Alpha-2 Agonist Dexmedetomidine Research Articles

Dexmedetomidine Versus Midazolam for End-of-Life Sedation and Agitation: Protocol for a Randomized Controlled Trial (The DREAMS Trial).

Sedation at the end of life is used to relieve distressing symptoms including agitation and delirium. Standard care may include infused benzodiazepines or antipsychotics. These agents often result in deep sedation with loss of interaction with loved ones, which may be distressing. The DREAMS (Dexmedetomidine for the Reduction of End-of-life Agitation and for optiMised Sedation) trial aimed to compare the sedative and antidelirium effects of the alpha-2 agonist dexmedetomidine, a novel palliative care sedative, compared with midazolam, a benzodiazepine when administered by subcutaneous infusion at the end of life, with doses of both agents targeting lighter, or potentially interactive sedation. Participants were recruited from adult inpatients admitted for end-of-life care under a palliative care team in regional New South Wales, Australia. Inclusion criteria included patients older than 18 years, with a preference for lighter sedation at the end of life. Exclusion criteria included severe cardiac dysfunction (contraindication to dexmedetomidine). Participants consented and were placed on a treatment-pending list. Upon experiencing terminal deterioration, patients were randomized to either arm 1 (dexmedetomidine) or arm 2 (midazolam) as their treatment arm. These treatments were administered by continuous subcutaneous infusion. The level of consciousness and agitation of the patients were measured by the Richmond Agitation-Sedation Scale-Palliative version and the Memorial Delirium Assessment Score. Richmond Agitation-Sedation Scale-Palliative version assessments were performed by both nursing and medical staff, while Memorial Delirium Assessment Score assessments were carried out by medical staff only. Families and patients were asked to complete, as able, a patient comfort assessment form, to gauge perceptions of distress. Data were collected and matched with the breakthrough medication doses administered, along with qualitative comments in the medical record. In addition, the study tracked symptoms and patient functional status that were recorded as part of the Palliative Care Outcomes Collaborative, a national tracking project for monitoring symptom outcomes in palliative care. The DREAMS trial was funded in May 2020, approved by the ethics committee in November 2020, and started recruiting participants in May 2021. Data collection commenced in May 2021 and is anticipated to continue until December 2024. Publication of results is anticipated from 2024 to 2026. The evidence base for sedative dosing in palliative care for distress and agitation is not robust, with standard care based primarily on clinical experience and not robust scientific evidence. This study is important because it will compare a standard and a novel sedative used in end-of-life treatment. By assessing the potential efficacy and benefits of both, it seeks to optimize the quality of dying by providing targeted sedation that can improve the communication between dying patients and their loved ones. Australia New Zealand Clinical Trials Register ACTRN12621000052831; https://uat.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=380889. DERR1-10.2196/55129.

Pharmacological interventions for the treatment of delirium in critically ill adults.

Pharmacological interventions for the treatment of delirium in critically ill adults.

Evaluation of analgesic efficacy of dexmedetomidine as adjuvant with ropivacaine in ultrasound-guided adductor canal block in patients following anterior cruciate ligament reconstruction surgeries.

Local anaesthetic (LA) with highly selective alpha-2 agonist dexmedetomidine has not been evaluated in adductor canal block (ACB) for arthroscopic anterior cruciate ligament (ACL) reconstruction surgeries. The study evaluates postoperative analgesic effect of ropivacaine with adjuvant dexmedetomidine following postoperative ultrasound-guided ACB. 105 randomized subjects received ultrasound-guided ACB using 15 mL of 0.5% ropivacaine, with 0.5 µg kg-1 of dexmedetomidine administered perineurally (Group II), intravenously (Group III) or none (Group I). Primary outcome included 24 hours' total morphine consumption postoperatively. Secondary outcomes included haemodynamics and adverse effects. The postoperative total morphine consumption was significantly reduced till 4 hours in II 0.57 mg (0.98 (0-3)) (p = 0.011) and up to 6 hours in Group III 0.77 mg (1.00 (0-4)) (p = 0.004) compared to Group I. The postoperative total morphine consumption was comparable at 24 hours in Group III 3.57 mg (1.73 (0-8)) and Group II 3.34 mg (1.92 (07)) (p = 1.000). The visual analogue scale (VAS) scores were comparable in all the three groups at all the time intervals studied (p > 0.05). There were no adverse effects observed during the study. Use of perineural dexmedetomidine with LA for ACB in the postoperative period resulted in significant reduction in total morphine consumption in initial 4 hours as compared to 6 hours with intravenous (IV) dexmedetomidine.

