33 results on '"Maze M"'
Search Results
2. Effect of Intraoperative Dexmedetomidine on Recovery of Gastrointestinal Function After Abdominal Surgery in Older Adults: A Randomized Clinical Trial.
- Author
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Lu Y, Fang PP, Yu YQ, Cheng XQ, Feng XM, Wong GTC, Maze M, and Liu XS
- Subjects
- Aged, China, Dexmedetomidine adverse effects, Digestive System Surgical Procedures methods, Digestive System Surgical Procedures statistics & numerical data, Double-Blind Method, Female, Gastrointestinal Tract physiology, Humans, Hypnotics and Sedatives adverse effects, Hypnotics and Sedatives pharmacology, Ileus etiology, Ileus prevention & control, Intraoperative Care methods, Intraoperative Care standards, Intraoperative Care statistics & numerical data, Male, Middle Aged, Postoperative Complications etiology, Postoperative Complications prevention & control, Time Factors, Dexmedetomidine pharmacology, Digestive System Surgical Procedures adverse effects, Gastrointestinal Tract drug effects
- Abstract
Importance: Postoperative ileus is common after abdominal surgery, and small clinical studies have reported that intraoperative administration of dexmedetomidine may be associated with improvements in postoperative gastrointestinal function. However, findings have been inconsistent and study samples have been small. Further examination of the effects of intraoperative dexmedetomidine on postoperative gastrointestinal function is needed., Objective: To evaluate the effects of intraoperative intravenous dexmedetomidine vs placebo on postoperative gastrointestinal function among older patients undergoing abdominal surgery., Design, Setting, and Participants: This multicenter, double-blind, placebo-controlled randomized clinical trial was conducted at the First Affiliated Hospital of Anhui Medical University in Hefei, China (lead site), and 12 other tertiary hospitals in Anhui Province, China. A total of 808 participants aged 60 years or older who were scheduled to receive abdominal surgery with an expected surgical duration of 1 to 6 hours were enrolled. The study was conducted from August 21, 2018, to December 9, 2019., Interventions: Dexmedetomidine infusion (a loading dose of 0.5 μg/kg over 15 minutes followed by a maintenance dose of 0.2 μg/kg per hour) or placebo infusion (normal saline) during surgery., Main Outcomes and Measures: The primary outcome was time to first flatus. Secondary outcomes were postoperative gastrointestinal function measured by the I-FEED (intake, feeling nauseated, emesis, physical examination, and duration of symptoms) scoring system, time to first feces, time to first oral feeding, incidence of delirium, pain scores, sleep quality, postoperative nausea and vomiting, hospital costs, and hospital length of stay., Results: Among 808 patients enrolled, 404 were randomized to receive intraoperative dexmedetomidine, and 404 were randomized to receive placebo. In total, 133 patients (60 in the dexmedetomidine group and 73 in the placebo group) were excluded because of protocol deviations, and 675 patients (344 in the dexmedetomidine group and 331 in the placebo group; mean [SD] age, 70.2 [6.1] years; 445 men [65.9%]) were included in the per-protocol analysis. The dexmedetomidine group had a significantly shorter time to first flatus (median, 65 hours [IQR, 48-78 hours] vs 78 hours [62-93 hours], respectively; P < .001), time to first feces (median, 85 hours [IQR, 68-115 hours] vs 98 hours [IQR, 74-121 hours]; P = .001), and hospital length of stay (median, 13 days [IQR, 10-17 days] vs 15 days [IQR, 11-18 days]; P = .005) than the control group. Postoperative gastrointestinal function (as measured by the I-FEED score) and delirium incidence were similar in the dexmedetomidine and control groups (eg, 248 patients [72.1%] vs 254 patients [76.7%], respectively, had I-FEED scores indicating normal postoperative gastrointestinal function; 18 patients [5.2%] vs 12 patients [3.6%] had delirium on postoperative day 3)., Conclusions and Relevance: In this randomized clinical trial, the administration of intraoperative dexmedetomidine reduced the time to first flatus, time to first feces, and length of stay after abdominal surgery. These results suggest that this therapy may be a viable strategy to enhance postoperative recovery of gastrointestinal function among older adults., Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR1800017232.
- Published
- 2021
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3. Dexmedetomidine for prevention of postoperative delirium in older adults undergoing oesophagectomy with total intravenous anaesthesia: A double-blind, randomised clinical trial.
- Author
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Hu J, Zhu M, Gao Z, Zhao S, Feng X, Chen J, Zhang Y, and Maze M
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- Aged, Anesthesia, Intravenous, Double-Blind Method, Esophagectomy adverse effects, Humans, Hypnotics and Sedatives adverse effects, Delirium epidemiology, Delirium prevention & control, Dexmedetomidine
- Abstract
Background: Dexmedetomidine is known to be a sedative. Recent studies suggest that administration of dexmedetomidine can prevent postoperative delirium (POD) which has been confirmed as a common complication after major surgery. However, its effects in patients undergoing oesophagectomy are scarce., Objective: To investigate the efficacy and safety of dexmedetomidine in reducing POD in elderly patients after transthoracic oesophagectomy with total intravenous anaesthesia (TIVA)., Design: A randomised, double-blind, placebo-controlled trial., Setting: Single-centre, tertiary care hospital, November 2016 to September 2018., Patients: Eligible patients (n = 177) undergoing transthoracic oesophagectomy were randomly assigned to receive total intravenous anaesthesia (TIVA, n = 87) or dexmedetomidine with TIVA (DEX-TIVA, n = 90)., Interventions: Patients receiving DEX-TIVA received a loading dose of dexmedetomidine (0.4 μg kg-1), over 15 min, followed by a continuous infusion at a rate of 0.1 μg kg-1 h-1 until 1 h before the end of surgery. Patients receiving TIVA received physiological saline with a similar infusion rate protocol., Outcome Measures: The primary outcome was the incidence of POD. The secondary endpoints were the incidence of emergence agitation, serum interleukin-6 (IL-6) levels and haemodynamic profile., Results: All randomised patients were included with planned intention-to-treat analyses for POD. Delirium occurred in 15 (16.7%) of 90 cases given dexmedetomidine, and in 32 (36.8%) of 87 cases given saline (P = 0.0036). The DEX-TIVA group showed less frequent emergence agitation than the TIVA group (22.1 vs. 48.0%, P = 0.0058). The incremental change in surgery-induced IL-6 levels was greater in the TIVA group than DEX-TIVA group (P < 0.0001)., Conclusion: Adding peri-operative dexmedetomidine to a total intravenous anaesthetic safely reduces POD and emergence agitation in elderly patients undergoing open transthoracic oesophagectomy. These benefits were associated with a postoperative reduction in circulating levels of the pro-inflammatory cytokine IL-6 and stabilisation of the haemodynamic profile., Trial Registration: Chinese Clinical Trials Register Identifier: ChiCTR-IPR-17010881., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Society of Anaesthesiology.)
- Published
- 2021
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4. Dexmedetomidine Exerts an Anti-inflammatory Effect via α2 Adrenoceptors to Prevent Lipopolysaccharide-induced Cognitive Decline in Mice.
- Author
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Li R, Lai IK, Pan JZ, Zhang P, and Maze M
- Subjects
- Animals, Anti-Inflammatory Agents, Critical Illness, Lipopolysaccharides, Male, Mice, Receptors, Adrenergic, Rodentia, Tumor Necrosis Factor-alpha, Cognitive Dysfunction, Dexmedetomidine
- Abstract
Background: Clinical studies have shown that dexmedetomidine ameliorates cognitive decline in both the postoperative and critical care settings. This study determined the mechanism(s) for the benefit provided by dexmedetomidine in a medical illness in mice induced by lipopolysaccharide., Methods: Cognitive decline, peripheral and hippocampal inflammation, blood-brain barrier permeability, and inflammation resolution were assessed in male mice. Dexmedetomidine was administered in the presence of lipopolysaccharide and in combination with blockers. Cultured macrophages (RAW 264.7; BV-2) were exposed to lipopolysaccharide ± dexmedetomidine ± yohimbine; tumor necrosis factor α release into the medium and monocyte NFκB activity was determined., Results: In vivo, lipopolysaccharide-induced cognitive decline and inflammation (mean ± SD) were reversed by dexmedetomidine (freezing time, 55.68 ± 12.31 vs. 35.40 ± 17.66%, P = 0.0286, n = 14; plasma interleukin [IL]-1β: 30.53 ± 9.53 vs. 75.68 ± 11.04 pg/ml, P < 0.0001; hippocampal IL-1β: 3.66 ± 1.88 vs. 28.73 ± 5.20 pg/mg, P < 0.0001; n = 8), which was prevented by α2 adrenoceptor antagonists. Similar results were found in 12-month-old mice. Lipopolysaccharide also increased blood-brain barrier leakage, inflammation-resolution orchestrator, and proresolving and proinflammatory mediators; each lipopolysaccharide effect was attenuated by dexmedetomidine, and yohimbine prevented dexmedetomidine's attenuating effect. In vitro, lipopolysaccharide-induced tumor necrosis factor α release (RAW 264.7: 6,308.00 ± 213.60 vs. 7,767.00 ± 358.10 pg/ml, P < 0.0001; BV-2: 1,075.00 ± 40.41 vs. 1,280.00 ± 100.30 pg/ml, P = 0.0003) and NFκB-p65 activity (nuclear translocation [RAW 264.7: 1.23 ± 0.31 vs. 2.36 ± 0.23, P = 0.0031; BV-2: 1.08 ± 0.26 vs. 1.78 ± 0.14, P = 0.0116]; phosphorylation [RAW 264.7: 1.22 ± 0.40 vs. 1.94 ± 0.23, P = 0.0493; BV-2: 1.04 ± 0.36 vs. 2.04 ± 0.17, P = 0.0025]) were reversed by dexmedetomidine, which was prevented by yohimbine., Conclusions: Preclinical studies suggest that the cognitive benefit provided by dexmedetomidine in mice administered lipopolysaccharide is mediated through α2 adrenoceptor-mediated anti-inflammatory pathways.
