male; Anesthetics; Dexmedetomidine; Eye Movements; Hypnotics and Sedatives; Propofol; Sleep
PubMed: 37268445
DOI: 10.1016/j.bja.2023.04.026 -
Journal of Orthopaedic Surgery and... Sep 2023Local anesthetics (LAs) are widely used to infiltrate into surgical wounds for postoperative analgesia. Different adjuvants like dexamethasone and dexmedetomidine, when... (Randomized Controlled Trial)
Randomized Controlled Trial
Dexamethasone and dexmedetomidine as adjuvants to ropivacaine do not prolong analgesia in wound infiltration for lumbar spinal fusion: a prospective randomized controlled study.
BACKGROUND AND OBJECTIVES
Local anesthetics (LAs) are widely used to infiltrate into surgical wounds for postoperative analgesia. Different adjuvants like dexamethasone and dexmedetomidine, when added to LA agents, could improve and prolong analgesia. The aim of this trial was to evaluate the analgesic efficacy and opioid-sparing properties of dexamethasone and dexmedetomidine when added to ropivacaine for wound infiltration in transforaminal lumbar interbody fusion (TLIF).
METHODS
We conducted a controlled study among 68 adult patients undergoing TLIF, which was prospective, randomized and double-blind in nature. The participants were divided into four equal groups at random. Group R was given 150 mg of 1% ropivacaine (15 mL) and 15 mL of normal saline. Group R + DXM received 150 mg of 1% ropivacaine (15 mL) and 10 mg of dexamethasone (15 mL). Group R + DEX received 150 mg of 1% ropivacaine (15 mL) and 1 µg/kg of dexmedetomidine (15 mL). Lastly, group R + DXM + DEX was given 150 mg of 1% ropivacaine (15 mL), 10 mg of dexamethasone and 1 µg/kg of dexmedetomidine (15 mL). The primary focus was on the length of pain relief provided. Additionally, secondary evaluations included the amount of hydromorphone taken after surgery, the numerical rating scale and safety assessments within 48 h after the operation.
RESULTS
Based on the p value (P > 0.05), there was no significant variance in the duration of pain relief or the total usage of hydromorphone after surgery across the four groups. Similarly, the numerical rating scale scores at rest and during activity at 6-, 12-, 24- and 48-h post-surgery for all four groups showed no difference (P > 0.05). However, the incidence of delayed anesthesia recovery was slightly higher in group R + DEX and group R + DXM + DEX when compared to group R or group R + DXM. Furthermore, there were no significant differences between the four groups in terms of vomiting, nausea, dizziness or delayed anesthesia recovery.
CONCLUSION
For wound infiltration in TLIF, the addition of dexamethasone and dexmedetomidine to ropivacaine did not result in any clinically significant reduction in pain or opioid consumption and could prompt some side effects.
Topics: Adult; Humans; Analgesia; Analgesics, Opioid; Dexamethasone; Dexmedetomidine; Hydromorphone; Lumbar Vertebrae; Pain; Prospective Studies; Ropivacaine; Spinal Fusion; Adjuvants, Anesthesia; Pain, Postoperative; Anesthesia, Local
PubMed: 37667295
DOI: 10.1186/s13018-023-04145-1 -
Medical Gas Research 2023Electroconvulsive therapy (ECT) is one of the therapeutic opportunities for patients with psychological disorders when they may decline to take medication. We sought to... (Randomized Controlled Trial)
Randomized Controlled Trial
Efficacy of ketamine, propofol, and dexmedetomidine for anesthesia in electroconvulsive therapy in treatment-resistant major depressive disorder patients: a double-blind randomized clinical trial.
