Selective Alpha 2-adrenergic Agonist Research Articles

Number Needed to Treat and Number Needed to Harm From Two Phase 3 Studies of Sublingual Dexmedetomidine for Treating Acute Agitation in Patients With Schizophrenia and Bipolar Disorder

AbstractBackgroundEpisodes of acute agitation can occur in individuals who suffer from schizophrenia or bipolar disorder and these can be a significant challenge for patients and for those who provide care to them. Sublingual dexmedetomidine is a selective alpha2-adrenergic receptor agonist that was recently approved by the US Food and Drug Administration for the treatment of agitation in adults with schizophrenia or bipolar disorder. The sublingual form of dexmedetomidine does not undergo first-pass hepatic metabolism, thus resulting in greater absorption than when ingested. In two Phase 3 studies of adults with schizophrenia or bipolar disorder, sublingual dexmedetomidine significantly reduced acute agitation at 2 hours, as measured by the five-item Positive and Negative Syndrome Scale-Excited Component (PEC). When initially appraising the potential utility of a new medication, number needed to treat (NNT) and needed to harm (NNH) can be helpful to assess the size of the treatment effect and, hence, clinical relevance.ObjectiveCalculation of NNT and NNH through post hoc analysis of Phase 3 data.MethodsPost hoc analysis of data were performed on data from two double-blind, randomized, placebo-controlled studies of sublingual dexmedetomidine in adults with schizophrenia or bipolar disorder experiencing acute agitation. Patients were randomized to a single dose of sublingual dexmedetomidine 180 μg, 120 μg, or placebo. The primary endpoint was mean change from baseline in the PEC total score. A therapeutic response was defined as a ≥40% reduction from baseline in PEC total score at 2 hours. NNT was calculated for PEC response rate for sublingual dexmedetomidine versus placebo. NNH was calculated using the incidence of adverse events for sublingual dexmedetomidine versus placebo. Likelihood to be helped or harmed (LHH) was calculated as the ratio of NNH to NNT.ResultsNNT (95% CI) was 3 (2, 3) for 180 mcg and 3 (3, 4) for 120 ug in patients with schizophrenia and 3 (2, 3) for 180 mcg and 4 (3, 6) for 120 ug in patients with bipolar disorder. NNH was greater than 10 for all AEs except somnolence, where NNH was 7 (5, 10) for all doses pooled from both studies. LLH values were greater than 1 for efficacy versus applicable tolerability outcomes in all cases.ConclusionsThis post hoc analysis demonstrated favorable NNT and NNH values for sublingual dexmedetomidine. In all instances therapeutic response was encountered more frequently than any adverse event. These values compare favorably to similar analyses for other approved agents for the treatment of agitation associated with schizophrenia or bipolar disorder, including intramuscular and inhaled formulations.FundingBioXcel Therapeutics, Inc.

Effect of Dexmedetomidine on Incidence of Emergence Delirium in Adult Nasal Surgery

Background/Purpose/Question. Emergence delirium (ED) is an acute phenomenon that develops in the early phase of recovery from general anesthesia, and characterized by confusion, disorientation, & possible violent behavior, and is a common occurrence particularly with nasal surgery. Dexmedetomidine is a highly selective alpha-2 adrenergic agonist that results in anxiolysis, sedation, analgesia, and sympatholysis without depressing ventilation. This educational scholarly project aimed to review the literature and investigate the effect of intraoperative dexmedetomidine on the incidence of ED in adults recovering from general anesthesia after nasal surgery. Methods/Evidence Search. PubMed and EMBASE were structurally searched from 2011 to 2021. Five randomized controlled studies (RCT) were selected that compared intraoperative dexmedetomidine to a placebo and how the recovery profile was affected in adults after nasal surgery. Key search terms included “anesthesia”, “dexmedetomidine”, “emergence”, “nasal surgery”. Synthesis of Literature/Results/Discussion. There were collectively 392 participants across these five studies, and the incidence of ED in dexmedetomidine groups was significantly lower than control groups (respectively 21% vs. 50%). The mean arterial pressure (MAP) and heart rate (HR) among dexmedetomidine groups exhibited less variability during emergence without hypotension, which indicates a more stable hemodynamic profile. Analgesic and antiemetic requirements in the post-anesthesia care unit (PACU) were decreased in dexmedetomidine groups, however these results were not statistically significant. Conclusion/Recommendations for Practice. Intraoperative dexmedetomidine significantly decreases the incidence of ED. Secondary effects, like hemodynamic stability and analgesia, were observed, but these qualities need to be further studied before they can be generalized. Overall, dexmedetomidine is a safe and effective anesthetic adjunct that facilitates a smoother emergence after nasal surgery without any complications. Keywords: Anesthesia, dexmedetomidine, emergence, nasal surgery