Additives used to reduce perioperative opioid consumption 1: Alpha2-agonists.

Because of their significant side effects, especially in obese patients, the routine perioperative use of opioids has been questioned recently. Alpha2-agonists are drugs with a considerable analgesic potency with the potential to reduce opioid consumption. Alpha2-agonists bind to alpha2-adrenergic receptors in the CNS and peripherally. They inhibit the central sympathetic outflow, resulting in an attenuation of blood pressure and heart rate and in a sparing effect on anaesthetics and analgesics. In the postoperative period alpha2-agonists provide an analgesic effect without respiratory depression and other known opioid side effects. Intraoperatively, a complete replacement of the synthetic opioid fentanyl by the alpha2-agonist dexmedetomidine has been demonstrated. Although alpha2-agonists have a sedative action, recovery times are not prolonged compared to those of opioids. Cardiovascular side effects such as bradycardia and hypotension have to be observed and treated.

Dexmedetomidine attenuates pyohemia-associated delirium in mice through the cholinergic anti-inflammatory pathway

Objective To study if the protective effect of dexmedetomidine on the pyohemia-associated delirium is through the cholinergic anti-inflammatory pathway. Methods Sixty male adult C57 mice were randomly divided into five groups (n=12 each): saline group (group C), dexmedetomidine (DEX) alone group (group DEX), endotoxemia (LPS) group (group LPS), dexmedetomidine protection group (group LPS+ DEX) and alpha-bungarotoxin (α-BGT) group (group α-BGT). Each group were assigned to two subunits (n=6 each), mice in subunit one were sacrificed after examining the open field test, mice in subunit two were sacrificed after testing the novel object recognition. The level of inflammatory factors were measured by enzyme-linked immune sorbent assay (ELISA). The ultrastructure changes of the hippocampus in mice were observed by transmission electron microscopy. Results Compared with group C, there are no significant differences in group DEX. Dexmedetomidine significantly attenuated the delirious syndrome after LPS induced endotoxemia, however, the effect of dexmedetomidine disappeared in group α-BGT, and the syndrome of cognitive dysfunction in LPS group were more severe than that in group α-BGT. (1) The open field test show that there are no significant differences each group with that before model establishment; after the models were established 24 h, compared with group C, group LPS show that the abilities of cognition to new environment、learning and memory were decreasing, the tension is increasing. preemptive administration of dexmedetomidine significantly attenuated the delirious syndrome after LPS induced endotoxemia; however, preemptive administration of dexmedetomidine failed to control the delirious syndrome in group α-BGT. (2) The novel object recognition testshow that compared to group C, the ability of exploring the novel object is decreasing; preemptive administration of dexmedetomidine significantly improve the exploration ability, however, preemptive administration of dexmedetomidine failed to control the delirious syndrome in group α-BGT. (3) The results of ELISA show that: Compared with group C, the concentrations of tumor necrosis factor-α (TNF-α) and interleukin (IL)-1β in serum and Hippocampus were all increased in LPS groups[Serum (ng/L) TNF-α: 794.80±93.99 vs. 23.60±3.03, IL-1β: 148.49±24.80 vs. 64.55±5.13, Hippocampus (pg/mg·prot) TNF-α: 176.14±11.25 vs. 6.71±0.49, IL-1β: 50.61±5.86 vs. 16.73±1.15, P=0.000], compared with group LPS, the concentrations were all significantly decreased in group LPS+ DEX[Serum (ng/L) TNF-α: 184.44±26.58 vs. 794.80±93.99, IL-1β: 77.43±10.75 vs. 148.49±24.80, Hippocampus (pg/mg·prot) TNF-α: 64.83±13.09 vs. 176.14±11.25, IL-1β: 17.97±2.26 vs. 50.61±5.86, P=0.000]. However, α-BGT can reverse the protective effect[Serum (ng/L): TNF-α: 812.31±86.25 vs. 184.44±26.58, IL-1β: 156.42±17.94 vs. 77.43±10.75, Hippocampus (pg/mg·prot) TNF-α: 181.94±8.69 vs. 64.83±13.09, IL-1β: 52.10±5.59 vs. 17.97±2.26, P=0.000]. TEM shown that the histopathological damage of hippocampus tissue in group LPS and α-BGT were heavier, which in group LPS+ DEX was reversed partially. Conclusion Central alpha-2 agonist dexmedetomidine attenuates sepsis-associated delirium syndrome likely through activating cholinergic anti-inflammatory pathway and inhibiting the inflammatory responses in serum and brain. Key words: Delirium; Dexmedetomidine; Endotoxemia; Cholinergic anti-inflammatory pathway; Inflammatory response