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- 2020
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5. Dexmedetomidine modulates neuroinflammation and improves outcome via alpha2-adrenergic receptor signaling after rat spinal cord injury.
- Author
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Gao J, Sun Z, Xiao Z, Du Q, Niu X, Wang G, Chang YW, Sun Y, Sun W, Lin A, Bresnahan JC, Maze M, Beattie MS, and Pan JZ
- Subjects
- Animals, Cells, Cultured, Disease Models, Animal, Female, Microglia drug effects, Rats, Rats, Long-Evans, Signal Transduction drug effects, Spinal Cord drug effects, Spinal Cord physiopathology, Adrenergic alpha-2 Receptor Agonists pharmacology, Dexmedetomidine pharmacology, Inflammation drug therapy, Receptors, Adrenergic, alpha-2 drug effects, Spinal Cord Injuries drug therapy, Spinal Cord Injuries physiopathology
- Abstract
Background: Spinal cord injury induces inflammatory responses that include the release of cytokines and the recruitment and activation of macrophages and microglia. Neuroinflammation at the lesion site contributes to secondary tissue injury and permanent locomotor dysfunction. Dexmedetomidine (DEX), a highly selective α2-adrenergic receptor agonist, is anti-inflammatory and neuroprotective in both preclinical and clinical trials. We investigated the effect of DEX on the microglial response, and histological and neurological outcomes in a rat model of cervical spinal cord injury., Methods: Anaesthetised rats underwent unilateral (right) C5 spinal cord contusion (75 kdyne) using an impactor device. The locomotor function, injury size, and inflammatory responses were assessed. The effect of DEX was also studied in a microglial cell culture model., Results: DEX significantly improved the ipsilateral upper-limb motor dysfunction (grooming and paw placement; P<0.0001 and P=0.0012), decreased the injury size (P<0.05), spared white matter (P<0.05), and reduced the number of activated macrophages (P<0.05) at the injury site 4 weeks post-SCI. In DEX-treated rats after injury, tissue RNA expression indicated a significant downregulation of pro-inflammatory markers (e.g. interleukin [IL]-1β, tumour necrosis factor-α, interleukin (IL)-6, and CD11b) and an upregulation of anti-inflammatory and pro-resolving M2 responses (e.g. IL-4, arginase-1, and CD206) (P<0.05). In lipopolysaccharide-stimulated cultured microglia, DEX produced a similar inflammation-modulatory effect as was seen in spinal cord injury. The benefits of DEX on these outcomes were mostly reversed by an α2-adrenergic receptor antagonist., Conclusions: DEX significantly improves neurological outcomes and decreases tissue damage after spinal cord injury, which is associated with modulation of neuroinflammation and is partially mediated via α2-adrenergic receptor signaling., (Copyright © 2019 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)
- Published
- 2019
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6. Impact of Dexmedetomidine on Long-term Outcomes After Noncardiac Surgery in Elderly: 3-Year Follow-up of a Randomized Controlled Trial.
- Author
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Zhang DF, Su X, Meng ZT, Li HL, Wang DX, Xue-Ying Li, Maze M, and Ma D
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- Aged, Analgesics, Non-Narcotic administration & dosage, Cognition physiology, Delirium etiology, Dose-Response Relationship, Drug, Female, Follow-Up Studies, Humans, Infusions, Intravenous, Male, Pain, Postoperative complications, Retrospective Studies, Time Factors, Treatment Outcome, Delirium prevention & control, Dexmedetomidine administration & dosage, Pain, Postoperative drug therapy, Postoperative Care methods, Quality of Life, Surgical Procedures, Operative
- Abstract
Objectives: The aim was to compare the long-term outcomes of low-dose dexmedetomidine versus placebo in a randomized controlled trial (ChiCTR-TRC-10000802)., Background: Low-dose dexmedetomidine infusion decreased delirium occurrence within 1 week after surgery in elderly admitted to the intensive care unit (ICU) after noncardiac surgery, but the long-term outcome of this intervention is unknown., Methods: Patients or their family members were telephone-interviewed for a 3-year follow-up data collection of survival, cognitive function assessed with the modified Telephone Interview for Cognitive Status, and quality of life evaluated with the World Health Organization Quality of Life., Results: Of the 700 patients, 23 (3.3%) were lost at 3-year follow-up. The 3-year overall survival was not statistically different between the dexmedetomidine and placebo groups [114 deaths vs 122/350; hazard ratio (HR) 0.87, 95% confidence interval (CI) 0.68-1.13, P = 0.303]. The survival rates at 6 months, 1 year, and 2 years were significantly higher in the dexmedetomidine than in the placebo group (rate difference of 5.2%, 5.3%, and 6.7% respectively; all P < 0.05). The remaining 98.4% (434/441) 3-year survivors, the dexmedetomidine group, had significantly better cognitive function (mean difference 4.7, 95% CI 3.8-5.6, P < 0.0001) and quality of life (physical domain: 13.6 [10.6-16.6]; psychological domain: 15.2 [12.5-18.0]; social relationship domain: 8.1 [5.5-10.7]; environment domain: 13.3 [10.9-15.7]; all P < 0.0001) than in the placebo group., Conclusions: For elderly admitted to ICU after noncardiac surgery, low-dose dexmedetomidine infusion did not significantly change 3-year overall survival, but increased survival up to 2 years, and improved cognitive function and quality of life in 3-year survivors.
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- 2019
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7. Dexmedetomidine Prevents Cognitive Decline by Enhancing Resolution of High Mobility Group Box 1 Protein-induced Inflammation through a Vagomimetic Action in Mice.
- Author
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Hu J, Vacas S, Feng X, Lutrin D, Uchida Y, Lai IK, and Maze M
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- Animals, Blood-Brain Barrier drug effects, Imidazoline Receptors physiology, Inflammation chemically induced, Male, Mice, Mice, Inbred C57BL, Netrin-1 analysis, Receptors, Nicotinic physiology, Cognitive Dysfunction prevention & control, Dexmedetomidine pharmacology, HMGB1 Protein pharmacology, Inflammation prevention & control, Vagus Nerve physiology
- Abstract
Background: Inflammation initiated by damage-associated molecular patterns has been implicated for the cognitive decline associated with surgical trauma and serious illness. We determined whether resolution of inflammation mediates dexmedetomidine-induced reduction of damage-associated molecular pattern-induced cognitive decline., Methods: Cognitive decline (assessed by trace fear conditioning) was induced with high molecular group box 1 protein, a damage-associated molecular pattern, in mice that also received blockers of neural (vagal) and humoral inflammation-resolving pathways. Systemic and neuroinflammation was assessed by proinflammatory cytokines., Results: Damage-associated molecular pattern-induced cognitive decline and inflammation (mean ± SD) was reversed by dexmedetomidine (trace fear conditioning: 58.77 ± 8.69% vs. 41.45 ± 7.64%, P < 0.0001; plasma interleukin [IL]-1β: 7.0 ± 2.2 pg/ml vs. 49.8 ± 6.0 pg/ml, P < 0.0001; plasma IL-6: 3.2 ± 1.6 pg/ml vs. 19.5 ± 1.7 pg/ml, P < 0.0001; hippocampal IL-1β: 4.1 ± 3.0 pg/mg vs. 41.6 ± 8.0 pg/mg, P < 0.0001; hippocampal IL-6: 3.4 ± 1.3 pg/mg vs. 16.2 ± 2.7 pg/mg, P < 0.0001). Reversal by dexmedetomidine was prevented by blockade of vagomimetic imidazoline and α7 nicotinic acetylcholine receptors but not by α2 adrenoceptor blockade. Netrin-1, the orchestrator of inflammation-resolution, was upregulated (fold-change) by dexmedetomidine (lung: 1.5 ± 0.1 vs. 0.7 ± 0.1, P < 0.0001; spleen: 1.5 ± 0.2 vs. 0.6 ± 0.2, P < 0.0001), resulting in upregulation of proresolving (lipoxin-A4: 1.7 ± 0.2 vs. 0.9 ± 0.2, P < 0.0001) and downregulation of proinflammatory (leukotriene-B4: 1.0 ± 0.2 vs. 3.0 ± 0.3, P < 0.0001) humoral mediators that was prevented by α7 nicotinic acetylcholine receptor blockade., Conclusions: Dexmedetomidine resolves inflammation through vagomimetic (neural) and humoral pathways, thereby preventing damage-associated molecular pattern-mediated cognitive decline.