Sublingual dexmedetomidine: repurposing an anesthetic as an anti-agitation agent

ABSTRACT Introduction Especially when acutely ill, individuals with schizophrenia and bipolar disorder can present with agitated behavior. The initial approach to agitation management are non-pharmacologic strategies such as verbal de-escalation techniques; however, pharmacologic interventions may be needed. Dexmedetomidine is a selective alpha-2 adrenergic receptor agonist, and a sublingual formulation has been approved in the US for the treatment of agitation associated with schizophrenia and bipolar disorder in adults. Areas covered The authors review the published literature on sublingual dexmedetomidine using the US National Library of Medicine’s PubMed.gov resource. Pharmacodynamics, pharmacokinetics, and efficacy and tolerability findings are summarized. The authors also provide a discussion to its potential place in the treatment armamentarium. Expert opinion Sublingual dexmedetomidine is an effective and well-tolerated pharmacologic option for the treatment of agitation associated with schizophrenia and bipolar disorder. The sublingual method of administration allows for a rapid onset of action with treatment effects beginning as early as 20 minutes after administration. Adverse effects include somnolence, hypotension, oral paresthesia, hypoesthesia, and dry mouth. Further study will be needed to evaluate sublingual dexmedetomidine in real-world patients receiving concomitant psychotropic medications.

Effect of Dexmedetomidine on Maintaining Perioperative Hemodynamic Stability in Elderly Patients: A Systematic Review and Meta-analysis

ObjectiveDexmedetomidine is a highly selective alpha-2 adrenergic receptor agonist with sedative and analgesic properties but without respiratory depression effect and has been widely used in perioperative anesthesia. Here we performed a systematic review and meta-analysis to evaluate the effect of dexmedetomidine on maintaining perioperative hemodynamic stability in elderly patients. MethodsPubMed, Web of Science, the Cochrane Library, China National Knowledge Infrastructure (CNKI), and Wanfang Data were searched for randomized-controlled trials (RCTs) on the application of dexmedetomidine in maintaining perioperative hemodynamic stability in elderly patients from their inception to September, 2021. The standardized mean differences (SMD) with 95% confidence interval (CI) were employed to analyze the data. The random-effect model was used for the potential clinical inconsistency. ResultsA total of 12 RCTs with 833 elderly patients (dexmedetomidine group, 546 patients; control group, 287 patients) were included. There was no significant increase in perioperative heart rate (HR), mean arterial pressure (MAP), and diastolic blood pressure (DBP) in the dexmedetomidine group before and during the operation. In addition, the variations of hemodynamic indexes including HR, MAP, SBP (systolic blood pressure), and DBP were significantly lower in the dexmedetomidine group compared with the control group (HR: SMD = −0.87, 95% CI: −1.13 to −0.62; MAP: SMD = −1.12, 95% CI: −1.60 to −0.63; SBP: SMD = −1.27, 95% CI: −2.26 to −0.27; DBP: SMD = −0.96, 95% CI: −1.33 to −0.59). Subgroup analysis found that with the prolongation of 1.0 μg/kg dexmedetomidine infusion, the patient's heart rate declined in a time-dependent way. ConclusionDexmedetomidine provides more stable hemodynamics during perioperative period in elderly patients. However, further well-conducted trials are required to assess the effective and safer doses of dexmedetomidine in elderly patients.