Dexmedetomidine for the treatment of hyperactive delirium refractory to haloperidol in non-intubated patients

Delirium is reported to occur in up to 89% of patients admitted to the intensive care unit (ICU) (1), and delirium is an independent risk factor for increased costs, longer hospital stays, neuropsychological dysfunction, and mortality (2-4). As such, the effective treatment of delirium represents a way to not only improve patient safety and outcomes but also to decrease costs and increase hospital throughput. Multiple modalities, including both typical and atypical anti-psychotics, are available as off-label use to treat the symptoms of delirium. These agents do not treat the underlying condition, and data are conflicting on whether they can prevent delirium or decrease its duration (5-7). A promising therapy that can not only treat delirium symptoms but may also prevent the development of delirium is the alpha-2 agonist dexmedetomidine. Several studies have shown that dexmedetomidine, when used for sedation of patients on mechanical ventilation, can reduce the incidence and duration of delirium (8-11) and hasten extubation of patients with hyperactive delirium (12,13). There is little data, however, on its effectiveness in non-intubated patients. This represents an important patient population because the consequences of over-sedation are potentially catastrophic in the absence of a secure airway. In their current work, Carrasco et al. (14) show that the use of dexmedetomidine in non-intubated patients who failed treatment with haloperidol resulted in reduced time with symptoms of agitated delirium, more time at the target sedation level, and decreased overall costs of the patient stay.

Spinal cord protection via alpha-2 agonist-mediated increase in glial cell-line–derived neurotrophic factor

ObjectivesDelayed paraplegia secondary to ischemia–reperfusion injury is a devastating complication of thoracoabdominal aortic surgery. Alpha-2 agonists have been shown to attenuate ischemia–reperfusion injury, but the mechanism for protection has yet to be elucidated. A growing body of evidence suggests that astrocytes play a critical role in neuroprotection by release of neurotrophins. We hypothesize that alpha-2 agonism with dexmedetomidine increases glial cell-line–derived neurotrophic factor in spinal cord astrocytes to provide spinal cord protection. MethodsSpinal cords were isolated en bloc from C57BL/6 mice, and primary spinal cord astrocytes and neurons were selected for and grown separately in culture. Astrocytes were treated with dexmedetomidine, and glial cell-line–derived neurotrophic factor was tested for by enzyme-linked immunosorbent assay. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was used to assess neuronal viability. ResultsSpinal cord primary astrocytes treated with dexmedetomidine at 1 μmol/L and 10 μmol/L had significantly increased glial cell-line–derived neurotrophic factor production compared with control (P < .05). Neurons subjected to oxygen glucose deprivation had significant preservation (P < .05) of viability with use of dexmedetomidine-treated astrocyte media. Glial cell-line–derived neurotrophic factor neutralizing antibody eliminated the protective effects of the dexmedetomidine-treated astrocyte media (P < .05). ConclusionsAstrocytes have been shown to preserve neuronal viability via release of neurotrophic factors. Dexmedetomidine increases glial cell–derived neurotrophic factor from spinal cord astrocytes via the alpha-2 receptor. Treatment with alpha-2 agonist dexmedetomidine may be a clinical tool for use in spinal cord protection in aortic surgery.

Dexmedetomidine controls systemic cytokine levels through the cholinergic anti-inflammatory pathway.