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- 2018
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8. Theseus, the Labyrinth, and the Minotaur of anaesthetic-induced developmental neurotoxicity.
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Sanders RD, Andropoulos D, Ma D, and Maze M
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- Anesthetics, Animals, Ear, Inner, Neurotoxicity Syndromes, Rats, Dexmedetomidine, Sevoflurane
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- 2017
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9. Neuroprotection and neurotoxicity in the developing brain: an update on the effects of dexmedetomidine and xenon.
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Alam A, Suen KC, Hana Z, Sanders RD, Maze M, and Ma D
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- Adrenergic alpha-2 Receptor Agonists pharmacology, Anesthetics, Inhalation pharmacology, Animals, Brain drug effects, Brain growth & development, Humans, Models, Neurological, Dexmedetomidine pharmacology, Neuroprotective Agents pharmacology, Neurotoxicity Syndromes prevention & control, Xenon pharmacology
- Abstract
Growing and consistent preclinical evidence, combined with early clinical epidemiological observations, suggest potentially neurotoxic effects of commonly used anesthetic agents in the developing brain. This has prompted the FDA to issue a safety warning for all sedatives and anesthetics approved for use in children under three years of age. Recent studies have identified dexmedetomidine, the potent α2-adrenoceptor agonist, and xenon, the noble gas, as effective anesthetic adjuvants that are both less neurotoxic to the developing brain, and also possess neuroprotective properties in neonatal and other settings of acute ongoing neurologic injury. Dexmedetomidine and xenon are effective anesthetic adjuvants that appear to be less neurotoxic than other existing agents and have the potential to be neuroprotective in the neonatal and pediatric settings. Although results from recent clinical trials and case reports have indicated the neuroprotective potential of xenon and dexmedetomidine, additional randomized clinical trials corroborating these studies are necessary. By reviewing both the existing preclinical and clinical evidence on the neuroprotective effects of dexmedetomidine and xenon, we hope to provide insight into the potential clinical efficacy of these agents in the management of pediatric surgical patients., (Copyright © 2017 Elsevier Inc. All rights reserved.)
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- 2017
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10. Dexmedetomidine for prevention of delirium in elderly patients after non-cardiac surgery: a randomised, double-blind, placebo-controlled trial.
- Author
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Su X, Meng ZT, Wu XH, Cui F, Li HL, Wang DX, Zhu X, Zhu SN, Maze M, and Ma D
- Subjects
- Adrenergic alpha-2 Receptor Agonists administration & dosage, Aged, Analgesics, Non-Narcotic therapeutic use, China epidemiology, Confusion diagnosis, Confusion etiology, Confusion prevention & control, Delirium epidemiology, Delirium etiology, Dexmedetomidine administration & dosage, Double-Blind Method, Drug Administration Schedule, Evidence-Based Medicine, Female, Humans, Incidence, Infusions, Intravenous, Intensive Care Units statistics & numerical data, Male, Middle Aged, Respiration, Artificial adverse effects, Time Factors, Treatment Outcome, Adrenergic alpha-2 Receptor Agonists therapeutic use, Critical Care methods, Delirium diagnosis, Delirium prevention & control, Dexmedetomidine therapeutic use, Primary Prevention methods, Surgical Procedures, Operative adverse effects
- Abstract
Background: Delirium is a postoperative complication that occurs frequently in patients older than 65 years, and presages adverse outcomes. We investigated whether prophylactic low-dose dexmedetomidine, a highly selective α
2 adrenoceptor agonist, could safely decrease the incidence of delirium in elderly patients after non-cardiac surgery., Methods: We did this randomised, double-blind, placebo-controlled trial in two tertiary-care hospitals in Beijing, China. We enrolled patients aged 65 years or older, who were admitted to intensive care units after non-cardiac surgery, with informed consent. We used a computer-generated randomisation sequence (in a 1:1 ratio) to randomly assign patients to receive either intravenous dexmedetomidine (0·1 μg/kg per h, from intensive care unit admission on the day of surgery until 0800 h on postoperative day 1), or placebo (intravenous normal saline). Participants, care providers, and investigators were all masked to group assignment. The primary endpoint was the incidence of delirium, assessed twice daily with the Confusion Assessment Method for intensive care units during the first 7 postoperative days. Analyses were done by intention-to-treat and safety populations. This study is registered with Chinese Clinical Trial Registry, www.chictr.org.cn, number ChiCTR-TRC-10000802., Findings: Between Aug 17, 2011, and Nov 20, 2013, of 2016 patients assessed, 700 were randomly assigned to receive either placebo (n=350) or dexmedetomidine (n=350). The incidence of postoperative delirium was significantly lower in the dexmedetomidine group (32 [9%] of 350 patients) than in the placebo group (79 [23%] of 350 patients; odds ratio [OR] 0·35, 95% CI 0·22-0·54; p<0·0001). Regarding safety, the incidence of hypertension was higher with placebo (62 [18%] of 350 patients) than with dexmedetomidine (34 [10%] of 350 patients; 0·50, 0·32-0·78; p=0·002). Tachycardia was also higher in patients given placebo (48 [14%] of 350 patients) than in patients given dexmedetomidine (23 [7%] of 350 patients; 0·44, 0·26-0·75; p=0·002). Occurrence of hypotension and bradycardia did not differ between groups., Interpretation: For patients aged over 65 years who are admitted to the intensive care unit after non-cardiac surgery, prophylactic low-dose dexmedetomidine significantly decreases the occurrence of delirium during the first 7 days after surgery. The therapy is safe., Funding: Braun Anaesthesia Scientific Research Fund and Wu Jieping Medical Foundation, Beijing, China. Study drugs were manufactured and supplied by Jiangsu Hengrui Medicine Co, Ltd, Jiangsu, China., (Copyright © 2016 Elsevier Ltd. All rights reserved.)- Published
- 2016
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11. From Bench to Bedside and Back Again: A Personal Journey with Dexmedetomidine.
- Author
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Maze M
- Subjects
- Animals, Dogs, Humans, Rats, Adrenergic alpha-2 Receptor Agonists, Dexmedetomidine
- Abstract
Dexmedetomidine Diminishes Halothane Anesthetic Requirements in Rats Through a Postsynaptic Alpha 2 Adrenergic Receptor. By Segal IS, Vickery RG, Walton JK, Doze VA, and Maze M. ANESTHESIOLOGY 1988; 125:590-4. Abstract reprinted with permission.The effect of 4(5)-[1-(2,3-dimethylphenyl)ethyl]imidazole (medetomidine), the α2 adrenergic agonist, on anesthetic requirements was investigated in rats anesthetized with halothane. Halothane MAC was determined before and after either dexmedetomidine (D-enantiomer) or levomedetomidine (L-enantiomer) 10, 30, and 100 μg/kg, or vehicle intraperitoneally. There was a dose-dependent increase in MAC with the D-, but not the L-, stereoisomer. At the highest dose of dexmedetomidine (100 μg/kg), halothane could be discontinued for up to 30 min with no response to tail clamping. To determine whether α2 adrenoreceptors mediated this effect of dexmedetomidine on MAC, cohorts of rats were pretreated with idazoxan, 10 mg/kg intraperitoneally, a highly selective α2 antagonist. This completely prevented the reduction of MAC caused by dexmedetomidine. To determine whether the reduction of MAC caused by dexmedetomidine was mediated in part through either opiate or adenosine receptors, groups of rats were pretreated with either naltrexone, 5 mg/kg intraperitoneally, an opiate antagonist, or 8-phenyltheophylline, 2.5 mg/kg intraperitoneally, an A1 adenosine antagonist. These two pretreatments did not alter the reduction of MAC by dexmedetomidine. To determine whether postsynaptic mechanisms mediate the anesthetic effect of dexmedetomidine, rats were depleted of central catecholamine stores with either n-(2-chloroethyl)-n-ethyl-2-bromobenzylamine or reserpine and α-methyl-para-tyrosine, and MAC was determined before and after each dose of dexmedetomidine. While the catecholamine-depleted rats had a lower basal MAC than the vehicle controls, there was still a profound reduction in halothane MAC after administration of dexmedetomidine. The reduction of MAC by dexmedetomidine was blocked with idazoxan in the catecholamine-depleted rats. These data indicate that the reduction of MAC caused by dexmedetomidine is mediated through α2 adrenoreceptors with no apparent involvement of either opiate or A1 adenosine receptors. Data from catecholamine-depleted rats suggest that the mediating mechanism must involve site(s) other than or in addition to the presynaptic α2 adrenergic receptors on noradrenergic neurons. The authors conclude that central postsynaptic α2 adrenergic receptors mediate a significant part of the reduction of anesthetic requirements caused by dexmedetomidine.