Compared Dexmedetomidine and Fentanyl on Sensory-Motor Block in Unilateral Intrathecal Anesthesia of Lower-limbs Orthopedic Surgeries: A Randomized Duble-blind Trials

Background: One of the alternatives for lower-limb orthopedic surgery is spinal anesthesia. It can affect the hemodynamic status and cause the prolonged motor and sensory blocks, as well as urinary retention, which are less common in the unilateral technique. Different drugs are used to improve the quality of the block and reduce its complications. Dexmedetomidine, a selective alpha-2 adrenergic receptor agonist, and fentanyl, an opioid medication, could administration as an adjuvant to increase the intrathecal block quality. Hence, this study aimed to compare unilateral spinal anesthesia with bupivacaine/dexmedetomidine (BD) and bupivacaine/fentanyl (BF) regimes on the sensory-motor block among patients with lower-limb orthopedic surgeries. Materials and Method: This randomized, double-blind clinical trial was performed on 36 patients who underwent lower-limb orthopedic surgeries in Qaem Hospital, Mashhad, Iran. The patients were randomly divided into two groups. Patients who received 5.7 mg hyperbaric bupivacaine 0.5% plus 10 µg fentanyl (BF group) or 5 µg dexmedetomidine (BD group) were administered for inducing unilateral spinal anesthesia. Patients and investigators responsible for data collection were not awarded from allocation groups. The sensory-motor block level, duration, postoperative analgesia, and complications were recorded and compared between the two groups. Results: No significant difference was observed between the two groups in hemodynamic changes (i.e., systolic and diastolic blood pressure and heart rate) before and after the blockage (P˃0.05). Also, there was no difference in the sensory-motor block level and anesthesia-related complications between BF and BD groups (P˃0.05). Conclusion: In patients for whom the use of opioids for unilateral spinal anesthesia is contraindicated, dexmedetomidine could be considered an appropriate alternative.

Dexmedetomidine alleviates intestinal barrier dysfunction and inflammatory response in mice via suppressing TLR4/MyD88/NF-κB signaling in an experimental model of ulcerative colitis.

Ulcerative colitis (UC) is a nonspecific intestinal inflammatory disease. Dexmedetomidine (DEX) is a selective alpha 2-adrenergic receptor agonist commonly used for analgesia and sedation in intensive care units. Herein, the role and mechanism of DEX in dextran sulfate sodium (DSS)-induced colitis was explored. A murine model of DSS-induced colitis was established by adding 3.5% (w/v) DSS in drinking water to C57BL/6J female mice. The severity of colitis was measured by the disease activity index (DAI) score, colon length and body weight of mice. The serum concentration and mRNA levels of inflammatory cytokines in colon tissues were assessed by ELISA and RT-qPCR, respectively. Protein levels of apoptotic markers, tight junction proteins and genes involved in the TLR4/MyD88/NF-κB signaling were quantified utilizing Western blotting. The pathological changes of colon tissues were evaluated by hematoxylin-eosin (HE) staining and histological score. Intestinal permeability in vivo was assessed by fluorescein isothiocyanate (FITC)-dextran (FITC-D) administration. TUNEL assay was used to determine cell apoptosis in the intestinal epithelium. DSS administration resulted in weight loss, shortening of the colon, increased DAI score, histological abnormalities, and increased serum FITC-D levels in mice, all of which were reversed by DEX injection. Moreover, DEX attenuated DSS-triggered inflammatory response, intestinal barrier injury and intestinal epithelial cell apoptosis. Mechanically, DEX inactivated the TLR4/MyD88/NF-κB signaling in the colon tissues. DEX exerts beneficial effects against the intestinal barrier dysfunction, inflammatory response, and apoptosis of intestinal epithelial cells via inactivation of the TLR4/MyD88/NF-κB signaling in mice with DSS-induced colitis.