Previous studies have shown that dexmedetomidine exerted anti-inflammatory effect on several animal models with inflammation, but the mechanism is not clear. This study intends to elucidate the anti-inflammatory mechanism of dexmedetomidine through the cholinergic anti-inflammatory pathway. To investigate this therapeutic potential of dexmedetomidine, a murine model of endotoxemia was established induced by lipopolysaccharide (LPS). Animals were assigned to one of four protocols. Protocol one: animals were randomly assigned to control group, dexmedetomidine group, and sterile saline group (n=20 each), and these animals were used for survival analysis. The survival rate was assessed up to 120 h after endotoxin injection. Protocol two: animals were randomly assigned to one of four groups (n=16 each): group 1 (group Saline), treated with sterile saline 15 min prior to endotoxin treatment (10 mg kg(-1) over 2 min); group 2 (group Dex), treated with dexmedetomidine 15 min prior to endotoxin treatment; group 3 (group αBGT+Dex), treated with alpha-7 nicotinic acetylcholine receptors (α7nAChR) antagonist alpha-bungarotoxin (αBGT, 1 μg/kg) 15 min prior to dexmedetomidine treatment; group 4 (group saline+Dex), treated with equivalent sterile saline 15 min prior to dexmedetomidine treatment. Protocol three: animals were randomly assigned to one of two groups (n=16 each): vagotomy group (group VNX+Dex), right cervical vagus nerve was exposed and transected; sham-operated group (group SHAM+Dex), the cervical vagus nerve was visualized, but was neither isolated from the surrounding tissues nor transected. Protocol four: animals were treated with dexmedetomidine (40 μg/kg) and sterile saline to observe the discharge activity of cervical vagus nerves by using BL-420F data acquisition and analysis system (n=16 each). In the survival analysis groups, the survival rate of dexmedetomidine group was significantly higher than that of the endotoxemia group (65 versus 25 %, P<0.01). Preemptive administration of dexmedetomidine significantly attenuated the cytokine response after lipopolysaccharide (LPS) induced endotoxemia (TNF-alpha, IL-1beta, IL-6, P<0.01, respectively). However, preemptive administration of dexmedetomidine failed to suppress cytokine response in α-bungarotoxin group and vagotomy group (TNF-alpha, IL-1beta, IL-6, P>0.05, respectively). Furthermore, preemptive administration of dexmedetomidine significantly increased the discharge frequency of cervical vagus nerves in comparison with sterile saline treatment (P<0.01).Our results demonstrate that the preemptive administration of dexmedetomidine increases the activity of cervical vagus nerve and have the ability to successfully improve survival in experimental endotoxemia by inhibiting the inflammatory cytokines release. However, administration of dexmedetomidine to vagotomy or α7 nAChR antagonist pretreatment mice failed to suppress TNF levels, indicating that the vagus nerve and α7nAChR-mediated cholinergic anti-inflammatory pathway is required for the anti-inflammatory effect of dexmedetomidine. These findings show that central alpha-2 agonist dexmedetomidine suppresses systemic inflammation through vagal- and α7nAChR-dependent mechanism.

Interruption of spinal cord microglial signaling by alpha-2 agonist dexmedetomidine in a murine model of delayed paraplegia

Despite investigation into preventable pharmacologic adjuncts, paraplegia continues to complicate thoracoabdominal aortic interventions. The alpha 2a adrenergic receptor agonist, dexmedetomidine, has been shown to preserve neurologic function and neuronal viability in a murine model of spinal cord ischemia reperfusion, although the mechanism remains elusive. We hypothesize that dexmedetomidine will blunt postischemic inflammation in vivo following thoracic aortic occlusion with in vitro demonstration of microglial inhibition following lipopolysaccharide (LPS) stimulation. Adult male C57BL/6 mice underwent 4 minutes of aortic occlusion. Mice received 25 μg/kg intraperitoneal dexmedetomidine (n = 8) or 0.9% normal saline (n = 7) at reperfusion and 12-hour intervals postoperatively until 48 hours. Additionally, sham mice (n = 3), which had aortic arch exposed with no occlusion, were included for comparison. Functional scoring was done at 6 hours following surgery and 12-hour intervals until 60 hours when spinal cords were removed and examined for neuronal viability and cytokine production. Additional analysis of microglia activation was done in 12 hours following surgery. Age- and sex-matched mice had spinal cord removed for microglial isolation culture. Cells were grown to confluence and stimulated with toll-like receptor-4 agonist LPS 100 ng/mL in presence of dexmedetomidine or vehicle control for 24 hours. Microglia and media were then removed for analysis of protein expression. Dexmedetomidine treatment at reperfusion significantly preserved neurologic function with mice in treatment group having a Basso Score of 6.3 in comparison to 2.3 in ischemic control group. Treatment was associated with a significant reduction in microglia activation and in interleukin-6 production. Microglial cells in isolation when stimulated with LPS had an increased production of proinflammatory cytokines and markers of activation. Treatment with dexmedetomidine significantly attenuated microglial activation and proinflammatory cytokine production in vitro with a greater than twofold reduction in tumor necrosis factor-α. Alpha 2a agonist, dexmedetomidine treatment at reperfusion preserved neurologic function and neuronal viability. Furthermore, dexmedetomidine treatment resulted in an attenuation of microglial activation and proinflammatory cytokine production both in vivo and in vitro following LPS stimulation. This finding lends insight into the mechanism of paralysis following thoracic aortic interventions and may guide future pharmacologic targets for attenuating spinal cord ischemia and reperfusion.