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- 2016
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12. Pharmacokinetics of dexmedetomidine combined with therapeutic hypothermia in a piglet asphyxia model.
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Ezzati M, Broad K, Kawano G, Faulkner S, Hassell J, Fleiss B, Gressens P, Fierens I, Rostami J, Maze M, Sleigh JW, Anderson B, Sanders RD, and Robertson NJ
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- Adrenergic alpha-2 Receptor Agonists blood, Adrenergic alpha-2 Receptor Agonists therapeutic use, Animals, Dexmedetomidine blood, Dexmedetomidine therapeutic use, Disease Models, Animal, Hypoxia-Ischemia, Brain etiology, Male, Metabolic Clearance Rate, Neuroprotective Agents blood, Neuroprotective Agents therapeutic use, Nonlinear Dynamics, Sus scrofa, Swine, Adrenergic alpha-2 Receptor Agonists pharmacokinetics, Asphyxia Neonatorum complications, Dexmedetomidine pharmacokinetics, Hypothermia, Induced, Hypoxia-Ischemia, Brain drug therapy, Neuroprotective Agents pharmacokinetics
- Abstract
Background: The highly selective α2 -adrenoreceptor agonist, dexmedetomidine, exerts neuroprotective, analgesic, anti-inflammatory and sympatholytic properties that may be beneficial for perinatal asphyxia. The optimal safe dose for pre-clinical newborn neuroprotection studies is unknown., Methods: Following cerebral hypoxia-ischaemia, dexmedetomidine was administered to nine newborn piglets in a de-escalation dose study in combination with hypothermia (whole body cooling to 33.5°C). Dexmedetomidine was administered with a loading dose of 1 μg/kg and maintenance infusion at doses from 10 to 0.6 μg/kg/h. One additional piglet was not subjected to hypoxia-ischaemia. Blood for pharmacokinetic analysis was sampled pre-insult and frequently post-insult. A one-compartment linear disposition model was used to fit data. Population parameter estimates were obtained using non-linear mixed effects modelling., Results: All dexmedetomidine infusion regimens led to plasma concentrations above those associated with sedation in neonates and children (0.4-0.8 μg/l). Seven out of the nine piglets with hypoxia-ischaemia experienced periods of bradycardia, hypotension, hypertension and cardiac arrest; all haemodynamic adverse events occurred in piglets with plasma concentrations greater than 1 μg/l. Dexmedetomidine clearance was 0.126 l/kg/h [coefficient of variation (CV) 46.6.%] and volume of distribution was 3.37 l/kg (CV 191%). Dexmedetomidine clearance was reduced by 32.7% at a temperature of 33.5°C. Dexmedetomidine clearance was reduced by 55.8% following hypoxia-ischaemia., Conclusions: Dexmedetomidine clearance was reduced almost tenfold compared with adult values in the newborn piglet following hypoxic-ischaemic brain injury and subsequent therapeutic hypothermia. Reduced clearance was related to cumulative effects of both hypothermia and exposure to hypoxia. High plasma levels of dexmedetomidine were associated with major cardiovascular complications., (© 2014 The Authors. The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)
- Published
- 2014
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13. Noradrenergic trespass in anesthetic and sedative states.
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Sanders RD and Maze M
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- Animals, Female, Male, Anesthetics, Inhalation toxicity, Dexmedetomidine toxicity, Dopamine beta-Hydroxylase deficiency, Drug Hypersensitivity metabolism, Hypnotics and Sedatives toxicity
- Published
- 2012
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14. Dexmedetomidine provides renoprotection against ischemia-reperfusion injury in mice.
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Gu J, Sun P, Zhao H, Watts HR, Sanders RD, Terrando N, Xia P, Maze M, and Ma D
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- Acute Kidney Injury pathology, Animals, Cell Line, Humans, Male, Mice, Mice, Inbred C57BL, Protective Agents therapeutic use, Reperfusion Injury pathology, Acute Kidney Injury metabolism, Acute Kidney Injury prevention & control, Dexmedetomidine therapeutic use, Reperfusion Injury metabolism, Reperfusion Injury prevention & control
- Abstract
Introduction: Acute kidney injury following surgery incurs significant mortality with no proven preventative therapy. We investigated whether the α2 adrenoceptor agonist dexmedetomidine (Dex) provides protection against ischemia-reperfusion induced kidney injury in vitro and in vivo., Methods: In vitro, a stabilised cell line of human kidney proximal tubular cells (HK2) was exposed to culture medium deprived of oxygen and glucose. Dex decreased HK2 cell death in a dose-dependent manner, an effect attenuated by the α2 adrenoceptor antagonist atipamezole, and likely transduced by phosphatidylinositol 3-kinase (PI3K-Akt) signaling. In vivo C57BL/6J mice received Dex (25 μg/kg, intraperitoneal (i.p.)) 30 minutes before or after either bilateral renal pedicle clamping for 25 minutes or right renal pedicle clamping for 40 minutes and left nephrectomy., Results: Pre- or post-treatment with Dex provided cytoprotection, improved tubular architecture and function following renal ischemia. Consistent with this cytoprotection, dexmedetomidine reduced plasma high-mobility group protein B1 (HMGB-1) elevation when given prior to or after kidney ischemia-reperfusion; pretreatment also decreased toll-like receptor 4 (TLR4) expression in tubular cells. Dex treatment provided long-term functional renoprotection, and even increased survival following nephrectomy., Conclusions: Our data suggest that Dex likely activates cell survival signal pAKT via α2 adrenoceptors to reduce cell death and HMGB1 release and subsequently inhibits TLR4 signaling to provide reno-protection.
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- 2011
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15. Dexmedetomidine provides cortical neuroprotection: impact on anaesthetic-induced neuroapoptosis in the rat developing brain.
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Sanders RD, Sun P, Patel S, Li M, Maze M, and Ma D
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- Androstadienes toxicity, Animals, Biomarkers, Cells, Cultured drug effects, Cerebral Cortex chemistry, Cerebral Cortex growth & development, Cerebral Cortex pathology, Dexmedetomidine pharmacology, Dose-Response Relationship, Drug, Drug Evaluation, Preclinical, Nerve Tissue Proteins analysis, Neuroprotective Agents pharmacology, Rats, Rats, Sprague-Dawley, Staurosporine toxicity, Wortmannin, Anesthetics, Inhalation toxicity, Apoptosis drug effects, Cerebral Cortex drug effects, Dexmedetomidine therapeutic use, Isoflurane toxicity, Neurons drug effects, Neuroprotective Agents therapeutic use
- Abstract
Background: Recent evidence has demonstrated the anti-apoptotic of dexmedetomidine in different brain injury models. Herein, we investigated whether dexmedetomidine could directly protect against cortical injury in vitro and in vivo., Methods: Apoptosis was induced by staurosporine or wortmannin treatment in cortical neuronal cultures in vitro or by 6 h of isoflurane (0.75%) administration to post-natal day 7 rat pups in vivo. Dexmedetomidine was then applied in escalating doses to assess the neuroprotective potential of this agent. Cell survival was quantified using an MTT assay in vitro and in vivo apoptosis was assessed using cleaved caspase-3 immunohistochemistry. Cortical Western blots were conducted for the cellular survival proteins Bcl-2 and phosphorylated extracellular signal-regulated protein kinase (pERK)1 and 2., Results: In vitro dexmedetomidine dose-dependently prevented both staurosporine- and wortmannin-induced injury in cortical neuronal cultures, indicating that dexmedetomidine can prevent apoptosis when applied directly. In vivo isoflurane induced cortical neuroapoptosis compared with air (327+/-80 vs. 34+/-9 caspase-3-positive neurons; P<0.05). Dexmedetomidine inhibited isoflurane-induced caspase-3 expression (P<0.05), although the protection achieved did not completely attenuate the isoflurane injury (P<0.05 vs. air). Isoflurane treatment decreased Bcl-2 and pERK protein expression relative to air, an effect reversed by dexmedetomidine treatment., Conclusions: Dexmedetomidine prevents cortical apoptosis in vitro and in vivo. However, using higher doses of dexmedetomidine does not further increase protection against isoflurane injury in the cortex than previously observed.
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- 2010
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16. Effect of dexmedetomidine versus lorazepam on outcome in patients with sepsis: an a priori-designed analysis of the MENDS randomized controlled trial.