Pathogenetic features of acute naphazoline poisoning in children

Introduction: Acute poisoning by nasal decongestants is an important issue in pediatrics due to physiological and anatomical characteristics of the child’s body and pharmacokinetics of drugs in early childhood.
 Epidemiology: The number of poisonings by this group of drugs ranged from 4% to 39% during the period from 2000 to 2018. All the studies reported that the most severe degree of intoxication was observed in children aged 1–3 years.
 Mechanism of action of nasal decongestants: The peculiarity of selective alpha2-adrenergic agonists is that when taken orally, misused or overdosed, they lose their selectivity for the target receptor. As a result, the drug causes acute poisoning and most often this effect occurs in children and adolescents.
 Clinical features and diagnostic criteria: Clinical signs of acute poisoning can appear both as a result of an overdose of the nasal decongestants and due to a therapeutic use of the drug according to the instruction. The symptoms are manifested by hypothermia, skin pallor, bradycardia, arterial hypotension, profuse sweating, and acrocyanosis.
 Imidazoline receptors and new opportunities: It is assumed that toxic effect of topical decongestants occurs not only by activation of alpha2-adrenergic receptors, but also through their influence on the selective imidazoline receptors. Based on the structure of these drugs, it is assumed that imidazoline receptors are the primary binding site for these drugs.
 Conclusion: Understanding the described mechanisms of alpha2-adrenergic agonist action and peculiarities of the child’s symptoms in acute poisoning is necessary for the timely diagnosis and selection of the correct treatment strategy.

The effect of dexmedetomidine on renal function after surgery: A systematic review and meta-analysis.

Acute kidney injury (AKI) is a complication following surgery and has been associated with worsened patient outcomes. Providers have used agents that may confer a degree of renal protection in the perioperative stage. Such is the case of dexmedetomidine, a selective alpha-2 adrenergic agonist used in the intensive care unit (ICU) as a sedative agent. The primary objective of this meta-analysis was to characterize the use of dexmedetomidine and to evaluate its impact on renal markers and outcomes in patients after surgery. A systematic review of manuscripts was performed to identify patients who received dexmedetomidine after surgery by searching the PubMed, Embase, and Cochrane databases. The following parameters were captured: blood urea nitrogen (BUN), serum creatinine, creatinine clearance, neutrophil gelatinase-associated lipoprotein (NGAL), cystatin C, urine output, duration of mechanical ventilation, ICU length of stay, AKI, need for dialysis, and mortality. Nineteen studies with 3,395 patients were included in the analyses. The mean bolus and infusion dose of dexmedetomidine were 0.82µg/kg and 0.54mcg/kg/hr, respectively. There was a significant difference in creatinine clearance and NGAL in favour of the dexmedetomidine group. In addition, the dexmedetomidine group had a shorter ICU length of stay, and a lower risk of acute kidney injury and mortality compared to the control. There was no difference in the rest of the parameters. Dexmedetomidine appears to have postoperative renal protective effects. This is evidenced by lower NGAL levels and increased creatinine clearance in those who received dexmedetomidine. These effects are associated with decreases in ICU length of stay and risk of AKI and mortality.

The effects of dexmedetomidine against ruptured abdominal aortic aneurysm injury to myocardial tissue induced by abdominal aorta clamping

Objectives: This study aims to examine the potential protective effect of the selective alpha-2 adrenergic receptor agonist dexmedetomidine (DEX) against aortic occlusion-induced myocardial injury. Patients and methods: A total of 30 rats were randomly assigned into three groups of 10 animals each as control, ischemia+reperfusion (I/Rep), and I/Rep+DEX. In the I/Rep and I/Rep+DEX groups, after the completion of the shock stage, 60-min lower torso ischemia was induced with the application of cross-clamps to the abdominal aorta, followed by 120-min reperfusion. The I/Rep+DEX group received intraperitoneal 100 μg/kg DEX 30 min before the ischemia period. Results: Malondialdehyde (MDA) levels in myocardial tissue increased with the application of I/Rep, while glutathione (GSH) levels decreased. We also observed swollen, degenerative, apoptotic cardiac myofibrils exhibiting caspase-3 positivity, widespread edematous areas, vascular congestion, and an increase in the heart damage scores. The MDA levels decreased with DEX administration, while the GSH levels increased. Degenerative, apoptotic cardiac myofibrils exhibiting loss of cytoplasm content, and vascular congestion also decreased. Conclusion: Our study results suggest that DEX may have a future role in the treatment of myocardial damage occurring due to reperfusion, following ruptured abdominal aortic aneurysm surgery.