The Use of Dexmedetomidine in Anesthesia and Intensive Care: A Review

The alpha-2 agonist dexmedetomidine is being increasingly used for sedation and as an adjunctive agent during general and regional anesthesia. It is used in a number of procedures and clinical settings including neuroanesthesia, vascular surgery, gastrointestinal endoscopy, fiberoptic intubation, and pediatric anesthesia. The drug is also considered a nearly ideal sedative agent in the intensive care setting. However, the drug frequently produces hypotension and bradycardia, and also decreases cerebral blood flow without concomitantly decreasing the cerebral metabolic rate for oxygen. This review discusses recent advances in the use of dexmedetomidine in anesthesia and intensive care settings, as well as discuss potential problems with its use.

Attenuation of Spinal Cord Ischemia-Reperfusion Injury With Treatment of Alpha-2 Agonist Dexmedetomidine

Despite surgical adjuncts, delayed lower extremity paralysis remains a devastating complication following thoracic aortic surgery. Dexmedetomidine is a selective α-2a agonist commonly used for sedation in the critical care setting. It has been shown to have both neuronal and renal protective affects against ischemia-reperfusion injuries. We hypothesized that treatment with dexmedetomidine will attenuate spinal cord ischemia-reperfusion injury via inhibition of microglial activation. Adult C57bL/6 mice underwent sternotomy followed by occlusion of the aortic arch for 4 minutes. Eight experimental mice received pretreatment with 25ìg/kg of intrapeirtoneal dexmedetomidine and at 12 hour intervals following reperfusion. Eight control mice received an equivalent amount of 0.9% normal saline. Functional analysis was obtained at 12 hours intervals and scored using the Basso, Beattie and Bresnahan (BBB) score until 60 hours. All mice were euthanized at 60 hours. Their spinal cords were removed en bloc and were stained with hematoxylin and eosin to asses neuronal viability. Immunofluorescence staining with Iba-1 marker a of activated microglia was done at 12 hours after reperfusion in three mice (1 sham, 1 ischemic , control and 1 dexmedetomidine treated). Treated mice demonstrated preserved motor function as compared with ischemic controls (Fig 1). In addition, cyto-architecture in ischemic control mice showed decreased neuronal viability by hematoxylin and eosin staining. Immunofluorescence staining of spinal cords at 12 hrs after reperfusion with Iba-1, marker of activated microglia, shows decreased activation of microglia in treatment groups. Treatment of mice with alpha-2 agonist dexmedetomidine preserves motor function after spinal cord ischemia- reperfusion injury. Additionally, dexmedetomidine preserves spinal cord cyto-architecture and reduces microglia activation. In conclusion dexmedetomidine appears to attenuate spinal cord ischemia-reperfusion injury through inhibition of microglia activation.

Effects of dexmedetomidine or methylprednisolone on inflammatory responses in spinal cord injury

The aim of this study was to compare the anti-inflammatory response of methylprednisolone and the alpha2-agonist dexmedetomidine in spinal cord injury (SCI). Twenty-four male adult Wistar albino rats, weight 200-250 g, were included in the study. The rats were divided into four groups as follows: the control group (n: 6) received only laminectomy; the SCI group (n: 6) with trauma alone; the SCI+methylprednisolone group (n: 6) with trauma and 30 mg/kg methylprednisolone, followed by a maintenance dose of 5.4 mg/kg/h; and the SCI+dexmedetomidine group (n: 6) with trauma and 10 microg/kg dexmedetomidine treatment intraperitoneally. Twenty-four hours after the trauma, spinal cord samples were taken for histopathological examination and serum samples were collected for interleukin-6 (IL-6) and tumor necrosis factor (TNF)-alpha measurement. TNF-alpha (P=0.009) and IL-6 (P=0.009) levels were significantly increased in the SCI group. TNF-alpha and IL-6 levels were significantly decreased with methylprednisolone (P=0.002, 0.002) and dexmedetomidine (P=0.002, 0.009) treatment, respectively. Methylprednisolone and dexmedetomidine treatment reduced neutrophils' infiltration in SCI. The current study does not clarify the definitive mechanism by which dexmedetomidine decreases inflammatory cytokines but it is the first study to report the anti-inflammatory effect of dexmedetomidine in SCI. Further studies are required to elucidate the effects of dexmedetomidine on the inflammatory response.