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Pandharipande PP, Sanders RD, Girard TD, McGrane S, Thompson JL, Shintani AK, Herr DL, Maze M, and Ely EW
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- Adult, Aged, Coma epidemiology, Delirium epidemiology, Dexmedetomidine administration & dosage, Dexmedetomidine pharmacology, Double-Blind Method, Female, Humans, Hypnotics and Sedatives administration & dosage, Hypnotics and Sedatives pharmacology, Intensive Care Units, Lorazepam administration & dosage, Lorazepam pharmacology, Male, Middle Aged, Respiration, Artificial statistics & numerical data, Sepsis mortality, Dexmedetomidine therapeutic use, Hypnotics and Sedatives therapeutic use, Lorazepam therapeutic use, Outcome Assessment, Health Care methods, Sepsis physiopathology
- Abstract
Introduction: Benzodiazepines and alpha2 adrenoceptor agonists exert opposing effects on innate immunity and mortality in animal models of infection. We hypothesized that sedation with dexmedetomidine (an alpha2 adrenoceptor agonist), as compared with lorazepam (a benzodiazepine), would provide greater improvements in clinical outcomes among septic patients than among non-septic patients., Methods: In this a priori-determined subgroup analysis of septic vs non-septic patients from the MENDS double-blind randomized controlled trial, adult medical/surgical mechanically ventilated patients were randomized to receive dexmedetomidine-based or lorazepam-based sedation for up to 5 days. Delirium and other clinical outcomes were analyzed comparing sedation groups, adjusting for clinically relevant covariates as well as assessing interactions between sedation group and sepsis., Results: Of the 103 patients randomized, 63 (31 dexmedetomidine; 32 lorazepam) were admitted with sepsis and 40 (21 dexmedetomidine; 19 lorazepam) without sepsis. Baseline characteristics were similar between treatment groups for both septic and non-septic patients. Compared with septic patients who received lorazepam, the dexmedetomidine septic patients had 3.2 more delirium/coma-free days (DCFD) on average (95% CI for difference, 1.1 to 4.9), 1.5 (-0.1, 2.8) more delirium-free days (DFD) and 6 (0.3, 11.1) more ventilator-free days (VFD). The beneficial effects of dexmedetomidine were more pronounced in septic patients than in non-septic patients for both DCFDs and VFDs (P-value for interaction = 0.09 and 0.02 respectively). Additionally, sedation with dexmedetomidine, compared with lorazepam, reduced the daily risk of delirium [OR, CI 0.3 (0.1, 0.7)] in both septic and non-septic patients (P-value for interaction = 0.94). Risk of dying at 28 days was reduced by 70% [hazard ratio 0.3 (0.1, 0.9)] in dexmedetomidine patients with sepsis as compared to the lorazepam patients; this reduction in death was not seen in non-septic patients (P-value for interaction = 0.11)., Conclusions: In this subgroup analysis, septic patients receiving dexmedetomidine had more days free of brain dysfunction and mechanical ventilation and were less likely to die than those that received a lorazepam-based sedation regimen. These results were more pronounced in septic patients than in non-septic patients. Prospective clinical studies and further preclinical mechanistic studies are needed to confirm these results., Trial Registration: NCT00095251.
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- 2010
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17. Dexmedetomidine attenuates isoflurane-induced neurocognitive impairment in neonatal rats.
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Sanders RD, Xu J, Shu Y, Januszewski A, Halder S, Fidalgo A, Sun P, Hossain M, Ma D, and Maze M
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- Animals, Animals, Newborn, Apoptosis drug effects, Apoptosis physiology, Cognition Disorders pathology, Dexmedetomidine pharmacology, Isoflurane antagonists & inhibitors, Mice, Mice, Inbred C57BL, Rats, Rats, Sprague-Dawley, Cognition Disorders chemically induced, Cognition Disorders prevention & control, Dexmedetomidine therapeutic use, Isoflurane adverse effects
- Abstract
Background: Neuroapoptosis is induced by the administration of anesthetic agents to the young. As alpha2 adrenoceptor signaling plays a trophic role during development and is neuroprotective in several settings of neuronal injury, the authors investigated whether dexmedetomidine could provide functional protection against isoflurane-induced injury., Methods: Isoflurane-induced injury was provoked in organotypic hippocampal slice cultures in vitro or in vivo in postnatal day 7 rats by a 6-h exposure to 0.75% isoflurane with or without dexmedetomidine. In vivo, the alpha2 adrenoceptor antagonist atipamezole was used to identify if dexmedetomidine neuroprotection involved alpha2 adrenoceptor activation. The gamma-amino-butyric-acid type A antagonist, gabazine, was also added to the organotypic hippocampal slice cultures in the presence of isoflurane. Apoptosis was assessed using cleaved caspase-3 immunohistochemistry. Cognitive function was assessed in vivo on postnatal day 40 using fear conditioning., Results: In vivo dexmedetomidine dose-dependently prevented isoflurane-induced injury in the hippocampus, thalamus, and cortex; this neuroprotection was attenuated by treatment with atipamezole. Although anesthetic treatment did not affect the acquisition of short-term memory, isoflurane did induce long-term memory impairment. This neurocognitive deficit was prevented by administration of dexmedetomidine, which also inhibited isoflurane-induced caspase-3 expression in organotypic hippocampal slice cultures in vitro; however, gabazine did not modify this neuroapoptosis., Conclusion: Dexmedetomidine attenuates isoflurane-induced injury in the developing brain, providing neurocognitive protection. Isoflurane-induced injury in vitro appears to be independent of activation of the gamma-amino-butyric-acid type A receptor. If isoflurane-induced neuroapoptosis proves to be a clinical problem, administration of dexmedetomidine may be an important adjunct to prevent isoflurane-induced neurotoxicity.
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- 2009
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18. Sedation improves early outcome in severely septic Sprague Dawley rats.
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Qiao H, Sanders RD, Ma D, Wu X, and Maze M
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- Animals, Blotting, Western, Caspase 3 metabolism, Interleukin-6 blood, Interleukin-6 metabolism, Male, Rats, Rats, Sprague-Dawley, Sepsis physiopathology, Severity of Illness Index, Signal Transduction, Spleen enzymology, Treatment Outcome, Tumor Necrosis Factor-alpha blood, Tumor Necrosis Factor-alpha metabolism, Dexmedetomidine therapeutic use, Hypnotics and Sedatives therapeutic use, Midazolam therapeutic use, Sepsis drug therapy
- Abstract
Introduction: Sepsis, a systemic inflammatory response to infective etiologies, has a high mortality rate that is linked both to excess cytokine activity and apoptosis of critical immune cells. Dexmedetomidine has recently been shown to improve outcome in a septic cohort of patients when compared to patients randomized to a benzodiazepine-based sedative regimen. We sought to compare the effects of dexmedetomidine and midazolam, at equi-sedative doses, on inflammation and apoptosis in an animal model of severe sepsis., Methods: After central venous access, Sprague Dawley rats underwent cecal ligation and intestinal puncture (CLIP) with an 18 G needle without antibiotic cover and received either saline, or an infusion of comparable volume of saline containing midazolam (0.6 mg.kg-1.h-1) or dexmedetomidine (5 ug.kg-1.h-1) for 8 hours. Following baseline measurements and CLIP, blood was sampled for cytokine measurement (tumour necrosis factor (TNF)-alpha and interleukin (IL)-6; n = 4-6 per group) at 2, 4 and 5 hours, and animal mortality rate (MR) was monitored (n = 10 per group) every 2 hours until 2 hours had elapsed. In addition, spleens were harvested and apoptosis was assessed by immunoblotting (n = 4 per group)., Results: The 24 hour MR in CLIP animals (90%) was significantly reduced by sedative doses of either dexmedetomidine (MR = 20%) or midazolam (MR = 30%). While both sedatives reduced systemic levels of the inflammatory cytokine TNF-alpha (P < 0.05); only dexmedetomidine reduced the IL-6 response to CLIP, though this narrowly missed achieving significance (P = 0.05). Dexmedetomidine reduced splenic caspase-3 expression (P < 0.05), a marker of apoptosis, when compared to either midazolam or saline., Conclusions: Sedation with midazolam and dexmedetomidine both improve outcome in polymicrobial severely septic rats. Possible benefits conveyed by one sedative regimen over another may become evident over a more prolonged time-course as both IL-6 and apoptosis were reduced by dexmedetomidine but not midazolam. Further studies are required to evaluate this hypothesis.
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- 2009
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19. Expecting the unexpected.
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Talke PO and Maze M
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- Atrial Fibrillation physiopathology, Cardiopulmonary Resuscitation, Hemodynamics drug effects, Humans, Risk Factors, Shock, Cardiogenic physiopathology, Shock, Cardiogenic therapy, Treatment Failure, Adrenergic alpha-Agonists adverse effects, Atrial Fibrillation diagnosis, Dexmedetomidine adverse effects, Electrophysiologic Techniques, Cardiac, Hypnotics and Sedatives adverse effects, Shock, Cardiogenic chemically induced
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- 2008
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20. Effect of sedation with dexmedetomidine vs lorazepam on acute brain dysfunction in mechanically ventilated patients: the MENDS randomized controlled trial.