Dexmedetomidine Versus Clonidine as Adjuvants in Epidural Analgesia in Gynecological Laparotomy

Abstract Pain is defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage. If the management of acute postoperative pain is not done properly, it can lead to the complication such as chronic pain. Epidural anesthesia reduces perioperative stress response in surgery, increasing the surgery outcome. Epidural analgesia is one of the potential acute postoperative pain treatments. The administration of α-2 agonists has analgesic and sedative effect when used as adjuvant in epidural analgesia. The administration of α-2 adrenergic agonists' adjuvant can increase the potential duration of analgesia and reduce the local anesthetic dose needed 30%–40% and can reduce the occurrence of the side effects. Dexmedetomidine is one of the most potent and high selective alpha-2 adrenergic receptor agonists. The use of dexmedetomidine during epidural anesthesia has faster onset and longer motor sensory blockade duration with hemodynamic stability that can be accepted. While clonidine acts as selective partial alpha-2 receptor agonists that cause the analgesic action of alpha-2 receptor in the dorsal of spinal cord. Clonidine has been shown its ability to reduce the local anesthesia needed and improve the pain scores when is combined with bupivacaine 0.125% with or without fentanyl opioid 1–2 μg/mL.

Successful treatment of the face post acne erythema using a topically applied selective alpha 1-Adrenergic receptor agonist, oxymetazoline 1.5%, a controlled left to right face comparative trial

Background Post-inflammatory erythema (PIE) is a common sequalae of acne inflammation, persistent post acne erythema (PAE) is cosmetically unacceptable and sometimes its complete clearance could not be achieved. Oxymetazoline (OXZ) is a synthetic, direct-acting, sympathomimetic agonist that is highly selective for the 1α-adrenoceptor. It is a potent vasoconstrictor and well known for its ability to clinically ‘get the red out’. Aim The aim of this study was to evaluate the efficacy and safety of topical oxymetazoline (OXZ) 1.5% in treatment of post acne erythema (PAE) in a left to right face comparative study. Methods This study was conducted on 40 patients diagnosed with post acne erythema for at least 3 months, the left side of the face was treated with topical OXZ 1.5% in liposomal base and was compared to the right side to which topical lipogel was applied as a control. Results According to the investigator’s global assessment of photographs and the analysis of erythema with image analysis software, topical OXZ was significantly effective in diminishing PAE when compared to topical placebo lipogel Conclusion Topical OXZ is a safe and effective treatment for post-acne erythema.

Dexmedetomidine had neuroprotective effects on hippocampal neuronal cells via targeting lncRNA SHNG16 mediated microRNA-10b-5p/BDNF axis