Clinical Experience with Dexmedetomidine for Implantation of Deep Brain Stimulators in Parkinson's Disease

The pharmacologic profile of the alpha-2 agonist dexmedetomidine (Dex) suggests that it may be an ideal sedative drug for deep brain stimulator (DBS) implantation. We performed a retrospective chart review of anesthesia records of patients who underwent DBS implantation from 2001 to 2004. In 2003, a clinical protocol with Dex sedation for DBS implantation was initiated. Demographic data, use of antihypertensive medication, and duration of mapping were compared between patients who received Dex (11 patients/13 procedures) and patients who did not receive any sedation (controls: 8 patients/9 procedures). There were no differences in severity of illness between the two groups. Dex provided patient comfort and surgical satisfaction with mapping in all cases, and significantly reduced the use of antihypertensive medication (54% in the Dex group, versus 100% in controls, P = 0.048). In DBS implantation, sedation with Dex did not interfere with electrophysiologic mapping, and provided hemodynamic stability and patient comfort. Routine use of Dex in these procedures may be indicated.

Hemodynamic and Anesthetic Advantages of Dexmedetomidine, an .ALPHA.2-Agonist, for Surgery in Prone Position

The alpha2-agonist dexmedetomidine (Dex), a sedative and analgesic, reduces heart rate (HR) and blood pressure, and has been used in the practice of anesthesia. In this study, we aimed to evaluate the effects of Dex on hemodynamic variables, anesthetic sparing effects, and recovery profiles in patients who underwent surgery in prone position. The prone position itself can cause a decrease in the systemic blood pressure. Forty patients who undergo lumbar discectomy were randomly assigned to receive either Dex (a loading dose 1 microg/ kg in 10 minutes followed by an infusion rate of 0.2 microg/ kg/ hr) or saline. In both groups, the anesthesia was induced with fentanyl, thiopental and rocuronium, and maintained with desflurane in 50% N(2)O. Mean arterial blood pressure (MAP), HR, cardiac output (CO), and level of anesthesia were monitored. Recovery times and analgesic requirements were also recorded. As a response to endotracheal intubation, a significant increase in MAP and HR was observed in the control group compared to the Dex group, but no difference in CO. The recovery times were significantly shorter in the Dex group compared to the control group. Anesthetic and analgesic requirements of the Dex group were lower than controls. Thus, the use of Dex caused no detrimental effects on the hemodynamic variables in prone position. In addition, Dex decreased pressure response to intubation, and anesthetic and analgesic requirements, shortened recovery times, and decreased postoperative pain level. Dex may be an alternative to currently used adjunctive anesthetic agents in lumbar discectomy operations.

Alpha-2B adrenoceptor polymorphism and peripheral vasoconstriction

Alpha-2B adrenoceptors (AR) mediate vasoconstriction in the mice. A human alpha-2B AR deletion (D) variant has been associated with loss of short-term agonist-promoted receptor desensitization, which may lead to increased vasoconstriction upon alpha-2 AR activation. This study tested the hypothesis that alpha-2 AR activation will induce enhanced vasoconstriction in carriers of the alpha-2B AR DD genotype, compared to carriers of the II or the DI genotypes. We administered 1 microg/kg dexmedetomidine (an alpha-2 agonist) intravenously to 80 surgical patients in whom sympatholytic effects of the drug were attenuated by general anesthesia. Measurements were made of finger blood volume (an indicator of vasoconstriction) by photoplethysmographic determination of light transmission through a finger (LTF) and of hemodynamic variables. Dexmedetomidine increased LTF (vasoconstriction), induced an initial increase in systolic blood pressure and decreased heart rate in all genotype groups (P<0.0001 for all). Three min after the start of dexmedetomidine infusion, the increase in LTF was more pronounced (P=0.014) in the DD group compared to the DI and II groups. There were no significant differences in LTF values between the groups at the end of or 5 min after dexmedetomidine infusion. There were no differences in systolic blood pressure or heart rate values between the groups during or after the dexmedetomidine infusion. The results of this study confirm that the alpha-2 agonist dexmedetomidine induced marked peripheral vasoconstriction. Subjects with the alpha 2B DD genotype had an enhanced vasoconstrictive response at the beginning of dexmedetomidine infusion. However, this enhanced vasoconstrictive response was not sustained throughout or after the 15-min dexmedetomidine infusion.