Electroconvulsive therapy (ECT) is one of the therapeutic opportunities for patients with psychological disorders when they may decline to take medication. We sought to systematically compare the anesthetic efficacy of ketamine, propofol, and dexmedetomidine for electroconvulsive therapy in treatment-resistant major depressive disorder patients. This double-blind trial enrolled treatment-resistant major depressive disorder patients (n = 85) who had been hospitalized for ECT in the Amir Kabir Hospital's psychiatric ward (Arak, Iran). The ketamine, propofol, and dexmedetomidine groups received a dose of 0.2 μg/kg ketamine, 1.5 mg/kg propofol, and 0.8 mg/kg dexmedetomidine, respectively. In all intervention groups, 10 mL of interventional drugs was injected intravenously for 10 minutes, and in the placebo group, 10 mL of normal saline was given over the same period. The dexmedetomidine group's blood pressure was revealed comparatively lower at all times. Dexmedetomidine-treated patients showed their marked satisfaction, while those treated with propofol had shorter recovery time, shorter seizure duration, and shorter time to achieve an Aldrete score of 9-10 and increased relaxation, and next dexmedetomidine produced deeper relaxation. Propofol could shorten recovery time and seizure duration, and enhance relaxation, while dexmedetomidine was associated with higher patient satisfaction. Considering that any anesthetic which does not shorten seizure duration may serve efficiently for ECT and that ketamine-treated patients had more prolonged seizure duration, the preferred drug can hence be considered from various angles, thereby offering anesthetic agents with highly favorable efficacy in treatment-resistant major depressive disorder patients needing ECT. The drug choice thus depends on physical conditions, underlying diseases, and psychiatrist consultation.
Topics: Humans; Propofol; Ketamine; Electroconvulsive Therapy; Depressive Disorder, Major; Dexmedetomidine; Anesthetics, Intravenous; Treatment Outcome; Anesthesia; Seizures
PubMed: 36571375
DOI: 10.4103/2045-9912.350860 -
Current Pain and Headache Reports Apr 2024The combination of ketamine with propofol and dexmedetomidine has gained popularity for sedation and general anesthesia in different populations. In our meta-nalysis, we... (Meta-Analysis)
Meta-Analysis Review
PURPOSE OF REVIEW
The combination of ketamine with propofol and dexmedetomidine has gained popularity for sedation and general anesthesia in different populations. In our meta-nalysis, we helped the anesthesiologists to know the efficiency and the efficacy of both combinations in adult and pediatric patients.
METHODS
We searched PubMed, CENTRAL, Web of Science, and Scopus from inception to August 1, 2023. Our outcome parameters for efficacy were recovery time, pain score, and physician satisfaction while for safety were the related cardiorespiratory, neurological, and gastrointestinal adverse events.
RECENT FINDINGS
Twenty-two trials were included with a total of 1429 patients. We found a significantly longer recovery time in the ketadex group of 7.59 min (95% CI, 4.92, 10.26; I = 94%) and a significantly less pain score of - 0.72 (95% CI, - 1.10, - 0.34; I = 0%). Adults had a significantly better physician satisfaction score with the ketofol group, odds ratio of 0.29 (95% CI, 0.12, 0.71; I = 0%). Recovery agitations were higher in the ketofol group with an odds ratio of 0.48 (95% CI, 0.24, 0.98; I = 36%). Furthermore, we found a significant difference between the combinations with a higher incidence in the ketadex group with pooled odds ratio of 1.75 (95% CI, 1.06, 2.88; I = 15%). Ketadex was associated with lower pain scores, hypoxic events and airway obstruction, and emergence agitation. At the same time, ketofol had much more clinician satisfaction which might be attributed to the shorter recovery time and lower incidence of nausea and vomiting. Therefore, we suppose that ketadex is the better combination in periprocedural sedation for both adult and pediatric patients who are not at greater risk for postoperative nausea and vomiting.
Topics: Adult; Humans; Child; Propofol; Dexmedetomidine; Ketamine; Anesthesia, General; Vomiting; Pain; Hypnotics and Sedatives
PubMed: 38214834
DOI: 10.1007/s11916-023-01208-0 -
Clinical Practice and Epidemiology in... 2023Depressive disorders (DD) are common, and their prevalence is expected to rise over the next decade. Depressive disorders are linked to significant morbidity and... (Review)
Review
Depressive disorders (DD) are common, and their prevalence is expected to rise over the next decade. Depressive disorders are linked to significant morbidity and mortality. The clinical conundrum of depressive disorders lies in the heterogeneity of their phenomenology and etiology. Further, the currently available antidepressants have several limitations, including a delayed onset of action, limited efficacy, and an unfavorable side effect profile. In this review, Dexmedetomidine (DEX), a highly selective and potent α2-adrenergic receptor (α2-AR) agonist, is proposed as a potentially novel antidepressant with multiple mechanisms of action targeting various depression pathophysiological processes. These mechanisms include modulation of the noradrenergic system, regulation of neuroinflammation and oxidative stress, influence on the Brain-Derived Neurotrophic Factor (BDNF) levels, and modulation of neurotransmitter systems, such as glutamate. The review begins with an introduction before moving on to a discussion of DEX's pharmacological features. The pathophysiological and phenomenological targets of DD are also explored, along with the review of the existing preclinical and clinical evidence for DEX's putative anti-depressant effects. Finally, the review ends by presenting the pertinent conclusions and future directions.