Dexmedetomidine (DEX), a highly selective alpha2 adrenergic receptor agonist, is a commonly used anesthetic drug in surgical procedures. Previous studies have indicated that DEX exerts neuroprotective effects while the detailed mechanism has not been fully elucidated. Here, we aim to study the role of lncRNA SHNG16 in DEX-induced brain protection and its underlying molecular mechanism. The rats underwent middle cerebral artery occlusion (MCAO) surgery and oxygen–glucose deprivation (OGD)-treated HT22 hippocampal neurons were treated with DEX, respectively. CCK8 was used to evaluate cell viability. sh-SHNG16 as well as miR-10b-5p mimics were transfected into hippocampal neurons to further explore the bio-function of SNHG16 and miR-10b-5p in vitro. Furthermore, the interactions between SHNG16 and miR-10b-5p, miR-10b-5p and BDNF gene were confirmed by dual-luciferase report assay. Our data revealed that DEX attenuated neurological damage of the MCAO rats and also increased the cell viability of the neurons significantly. Besides, expression of SHNG16 and BDNF were both downregulated while miR-10b-5p was upregulated in MCAO brain tissues or OGD treated neurons. DEX inhibited miR-10b-5p expression but increased SHNG16 and BDNF levels with a dosage effect. After transfection with sh-SHNG16 or miR-10b-5p mimics, the expression of BDNF protein was downregulated, accompanied with decreased neuron viability. Dual-luciferase assay showed that SHNG16 targeted on miR-10b-5p, which also could bind directly to the 3′-UTR sites of BDNF and negatively regulate its expression. In conclusion, DEX exerts neuroprotective in ischemic stroke via improving neuron damage, the underlying mechanism may be upregulating SHNG16 and BDNF via sponging miR-10b-5p.

AB227. Tackling a challenging intubation in a child: awake fibre-optic intubation using dexmedetomidine

: Awake fibre-optic intubation is uncommon, particularly in children. Dexmedetomidine is the sedating agent of choice in our centre for adult awake fibre-optic intubation. However, it has not been licensed for use in patients of less than 18 years and consequently, there is scarce research available concerning its use in this cohort. Nevertheless, dexmedetomidine is commonly used as a pre-medication in children in the intensive care setting. It is a selective alpha-2 adrenergic receptor agonist with both sedative and analgesic effects. Unlike most sedatives however, it causes minimal respiratory depression. Its duration of action is 30 minutes, and with its extended recovery time, post-sedation agitation is lessened. These factors contribute to the use of dexmedetomidine as our agent of choice for awake-fibre optic intubation; a procedure not deemed to be overly painful, but requires sedation. The case to be discussed is that of a 14-year-old male who presented to a hospital in the west of Ireland with a 3-day history of reduced mouth-opening, left-sided jaw stiffness, and coryzal symptoms. Following a variety of antimicrobial regimes and investigation by X-ray, nasoendoscopy, ultrasound and computed tomography, the patient was found to have a left lateral pterygoid abscess which required surgical drainage, under general anaesthesia. This posed obvious difficulties from an airway point of view, with the child’s mouth opening at less than one finger breadth. This challenge was overcome with the use of a dexmedetomidine infusion of 1.5 micrograms per kilogram per hour to perform an awake-fibre optic intubation. This procedure was atraumatic and performed without patient distress.

Effect of Dexmedetomidine on duration of mechanical ventilation in septic patients: a systematic review and meta-analysis

BackgroundBecause of its analgesic and light sedative properties, the highly selective alpha-2 adrenergic receptor agonist dexmedetomidine (DEX) has been suggested for the treatment of septic patients, but its effect on the duration of mechanical ventilation remains unclear. The present study was conducted to review the extant literature in DEX and determine its influence on ventilation time in adult septic patients.MethodsDatabases of PubMed, Cochrane, and EMBASE were applied till 20th January 2019 without language restriction. The searching strategy as following: sepsis OR septic AND mechanical ventilation AND dexmedetomidine. Two authors screened titles, abstracts, and even articles to meet the including criterion independently. In addition, references of related articles or reviews were also referred. Data was recorded in a table and analyzed using the software of Review Manager 5.0.ResultsFour studies with a total of 349 patients were included. Three trials with 267 patients revealed the effect of DEX on duration of mechanical ventilation, two trials with 264 patients on ventilator-free days and four trials with 334 patients on 28-day mortality. The analyzed results indicated that DEX was not associated with significantly different durations of mechanical ventilation (MD 0.65, 95% CI, − 0.13 to 1.42, P = 0.10). However, there were significant differences in ventilator-free days (MD 3.57, 95% CI, 0.26 to 6.89, P = 0.03) and 28-day mortality (RR 0.61, 95% CI, 0.49 to 0.94, P = 0.02) in the septic patients.ConclusionAdministration of DEX for sedation in septic patients was not associated with the duration of mechanical ventilation, but it increased the ventilator-free days and reduced 28-day mortality.