Comparison between dexmedetomidine and propofol for sedation in the intensive care unit: patient and clinician perceptions

The alpha2 agonist dexmedetomidine is a new sedative and analgesic agent which is licensed in the USA for post-operative intensive care sedation. We compared dexmedetomidine with propofol in patients requiring sedation in intensive care. Twenty adult patients expected to require a minimum of 8 h artificial ventilation after surgery were randomized to receive sedation with either dexmedetomidine or propofol infusions. Additional analgesia, if required, was provided by an alfentanil infusion. Depth of sedation was monitored using both the Ramsay sedation score (RSS) and the bispectral index (BIS). Cardiovascular, respiratory, biochemical and haematological data were obtained. Patients' perceptions of their intensive care stay were assessed using the Hewitt questionnaire. Sedation was equivalent in the two groups [median (interquartile range): RSS, propofol group 5 (4-5), dexmedetomidine group 5 (4-6) (P=0.68); BIS, propofol group 53 (41-64), dexmedetomidine group 46 (36-58); P=0.32], but the propofol group received three times more alfentanil compared with patients sedated with dexmedetomidine [2.5 (2.2-2.9) mg h(-1) versus 0.8 (0.65-1.2) mg h(-1) (P=0.004)]. No differences were found in arterial pressures between the groups, but heart rate was significantly lower in the dexmedetomidine group [mean (SD) 75 (6) vs 90 (4) beats min(-1)]. Extubation times were similar and rapid with the use of both sedative agents [median (range) 28 (20-50) and 29 (15-50) min (P=0.63) respectively for the propofol and dexmedetomidine groups]. No adverse events related to the sedative infusions occurred in either group. Despite ventilation and intubation, patients sedated with dexmedetomidine could be easily roused to cooperate with procedures (e.g. physiotherapy, radiology) without showing irritation. From the clinician's and patient's perspectives, dexmedetomidine is a safe and acceptable sedative agent for those requiring intensive care. The rate pressure product is reduced in patients receiving dexmedetomidine, which may protect against myocardial ischaemia. Dexmedetomidine reduces the requirement for opioid analgesia.

The effects of dexmedetomidine on neuromuscular blockade in human volunteers.

The neuromuscular effects of dexmedetomidine in humans are unknown. We evaluated the effect of dexmedetomidine on neuromuscular block and hemodynamics during propofol/alfentanil anesthesia. During propofol/alfentanil anesthesia, the rocuronium infusion rate was adjusted in 10 volunteers to maintain a stable first response (T1) in the train-of-four sequence at 50% +/- 3% of the pre-rocuronium value. Dexmedetomidine was then administered by computer-controlled infusion, targeting a plasma dexmedetomidine concentration of 0.6 ng/mL for 45 min. The evoked mechanical responses of the adductor pollicis responses (T1 response and T4/T1 ratio), systolic blood pressure (SBP), heart rate (HR), and transmitted light through a fingertip were measured during the dexmedetomidine infusion and compared with predexmedetomidine values using repeated-measures analysis of variance and Dunnett's test. Plasma dexmedetomidine levels ranged from 0.68 to 1.24 ng/mL. T1 values decreased during the infusion, from 51% +/- 2% to 44% +/- 9% (P < 0.0001). T4/T1 values did not change during the infusion. Plasma rocuronium concentrations increased during the infusion (P = 0.02). Dexmedetomidine increased SBP (P < 0.001) and decreased HR (P < 0.001) (5-min median values) during the infusion compared with values before the infusion. Dexmedetomidine increased the transmitted light through the fingertip by up to 41% +/- 8% during the dexmedetomidine infusion (P < 0.001).We demonstrated that dexmedetomidine (0.98 +/- 0.01 microg/kg) increased the plasma rocuronium concentration, decreased T1, increased SBP, and decreased finger blood flow during propofol/alfentanil anesthesia. We conclude that dexmedetomidine-induced vasoconstriction may alter the pharmacokinetics of rocuronium. We studied the effect of an alpha2-agonist (dexmedetomidine) on rocuronium-induced neuromuscular block during propofol/alfentanil anesthesia. We found that the rocuronium concentration increased and the T1 response decreased during the dexmedetomidine administration. Although these effects were statistically significant, it is unlikely that they are of clinical significance.