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Pandharipande PP, Pun BT, Herr DL, Maze M, Girard TD, Miller RR, Shintani AK, Thompson JL, Jackson JC, Deppen SA, Stiles RA, Dittus RS, Bernard GR, and Ely EW
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- Aged, Coma diagnosis, Delirium diagnosis, Dexmedetomidine adverse effects, Dexmedetomidine economics, Double-Blind Method, Female, Humans, Hypnotics and Sedatives adverse effects, Hypnotics and Sedatives economics, Intensive Care Units economics, Lorazepam adverse effects, Lorazepam economics, Male, Middle Aged, Neuropsychological Tests, Coma chemically induced, Conscious Sedation economics, Delirium chemically induced, Dexmedetomidine administration & dosage, Hypnotics and Sedatives administration & dosage, Lorazepam administration & dosage, Respiration, Artificial economics
- Abstract
Context: Lorazepam is currently recommended for sustained sedation of mechanically ventilated intensive care unit (ICU) patients, but this and other benzodiazepine drugs may contribute to acute brain dysfunction, ie, delirium and coma, associated with prolonged hospital stays, costs, and increased mortality. Dexmedetomidine induces sedation via different central nervous system receptors than the benzodiazepine drugs and may lower the risk of acute brain dysfunction., Objective: To determine whether dexmedetomidine reduces the duration of delirium and coma in mechanically ventilated ICU patients while providing adequate sedation as compared with lorazepam., Design, Setting, Patients, and Intervention: Double-blind, randomized controlled trial of 106 adult mechanically ventilated medical and surgical ICU patients at 2 tertiary care centers between August 2004 and April 2006. Patients were sedated with dexmedetomidine or lorazepam for as many as 120 hours. Study drugs were titrated to achieve the desired level of sedation, measured using the Richmond Agitation-Sedation Scale (RASS). Patients were monitored twice daily for delirium using the Confusion Assessment Method for the ICU (CAM-ICU)., Main Outcome Measures: Days alive without delirium or coma and percentage of days spent within 1 RASS point of the sedation goal., Results: Sedation with dexmedetomidine resulted in more days alive without delirium or coma (median days, 7.0 vs 3.0; P = .01) and a lower prevalence of coma (63% vs 92%; P < .001) than sedation with lorazepam. Patients sedated with dexmedetomidine spent more time within 1 RASS point of their sedation goal compared with patients sedated with lorazepam (median percentage of days, 80% vs 67%; P = .04). The 28-day mortality in the dexmedetomidine group was 17% vs 27% in the lorazepam group (P = .18) and cost of care was similar between groups. More patients in the dexmedetomidine group (42% vs 31%; P = .61) were able to complete post-ICU neuropsychological testing, with similar scores in the tests evaluating global cognitive, motor speed, and attention functions. The 12-month time to death was 363 days in the dexmedetomidine group vs 188 days in the lorazepam group (P = .48)., Conclusion: In mechanically ventilated ICU patients managed with individualized targeted sedation, use of a dexmedetomidine infusion resulted in more days alive without delirium or coma and more time at the targeted level of sedation than with a lorazepam infusion., Trial Registration: clinicaltrials.gov Identifier: NCT00095251.
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- 2007
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21. Translational research: addressing problems facing the anesthesiologist.
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Sanders RD and Maze M
- Subjects
- Analgesics, Opioid adverse effects, Anesthesiology, Animals, Anterior Horn Cells pathology, Biomedical Research, Dexmedetomidine pharmacology, Humans, Nerve Degeneration chemically induced, Paraplegia etiology, Paraplegia prevention & control, Rats, Spinal Cord Ischemia complications, Analgesics, Non-Narcotic administration & dosage, Analgesics, Opioid toxicity, Anterior Horn Cells drug effects, Dexmedetomidine administration & dosage, Morphine toxicity, Nerve Degeneration prevention & control, Spinal Cord Ischemia pathology
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- 2007
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22. Neuroprotective interaction produced by xenon and dexmedetomidine on in vitro and in vivo neuronal injury models.
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Rajakumaraswamy N, Ma D, Hossain M, Sanders RD, Franks NP, and Maze M
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- Animals, Brain Infarction drug therapy, Brain Infarction pathology, Carotid Artery, Common physiology, Cell Hypoxia drug effects, Dose-Response Relationship, Drug, Drug Synergism, Glucose deficiency, Hypoxia, Brain drug therapy, Hypoxia, Brain pathology, L-Lactate Dehydrogenase metabolism, Ligation, Mice, Mice, Inbred BALB C, Rats, Rats, Sprague-Dawley, Adrenergic alpha-Agonists pharmacology, Anesthetics, Inhalation pharmacology, Dexmedetomidine pharmacology, Neuroglia drug effects, Neuroglia pathology, Neurons drug effects, Neurons pathology, Neuroprotective Agents, Receptors, N-Methyl-D-Aspartate antagonists & inhibitors, Xenon pharmacology
- Abstract
Xenon, an NMDA receptor antagonist and dexmedetomidine (Dex), an alpha(2)-adrenoceptor agonist, both exhibit neuroprotective effects. We investigated the nature of their interaction. In vitro: a primary co-culture of neuronal and glial cells derived from neonatal mice was exposed to oxygen and glucose deprivation (OGD) and the resulting neuronal injury was assessed by the release of lactate dehydrogenase (LDH). In vivo: Postnatal rats aged 7 days underwent right common carotid artery ligation followed by 90 min of hypoxia. The area of infarction was assessed at four days post-injury by morphological criteria. Long-term neurological function was evaluated at 30 days post-injury by testing co-ordination on rotarod. Both xenon and Dex concentration-dependently reduced LDH release with IC50 values of 42% atm (95% CI: 35-52) and 0.10 microM (95% CI: 0.08-0.16), respectively. Isobolographic analysis showed that combined effect of xenon and Dex in vitro was additive. In vivo, a combination of xenon and Dex, at doses that are individually not neuroprotective, produced significant neuroprotective effect as measured by reduction in area of infarction. The long-term neurological function data corroborated these morphological data. Our study demonstrates that the combination of xenon and Dex offers neuroprotection additively in vitro and synergistically in vivo.
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- 2006
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23. Dexmedetomidine exerts dose-dependent age-independent antinociception but age-dependent hypnosis in Fischer rats.
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Sanders RD, Giombini M, Ma D, Ohashi Y, Hossain M, Fujinaga M, and Maze M
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- Age Factors, Animals, Dose-Response Relationship, Drug, Proto-Oncogene Proteins c-fos analysis, Rats, Rats, Inbred F344, Analgesics, Non-Narcotic pharmacology, Dexmedetomidine pharmacology, Hypnotics and Sedatives pharmacology
- Abstract
Dexmedetomidine (Dex), an alpha(2)-adrenoceptor agonist, is an effective analgesic and sedative drug in adults; however, little information is available about its efficacy in pediatric populations. Some anesthetics exhibit an age-dependent analgesic effect, e.g., nitrous oxide, being relatively ineffective in newborn rats. We investigated the analgesic and hypnotic efficacy of Dex using 6 cohorts of Fischer rats aged 7, 15, 19, 23, and 29 days and adults exposed to either Dex (10 or 50 microg/kg) or saline subcutaneously. Formalin plantar testing was used to mimic inflammatory pain, and its effect was assessed using immunohistochemical (c-Fos staining) and behavioral methods. The hypnotic action of Dex was assessed by loss of righting reflex. Formalin administration produced a typical nociceptive response in each age group; these nociceptive responses were significantly attenuated by Dex 50 microg/kg at all ages (P < 0.05), whereas Dex 10 microg/kg had little effect. Neonatal rats showed the greatest hypnotic sensitivity to Dex (P < 0.05).
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- 2005
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24. Dexmedetomidine and opioid interactions: defining the role of dexmedetomidine for intensive care unit sedation.
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Maze M and Angst MS
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- Analgesics, Opioid pharmacology, Dexmedetomidine pharmacology, Drug Interactions, Humans, Hypnotics and Sedatives pharmacology, Respiration, Artificial, Respiratory Mechanics drug effects, Analgesics, Opioid pharmacokinetics, Critical Care, Dexmedetomidine pharmacokinetics, Hypnotics and Sedatives pharmacokinetics
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- 2004
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25. Dexmedetomidine produces its neuroprotective effect via the alpha 2A-adrenoceptor subtype.