Comparison of bupivacaine (0.5%) and bupivacaine (0.5%) with dexmedetomidine (1 microgram/kg) in paravertebral block for inguinal hernia repair

Background: Paravertebral block(PVB),for inguinal hernia repair has been found to be effective than conventional spinal anaesthesia in terms of anaesthetic and analgesic technique , early ambulation and better postoperative pain score. Bupivacaine, an amide local anaesthetic, having a slow onset of action, provides early onset , prolonged duration of analgesia and adequate sedation in case of PVB with an adjuvant dexmedetomidine ,a highly selective alpha2 adrenergic agonist. Aims: To compare the efficacy as well as onset and duration of sensory and motor block ,duration of post operative analgesia ,any complication of the drugs bupivacaine and a combination of bupivacaine with dexmedetomidine in paravertebral block for inguinal hernia repair. Material and Method: 60 patients aged between 18-60 yrs of ASA physical status I and II , randomized in two groups of 30 to receive bupivacaine (0.5%) 1mgkg—1 in control group A and bupivacaine (0.5%) 1mgkg —1combined with dexmedetomidine (1 μgkg—1) in study group B for PVB. Results: Gr A vs Gr B was significant (P

Dexmedetomidine modulates transient receptor potential vanilloid subtype 1

Dexmedetomidine, a highly selective alpha-2 adrenergic receptor agonist and novel sedative drug with minimal respiratory suppression, have shown anti-nociceptive activity in various pain models by poorly understood mechanisms. Because alpha-2 adrenergic receptor is co-localized with TRPV1 polymodal nociceptive receptor in dorsal root ganglion neurons and up-regulated in neuropathic pain animal models, the analgesic activity might be mediated through inhibition of TRPV1 in the peripheral nervous system. In an effort to elucidate whether modulatory effect of dexmedetomidine on TRPV1 activity could be the potential peripheral mechanism underlying the antinociceptive effect of dexmedetomidine, intracellular calcium concentration after capsaicin application was investigated in mice dorsal root ganglion (DRG) neurons, with and without pretreatment of dexmedetomidine. Dexmedetomidine (10 μM) reduced capsaicin-induced calcium responses by 29.7 ± 7.39% (n = 34, p < 0.0001), in dose-dependent manner. Higher level of inhibition was observed with increased dose of dexmedetomidine (50 μM, 45.1 ± 8.58%, n = 15, p = 0.0002), and lower inhibition by decreased dose (1 μM, 18.8 ± 1.48%, n = 148, p = 0.004). RT-PCR analysis revealed expression of TRPV1 and alpha-2A, alpha-2B and alpha-2C subtypes of adrenergic receptor in mice DRG neurons, and immunocytochemical analysis revealed co-expression of TRPV1 and alpha-2A receptors in primary cultured DRG neurons. In summary, these results suggested the inhibition of TRPV1 expressed in the primary sensory neurons as a potential mechanism that contributes to the anti-nociceptive action of dexmedetomidine.

The impact of dexmedetomidine added to ropivicaine for transversus abdominis plane block on stress response in laparoscopic surgery: a randomized controlled trial