The Effects of Dexmedetomidine on Neuromuscular Blockade in Human Volunteers

The neuromuscular effects of dexmedetomidine in humans are unknown.We evaluated the effect of dexmedetomidine on neuromuscular block and hemodynamics during propofol/alfentanil anesthesia. During propofol/alfentanil anesthesia, the rocuronium infusion rate was adjusted in 10 volunteers to maintain a stable first response (T1) in the train-of-four sequence at 50% +/- 3% of the pre-rocuronium value. Dexmedetomidine was then administered by computer-controlled infusion, targeting a plasma dexmedetomidine concentration of 0.6 ng/mL for 45 min. The evoked mechanical responses of the adductor pollicis responses (T1 response and T4/T1 ratio), systolic blood pressure (SBP), heart rate (HR), and transmitted light through a fingertip were measured during the dexmedetomidine infusion and compared with pre-dexmedetomidine values using repeated-measures analysis of variance and Dunnett's test. Plasma dexmedetomidine levels ranged from 0.68 to 1.24 ng/mL. T1 values decreased during the infusion, from 51% +/- 2% to 44% +/- 9% (P < 0.0001). T4/T1 values did not change during the infusion. Plasma rocuronium concentrations increased during the infusion (P = 0.02). Dexmedetomidine increased SBP (P < 0.001) and decreased HR (P < 0.001) (5-min median values) during the infusion compared with values before the infusion. Dexmedetomidine increased the transmitted light through the fingertip by up to 41% +/- 8% during the dexmedetomidine infusion (P < 0.001). We demonstrated that dexmedetomidine (0.98 +/- 0.01 [micro sign]g/kg) increased the plasma rocuronium concentration, decreased T1, increased SBP, and decreased finger blood flow during propofol/alfentanil anesthesia. We conclude that dexmedetomidine-induced vasoconstriction may alter the pharmacokinetics of rocuronium. Implications: We studied the effect of an alpha2-agonist (dexmedetomidine) on rocuronium-induced neuromuscular block during propofol/alfentanil anesthesia. We found that the rocuronium concentration increased and the T1 response decreased during the dexmedetomidine administration. Although these effects were statistically significant, it is unlikely that they are of clinical significance. (Anesth Analg 1999;88:633-9)

The Analgesic Potency of Dexmedetomidine Is Enhanced After Nerve Injury

This study investigated the analgesic potency and site of action of systemic dexmedetomidine, a selective alpha2-adrenoceptor (alpha2AR) agonist, in normal and neuropathic rats. Ligation of the L5-6 spinal nerves produced a chronic mechanical and thermal neuropathic hyperalgesia in rats. von Frey fibers and a thermoelectric Peltier device were used to measure mechanical and heat withdrawal thresholds over the hindpaw. Systemic dexmedetomidine dose-dependently increased the mechanical and thermal thresholds in the control animals (50% effective dose [ED50] 144 and 180 microg/kg intraperitoneally [i.p.], respectively). Neuropathic animals responded to much smaller doses of dexmedetomidine with mechanical and thermal ED50 values of 52 and 29 microg/kg i.p., respectively. There was no difference between the control and neuropathic animals with respect to dexmedetomidine-evoked sedation, as determined by decreased grid crossings in an open-field activity chamber (ED50 12 and 9 microg/kg i.p., respectively). Atipamezole, a selective alpha2AR antagonist, blocked the analgesic and sedative actions of dexmedetomidine inboth the neuropathic and control animals. However, L-659,066, a peripherally restricted alpha2AR antagonist, could only block the analgesic actions of dexmedetomidine in the neuropathic rats, with no effect in control animals. In conclusion, nerve injury enhanced the analgesic but not the sedative potency of systemic dexmedetomidine and may have shifted the site of alpha2 analgesic action to outside the blood-brain barrier. We tested the analgesic efficacy of the alpha2 agonist dexmedetomidine in normal and nerve-injured rats. The analgesic potency of dexmedetomidine was enhanced after nerve injury with a site of action outside the central nervous system. Peripherally restricted alpha2 agonists may be useful in the management of neuropathic pain.

Indomethacin and staurosporine reverse α2 inhibition of water transport in rat IMCD

These studies were conducted to determine if the prostaglandin-synthesis inhibitor indomethacin or the protein kinase C (PKC) inhibitor staurosporine affect the inhibition of osmotic water permeability (Pf) by the alpha-2 (alpha 2) agonist dexmedetomidine in the rat inner medullary collecting duct (IMCD). Terminal IMCDs from Wistar rats were perfused and Pf was increased with either 220 pM arginine vasopressin (AVP) or 0.1 mM 8-chlorophenylthio cyclic adenosine monophosphate (8CPTcAMP). All agents were added to the bathing solution. Dexmedetomidine at 100 nM inhibited both AVP- and 8CPTcAMP-stimulated Pf. When Pf was increased by AVP, indomethacin at 0.1 mM or 5 microM reversed the dexmedetomidine-induced inhibition by 68% and 43%, respectively. When Pf was increased by 8CPTcAMP, indomethacin at 0.1 mM or 5 microM reversed inhibition by 83% and 70%, respectively. Indomethacin increased AVP and 8CPTcAMP-stimulated Pf by 20 to 30% and dexmedetomidine inhibited the AVP+ indomethacin-stimulated Pf. Staurosporine at 10 nM yielded similar results. Results suggest that PKC and prostaglandins are involved in the alpha 2 mediated mechanism, and staurosporine and indomethacin-sensitive cellular mediators modulate basal Pf.