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Ma D, Hossain M, Rajakumaraswamy N, Arshad M, Sanders RD, Franks NP, and Maze M
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- Adrenergic alpha-2 Receptor Antagonists, Animals, Cells, Cultured, Cerebral Cortex metabolism, Dose-Response Relationship, Drug, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Transgenic, Cerebral Cortex drug effects, Dexmedetomidine pharmacology, Neuroprotective Agents pharmacology, Receptors, Adrenergic, alpha-2 metabolism
- Abstract
Which of the three alpha2-adrenoceptor subtypes of alpha2A, alpha2B, or alpha2C mediates the neuroprotective effect of dexmedetomidine was examined in cell culture as well as in an in vivo model of neonatal asphyxia. Dexmedetomidine dose-dependently attenuated neuronal injury (IC50=83+/-1 nM) in neuronal-glial co-cultures derived from wild-type mice; contrastingly, dexmedetomidine did not exert neuroprotection in injured cells from transgenic mice (D79N) expressing dysfunctional alpha2A-adrenoceptors. An alpha2A-adrenoceptor subtype-preferring antagonist 2-[(4,5-Dihydro-1H-imidazol-2-yl)methyl]-2,3-dihydro-1-methyl-1H-isoindole maleate (BRL44408) completely reversed dexmedetomidine-induced neuroprotection, while other subtype-preferring antagonists 2-[2-(4-(2-Methoxyphenyl)piperazin-1-yl)ethyl]-4,4-dimethyl-1,3-(2H,4H)-isoquinolindione dihydrochloride (ARC239) (alpha2B) and rauwolscine (alpha2C) had no significant effect on the neuroprotective effect of dexmedetomidine in neuronal-glial co-cultures. Dexmedetomidine also protected against exogenous glutamate induced cell death in pure cortical neuron cultures assessed by flow cytometry and reduced both apoptotic and necrotic types of cell death. Likewise this neuroprotective effect was antagonised by BRL44408 but not ARC239 or rauwolscine. Dexmedetomidine exhibited dose-dependent protection against brain matter loss in vivo (IC50=40.3+/-6.1 microg/kg) and improved the neurologic functional deficit induced by the hypoxic-ischemic insult. Protection by dexmedetomidine against hypoxic-ischemic-induced brain matter loss was reversed by the alpha2A-adrenoceptor subtype-preferring antagonist BRL44408; neither ARC239 nor rauwolscine reversed the neuroprotective effect of dexmedetomidine in vivo. Our data suggest that the neuroprotective effect of dexmedetomidine is mediated by activation of the alpha2A adrenergic receptor subtype.
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- 2004
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26. Comparative analgesic and mental effects of increasing plasma concentrations of dexmedetomidine and alfentanil in humans.
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Angst MS, Ramaswamy B, Davies MF, and Maze M
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- Adult, Dose-Response Relationship, Drug, Double-Blind Method, Electric Stimulation, Female, Gas Chromatography-Mass Spectrometry, Hemodynamics drug effects, Hot Temperature, Humans, Hypnotics and Sedatives pharmacology, Infusions, Intravenous, Male, Neuropsychological Tests, Pain Measurement drug effects, Reaction Time drug effects, Adrenergic alpha-Agonists blood, Adrenergic alpha-Agonists pharmacology, Alfentanil blood, Alfentanil pharmacology, Analgesics, Non-Narcotic blood, Analgesics, Non-Narcotic pharmacology, Analgesics, Opioid blood, Analgesics, Opioid pharmacology, Dexmedetomidine blood, Dexmedetomidine pharmacology, Mental Processes drug effects
- Abstract
Background: In animals, systemic and intrathecal administration of the alpha2 -adrenergic receptor agonist dexmedetomidine results in robust antinociceptive effects in models of heat pain. In humans, systemically administered dexmedetomidine is approved for sedating patients in the intensive care unit. However, whether systemic administration of dexmedetomidine in humans produces significant analgesia at doses causing sedation but not unconsciousness remains controversial., Methods: This study in human volunteers used a placebo-controlled, double-blind, and randomized design to examine whether dexmedetomidine at doses causing mild to severe sedation produces analgesia in experimental models of heat and electrical pain. Results were compared to the effects of the mu-opioid receptor agonist alfentanil. A computer-controlled infusion provided four median step-up plasma concentrations of dexmedetomidine (0.09, 0.24, 0.54, and 1.23 ng/ml) and alfentanil (13.4, 33.8, 67.8, and 126.1 ng/ml)., Results: Sedative and cognitive effects of dexmedetomidine were dose-dependent, resulting in a median sedation score of 95 of 100 and slowing of cognitive speed (reaction time, trail-making test) by a factor of about two at the highest plasma concentration. Dexmedetomidine did not attenuate heat or electrical pain. Alfentanil caused severe sedation (median sedation score 88 of 100) and slowed cognitive speed by a factor of approximately 1.4 at the highest plasma concentration. Alfentanil attenuated heat and electrical pain dose dependently., Conclusion: This study documents that systemic dexmedetomidine lacks analgesic efficacy for heat and electrical pain at doses causing mild to severe sedation. These results provide further evidence suggesting that systemic administration of dexmedetomidine lacks broad analgesic activity in models of acute pain at doses not rendering humans unconscious.
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- 2004
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27. Dexmedetomidine: another arrow for the clinician's quiver.
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Ebert T and Maze M
- Subjects
- Humans, Receptors, Adrenergic, alpha-2 drug effects, Receptors, Adrenergic, alpha-2 physiology, Respiratory Mechanics drug effects, Adrenergic alpha-Agonists pharmacology, Anesthesia, General, Dexmedetomidine pharmacology, Hypnotics and Sedatives pharmacology
- Published
- 2004
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28. Dexmedetomidine enhances analgesic action of nitrous oxide: mechanisms of action.
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Dawson C, Ma D, Chow A, and Maze M
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- Animals, Dose-Response Relationship, Drug, Drug Synergism, Drug Tolerance, Genes, fos, Male, Rats, Rats, Sprague-Dawley, Analgesics pharmacology, Dexmedetomidine pharmacology, Nitrous Oxide pharmacology
- Abstract
Background: Nitrous oxide and dexmedetomidine are thought to mediate analgesia (antinociception in a noncommunicative organism) via alpha 2B- and alpha 2A-adrenergic receptor subtypes within the spinal cord, respectively. Nitrous oxide and dexmedetomidine exert diametrically opposite effects on neuronal activity within the locus ceruleus, a pivotal site for modulation of analgesia. Because of these differences, the authors explored whether the two analgesics in combination would provide satisfactory analgesia., Methods: The analgesic effects of nitrous oxide and dexmedetomidine given both intraperitoneally and intrathecally were evaluated using the tail-flick latency test in rats. For investigation of the interaction, rats were pretreated with dexmedetomidine, either intraperitoneally or intrathecally, immediately before nitrous oxide exposure such that peak antinociceptive effects of each drug coincided. For assessment of the effect on tolerance, dexmedetomidine was administered as tolerance to nitrous oxide developed. Expression of c-Fos was used to assess neuronal activity in the locus ceruleus., Results: Nitrous oxide and dexmedetomidine increased tail-flick latency with an ED50 (mean +/- SEM) of 55.0 +/- 2.2% atm for nitrous oxide, 27.6 +/- 5.1 for microg/kg intraperitoneal dexmedetomidine, and 2.9 +/- 0.1 microg for intrathecal dexmedetomidine. Combinations of systemically administered dexmedetomidine and nitrous oxide produced an additive analgesic interaction; however, neuraxially administered dexmedetomidine interacted synergistically with nitrous oxide. Tolerance to nitrous oxide was reversed by coadministration of dexmedetomidine. Prazosin, the alpha 1-/alpha 2B-adrenoceptor antagonist, attenuated the analgesic effect of nitrous oxide and prevented dexmedetomidine-induced reversal of tolerance to nitrous oxide. Nitrous oxide-induced increase of neuronal activity in the locus ceruleus was reversed by dexmedetomidine., Conclusion: The synergistic analgesic interaction between nitrous oxide and dexmedetomidine within the spinal cord is obscured by a supraspinal antagonism when dexmedetomidine is administered systemically in the pretolerant state. After tolerance to nitrous oxide develops, supraspinal functional antagonism no longer obtains exposing the synergistic action at the level of the spinal cord, which expresses itself as a reversal of the tolerant state. The authors speculate that the addition of dexmedetomidine to nitrous oxide is likely to provide enhanced and more durable analgesia in settings in which nitrous oxide is currently used alone (e.g., labor and dental surgery).
- Published
- 2004
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29. The alpha2-adrenoceptor agonist dexmedetomidine converges on an endogenous sleep-promoting pathway to exert its sedative effects.