PubMed: 37916205
DOI: 10.2174/17450179-v19-230823-2023-4 -
Biomedicine & Pharmacotherapy =... Sep 2023Long periods of sleep deprivation (SD) have serious effects on health. While the α adrenoceptor agonist dexmedetomidine (DEX) can improve sleep quality for patients who...
Long periods of sleep deprivation (SD) have serious effects on health. While the α adrenoceptor agonist dexmedetomidine (DEX) can improve sleep quality for patients who have insomnia, the effect of DEX on cognition and mechanisms after SD remains elusive. C57BL/6 mice were subjected to 20 h SD daily for seven days. DEX (100 μg/kg) was administered intravenously twice daily (at 1:00 p.m. and 3:00 p.m.) during seven days of SD. We found that systemic administration of DEX attenuated cognitive deficits by performing the Y maze and novel object recognition tests and increased DCX+, SOX2+, Ki67+, and BrdU+NeuN+/NeuN+ cell numbers in the dentate gyrus (DG) region of SD mice by using immunofluorescence, western blotting, and BrdU staining. DEX did not reverse the decrease in DCX+, SOX2+, or Ki67+ cell numbers in SD mice after administration of the α-adrenoceptor antagonist BRL-44408. Furthermore, the vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor 2 (VEGFR2) expression was upregulated in SD+DEX mice compared with SD mice. Luminex analysis showed that the neurogenic effects of DEX were possibly related to the inhibition of neuroinflammation, including IL-1α, IL-2, CCL5, and CXCL1. Our results suggested that DEX alleviated the impaired learning and memory of SD mice potentially by inducing hippocampal neurogenesis via the VEGF-VEGFR2 signaling pathway and by suppressing neuroinflammation, and α adrenoceptors are required for the neurogenic effects of DEX after SD. This novel mechanism may add to our knowledge of DEX in the clinical treatment of impaired memory caused by SD.
Topics: Mice; Animals; Dexmedetomidine; Vascular Endothelial Growth Factor A; Neuroinflammatory Diseases; Sleep Deprivation; Vascular Endothelial Growth Factor Receptor-2; Bromodeoxyuridine; Ki-67 Antigen; Mice, Inbred C57BL; Hippocampus; Adrenergic alpha-2 Receptor Agonists; Signal Transduction; Neurogenesis
PubMed: 37392656
DOI: 10.1016/j.biopha.2023.115085 -
American Journal of Veterinary Research Dec 2023To evaluate skin perfusion in cats receiving dexmedetomidine compared to a placebo.
OBJECTIVE
To evaluate skin perfusion in cats receiving dexmedetomidine compared to a placebo.
ANIMALS
9 healthy adult research cats.
METHODS
A randomized, blinded, placebo-controlled study design was used. Two sites, the dorsal metatarsus (site: limb) and lateral flank (site: flank), were evaluated with laser speckle contrast imaging (LSCI) at baseline and following administration of dexmedetomidine (1, 3, or 5 mcg/kg, IV) or a placebo (0.9% saline, IV). Mean speckle contrast (MSC), a surrogate for perfusion, was obtained from LSCI and compared between treatments. Heart rate, sedation score, and body temperature were recorded. Skin perfusion to the flank and limb, reported as MSC, was assessed via LSCI at baseline and at 5, 10, and 15 minutes posttreatment.
RESULTS
There was a significant decrease in heart rate (P < .001) in cats receiving 1, 3, and 5 mcg/kg dexmedetomidine compared to placebo. There was a significant increase in median sedation score at all time points postsedation compared to baseline (P < .018). Changes in MSC for the metatarsus were not significantly different between treatments at any time point (P = .12). For the flank, MSC was significantly higher for cats treated with dexmedetomidine compared to baseline (P ≤ .01). Skin perfusion to the flank decreased as early as 5 minutes posttreatment with dexmedetomidine and persisted for at least 15 minutes, regardless of dexmedetomidine dose.