- Author
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Nelson LE, Lu J, Guo T, Saper CB, Franks NP, and Maze M
- Subjects
- Adrenergic alpha-Antagonists pharmacology, Animals, Cell Count, Electroencephalography drug effects, Electromyography drug effects, Excitatory Amino Acid Agonists pharmacology, GABA Antagonists pharmacology, GABA-A Receptor Agonists, Gene Expression Regulation drug effects, Genes, fos drug effects, Ibotenic Acid pharmacology, Imidazoles pharmacology, Immunohistochemistry, In Situ Hybridization, Mice, Mice, Inbred C57BL, Neural Pathways drug effects, Postural Balance drug effects, Pyridazines pharmacology, Rats, Rats, Inbred F344, Receptors, Adrenergic, alpha-2 genetics, Sleep, REM drug effects, Adrenergic alpha-2 Receptor Agonists, Adrenergic alpha-Agonists pharmacology, Dexmedetomidine pharmacology, Hypnotics and Sedatives pharmacology, Sleep drug effects
- Abstract
Background: The authors investigated whether the sedative, or hypnotic, action of the general anesthetic dexmedetomidine (a selective alpha -adrenoceptor agonist) activates endogenous nonrapid eye movement (NREM) sleep-promoting pathways., Methods: c-Fos expression in sleep-promoting brain nuclei was assessed in rats using immunohistochemistry and hybridization. Next, the authors perturbed these pathways using (1) discrete lesions induced by ibotenic acid, (2) local and systemic administration of gamma-aminobutyric acid receptor type A (GABA ) receptor antagonist gabazine, or (3) alpha2-adrenoceptor antagonist atipamezole in rats, and (4) genetic mutation of the alpha -adrenoceptor in mice., Results: Dexmedetomidine induced a qualitatively similar pattern of c-Fos expression in rats as seen during normal NREM sleep, a decrease in the locus ceruleus (LC) and tuberomammillary nucleus (TMN) and an increase in the ventrolateral preoptic nucleus (VLPO). These changes were attenuated by atipamezole and were not seen in mice lacking functional alpha2a-adrenoceptors, which do not show a sedative response to dexmedetomidine. Bilateral VLPO lesions attenuated the sedative response to dexmedetomidine, and the dose-response curve to dexmedetomidine was shifted right by gabazine administered systemically or directly into the TMN. VLPO lesions and gabazine pretreatment altered c-Fos expression in the TMN but in not the LC after dexmedetomidine administration, indicating a hierarchical sequence of changes., Conclusions: The authors propose that endogenous sleep pathways are causally involved in dexmedetomidine-induced sedation; dexmedetomidine's sedative mechanism involves inhibition of the LC, which disinhibits VLPO firing. The increased release of GABA at the terminals of the VLPO inhibits TMN firing, which is required for the sedative response.
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- 2003
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30. Dexmedetomidine PK with hypothermia
- Author
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EZZATI, M, BROAD, K, KAWANO, G, FAULKNER, S, HASSELL, J, FLEISS, B, GRESSENS, P, FIERENS, I, ROSTAMI, J, MAZE, M, SLEIGH, JW, ANDERSON, B, SANDERS, RD, and ROBERTSON, NJ
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Paediatrics ,Biomedical and Clinical Sciences ,Physical Injury - Accidents and Adverse Effects ,Heart Disease ,Perinatal Period - Conditions Originating in Perinatal Period ,Neurosciences ,Pediatric ,Cardiovascular ,Adrenergic alpha-2 Receptor Agonists ,Animals ,Asphyxia Neonatorum ,Dexmedetomidine ,Disease Models ,Animal ,Hypothermia ,Induced ,Hypoxia-Ischemia ,Brain ,Male ,Metabolic Clearance Rate ,Neuroprotective Agents ,Nonlinear Dynamics ,Sus scrofa ,Swine ,Clinical Sciences ,Medical Physiology ,Anesthesiology ,Clinical sciences - Abstract
BackgroundThe highly selective α2 -adrenoreceptor agonist, dexmedetomidine, exerts neuroprotective, analgesic, anti-inflammatory and sympatholytic properties that may be beneficial for perinatal asphyxia. The optimal safe dose for pre-clinical newborn neuroprotection studies is unknown.MethodsFollowing cerebral hypoxia-ischaemia, dexmedetomidine was administered to nine newborn piglets in a de-escalation dose study in combination with hypothermia (whole body cooling to 33.5°C). Dexmedetomidine was administered with a loading dose of 1 μg/kg and maintenance infusion at doses from 10 to 0.6 μg/kg/h. One additional piglet was not subjected to hypoxia-ischaemia. Blood for pharmacokinetic analysis was sampled pre-insult and frequently post-insult. A one-compartment linear disposition model was used to fit data. Population parameter estimates were obtained using non-linear mixed effects modelling.ResultsAll dexmedetomidine infusion regimens led to plasma concentrations above those associated with sedation in neonates and children (0.4-0.8 μg/l). Seven out of the nine piglets with hypoxia-ischaemia experienced periods of bradycardia, hypotension, hypertension and cardiac arrest; all haemodynamic adverse events occurred in piglets with plasma concentrations greater than 1 μg/l. Dexmedetomidine clearance was 0.126 l/kg/h [coefficient of variation (CV) 46.6.%] and volume of distribution was 3.37 l/kg (CV 191%). Dexmedetomidine clearance was reduced by 32.7% at a temperature of 33.5°C. Dexmedetomidine clearance was reduced by 55.8% following hypoxia-ischaemia.ConclusionsDexmedetomidine clearance was reduced almost tenfold compared with adult values in the newborn piglet following hypoxic-ischaemic brain injury and subsequent therapeutic hypothermia. Reduced clearance was related to cumulative effects of both hypothermia and exposure to hypoxia. High plasma levels of dexmedetomidine were associated with major cardiovascular complications.
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- 2014
31. Adrenergic and Cholinergic Compounds
- Author
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Sanders, R. D., Maze, M., Starke, K., editor, Born, G. V. R., editor, Duckles, S., editor, Eichelbaum, M., editor, Ganten, D., editor, Hofmann, F., editor, Rosenthal, W., editor, Rubanyi, G., editor, and Stein, Christoph, editor
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- 2007
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32. Effect of Intraoperative Dexmedetomidine on Recovery of Gastrointestinal Function After Abdominal Surgery in Older Adults: A Randomized Clinical Trial
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Yu Yq, Liu Xs, Fang Pp, Lu Y, Feng Xm, Cheng Xq, Wong Gtc, and Maze M
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Male ,China ,Time Factors ,Placebo ,Loading dose ,law.invention ,Ileus ,Postoperative Complications ,Randomized controlled trial ,Double-Blind Method ,law ,Medicine ,Humans ,Hypnotics and Sedatives ,Dexmedetomidine ,Digestive System Surgical Procedures ,Original Investigation ,Aged ,Intraoperative Care ,business.industry ,Maintenance dose ,General Medicine ,Middle Aged ,Gastrointestinal Tract ,Anesthesia ,Female ,medicine.symptom ,Gastrointestinal function ,business ,Postoperative nausea and vomiting ,Abdominal surgery ,medicine.drug - Abstract
IMPORTANCE: Postoperative ileus is common after abdominal surgery, and small clinical studies have reported that intraoperative administration of dexmedetomidine may be associated with improvements in postoperative gastrointestinal function. However, findings have been inconsistent and study samples have been small. Further examination of the effects of intraoperative dexmedetomidine on postoperative gastrointestinal function is needed. OBJECTIVE: To evaluate the effects of intraoperative intravenous dexmedetomidine vs placebo on postoperative gastrointestinal function among older patients undergoing abdominal surgery. DESIGN, SETTING, AND PARTICIPANTS: This multicenter, double-blind, placebo-controlled randomized clinical trial was conducted at the First Affiliated Hospital of Anhui Medical University in Hefei, China (lead site), and 12 other tertiary hospitals in Anhui Province, China. A total of 808 participants aged 60 years or older who were scheduled to receive abdominal surgery with an expected surgical duration of 1 to 6 hours were enrolled. The study was conducted from August 21, 2018, to December 9, 2019. INTERVENTIONS: Dexmedetomidine infusion (a loading dose of 0.5 μg/kg over 15 minutes followed by a maintenance dose of 0.2 μg/kg per hour) or placebo infusion (normal saline) during surgery. MAIN OUTCOMES AND MEASURES: The primary outcome was time to first flatus. Secondary outcomes were postoperative gastrointestinal function measured by the I-FEED (intake, feeling nauseated, emesis, physical examination, and duration of symptoms) scoring system, time to first feces, time to first oral feeding, incidence of delirium, pain scores, sleep quality, postoperative nausea and vomiting, hospital costs, and hospital length of stay. RESULTS: Among 808 patients enrolled, 404 were randomized to receive intraoperative dexmedetomidine, and 404 were randomized to receive placebo. In total, 133 patients (60 in the dexmedetomidine group and 73 in the placebo group) were excluded because of protocol deviations, and 675 patients (344 in the dexmedetomidine group and 331 in the placebo group; mean [SD] age, 70.2 [6.1] years; 445 men [65.9%]) were included in the per-protocol analysis. The dexmedetomidine group had a significantly shorter time to first flatus (median, 65 hours [IQR, 48-78 hours] vs 78 hours [62-93 hours], respectively; P
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- 2021
33. Dexmedetomidine for sedation and perioperative management of critically ill patients.
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Pandharipande, P., Ely, E.W., and Maze, M.
- Abstract
Benzodiazepines and opioids are routinely used in the perioperative period and the intensive care unit (ICU) to prevent anxiety and pain. These agents have the potential for side effects that may worsen outcomes in critically ill patients. Alpha
2 agonists are increasingly being used as adjuvant therapeutic agents in the perioperative period because of their ability to block the sympathetic stress response, complete with their anesthetic and analgesic sparing properties, lack of respiratory depression, and low and predictable side effect profile. The recent approval of dexmedetomidine, a parentally administered alpha2 agonist, provides an alternative to the conventional strategy of sedation and analgesia utilizing benzodiazepines and opiates. This state of the art review examines the physiological properties and uses of alpha2 agonists, with emphasis on dexmedetomidine, in the perioperative period and in the ICU. [Copyright &y& Elsevier]- Published
- 2006
- Full Text
- View/download PDF
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