CLINICAL RELEVANCE
Dexmedetomidine decreased skin perfusion in cats, even at low doses. Veterinarians may elect for an alternative sedative medication when decreased skin perfusion is a concern.
Topics: Cats; Animals; Dexmedetomidine; Hypnotics and Sedatives; Heart Rate; Perfusion
PubMed: 38039627
DOI: 10.2460/ajvr.23.06.0137 -
Veterinary Sciences Oct 2023Intra-abdominal pressure (IAP) elevation during capnoperitoneum can cause adverse cardiovascular and respiratory effects. This study aimed to determine if a sequentially...
Intra-abdominal pressure (IAP) elevation during capnoperitoneum can cause adverse cardiovascular and respiratory effects. This study aimed to determine if a sequentially increased IAP affects cardiovascular and respiratory variables in anesthetized dogs and evaluate the effects of the constant-rate infusion of dexmedetomidine (Dex) on cardiovascular and respiratory variables with increased IAP. Five dogs were anesthetized and instrumented, and a Veress needle was equipped to adjust the IAP using a carbon dioxide insufflator. Stabilization was conducted for 1 h, and physiological variables were measured at IAPs of 0, 5, 10, 15, and 20 mmHg and after desufflation. After the washout period, the dogs underwent similar procedures along with a constant-rate infusion of dexmedetomidine. The cardiovascular effects of increased IAP up to 20 mmHg were not significant in healthy beagle dogs and those administered with dexmedetomidine. When comparing the control and dexmedetomidine groups, the overall significant effects of dexmedetomidine were noted on heart rate, cardiac output, and systemic vascular resistance during the experiment. Respiratory effects were not observed during abdominal insufflation when compared between different IAPs and between the two groups. Overall, an increased IAP of up to 20 mmHg did not significantly affect cardiovascular and respiratory variables in both the control and dexmedetomidine groups. This study suggests that the administration of a dexmedetomidine infusion is applicable in laparoscopic procedures in healthy dogs.
PubMed: 37999457
DOI: 10.3390/vetsci10110634 -
Clinical and Translational Science Sep 2023Despite complex pathways of drug disposition, clinical pharmacogenetic predictors currently rely on only a few high effect variants. Quantification of the polygenic...
Despite complex pathways of drug disposition, clinical pharmacogenetic predictors currently rely on only a few high effect variants. Quantification of the polygenic contribution to variability in drug disposition is necessary to prioritize target drugs for pharmacogenomic approaches and guide analytic methods. Dexmedetomidine and fentanyl, often used in postoperative care of pediatric patients, have high rates of inter-individual variability in dosing requirements. Analyzing previously generated population pharmacokinetic parameters, we used Bayesian hierarchical mixed modeling to measure narrow-sense (additive) heritability ( ) of dexmedetomidine and fentanyl clearance in children and identify relative contributions of small, moderate, and large effect-size variants to . We used genome-wide association studies (GWAS) to identify variants contributing to variation in dexmedetomidine and fentanyl clearance, followed by functional analyses to identify associated pathways. For dexmedetomidine, median clearance was 33.0 L/h (interquartile range [IQR] 23.8-47.9 L/h) and was estimated to be 0.35 (90% credible interval 0.00-0.90), with 45% of attributed to large-, 32% to moderate-, and 23% to small-effect variants. The fentanyl cohort had median clearance of 8.2 L/h (IQR 4.7-16.7 L/h), with estimated of 0.30 (90% credible interval 0.00-0.84). Large-effect variants accounted for 30% of , whereas moderate- and small-effect variants accounted for 37% and 33%, respectively. As expected, given small sample sizes, no individual variants or pathways were significantly associated with dexmedetomidine or fentanyl clearance by GWAS. We conclude that clearance of both drugs is highly polygenic, motivating the future use of polygenic risk scores to guide appropriate dosing of dexmedetomidine and fentanyl.
Topics: Humans; Child; Dexmedetomidine; Fentanyl; Genome-Wide Association Study; Bayes Theorem
PubMed: 37353859
DOI: 10.1111/cts.13574