BackgroundIntravenous dexmedetomidine is known to attenuate stress response in patients undergoing laparoscopic surgery. We investigated whether the addition of the highly selective alpha-2 adrenergic agonist dexmedetomidine into ropivacaine for ultrasound-guided transversus abdominis plane block could inhibit stress response during laparoscopic surgery, and determined the optimal dose of dexmedetomidine in it.MethodsOne hundred and twenty-five patients undergoing laparoscopic gynecological surgery were included in this prospective and randomized double-blind study. Patients received general anesthesia with or without a total of 60 ml of 0.2% ropivacaine in combination with low (0.25 μg/kg), medium (0.50 μg/kg) or high dose (1.0 μg/kg) of dexmedetomidine for the four-quadrant transversus abdominis plane block (n = 25). The primary outcomes were stress marker levels during the operation.ResultsOne hundred and twenty patients completed the study protocol. Dexmedetomidine added to ropivacaine for transversus abdominis plane block significantly reduced serum levels of cortisol, norepinephrine, epinephrine, interleukin-6, blood glucose, mean arterial pressure and heart rate in a dose-dependent manner (P < 0.05), accompanied with decreased anesthetic and opioid consumption during the operation (P < 0.05), but the high dose of dexmedetomidine induced higher incidences of bradycardia than low or medium dose of dexmedetomidine (P < 0.05).ConclusionThe addition of dexmedetomidine at the dose of 0.5 μg/kg into ropivacaine for ultrasound-guided transversus abdominis plane block is the optimal dose to inhibit stress response with limited impact on blood pressure and heart rate in patients undergoing laparoscopy gynecological surgery.Trial registrationThis study was registered at www.chictr.org.cn on November 6th, 2016 (ChiCTR-IOR-16009753).

A Population Pharmacokinetic Model of Intravenous Dexmedetomidine for Mechanically Ventilated Children after Neurosurgery.

Dexmedetomidine is a selective alpha-2 adrenergic agonist with concurrent sedative and analgesic effects, and it is being increasingly used in pediatric anesthesia and intensive care. This study aimed to investigate the pharmacokinetics of intravenous dexmedetomidine in mechanically ventilated children in the intensive care unit (ICU) after neurosurgery. Pediatric patients aged 2–12 years, who were mechanically ventilated in ICU after neurosurgery, were allocated into a low-dose (n = 15) or high-dose (n = 14) group. The low-dose group received dexmedetomidine at a loading dose of 0.25 µg/kg for 10 min, followed by a maintenance dose of 0.25 µg/kg/h for 50 min, whereas the high-dose group received dexmedetomidine at a loading dose of 0.5 µg/kg for 10 min, followed by a maintenance dose of 0.5 µg/kg/h for 50 min. Serial blood samples were collected for a pharmacokinetic analysis up to 480 min after the end of the infusion. The sedative effect of dexmedetomidine was assessed using the Bispectral Index and University of Michigan Sedation Scale. Adverse reactions, electrocardiography findings, and vital signs were monitored for a safety assessment. A population pharmacokinetic analysis was performed using non-linear mixed effects modeling. Dexmedetomidine induced a moderate-to-deep degree of sedation during infusion in both groups. The pharmacokinetics of dexmedetomidine were best described by a two-compartment disposition model with first-order elimination kinetics. The parameters were standardized for a body weight of 70 kg using an allometric power model. The population estimates (95% confidence interval) per 70 kg body weight were as follows: clearance of 81.0 (72.9–90.9) L/h, central volume of distribution of 64.2 (50.6–81.0) L, intercompartment clearance of 116.4 (90.6–156.0) L/h, and peripheral volume of distribution of 167 (132–217) L. No serious adverse reactions or hemodynamic changes requiring the discontinuation of dexmedetomidine were observed. Dexmedetomidine had increased clearance and volume of distribution in mechanically ventilated children in ICU after neurosurgery, thereby indicating the need to adjust the dosage to obtain a target plasma concentration.

Dexmedetomidine attenuates the increase of ultrasonographic optic nerve sheath diameter as a surrogate for intracranial pressure in patients undergoing robot-assisted laparoscopic prostatectomy

Background:Pneumoperitoneum and steep Trendelenburg position during robot-assisted laparoscopic prostatectomy (RALP) can increase intracranial pressure (ICP). Dexmedetomidine, a highly selective alpha-2 adrenergic receptor agonist, can cause cerebral vasoconstriction and decrease cerebral blood flow by stimulating the postsynaptic alpha-2 adrenergic receptors on cerebral blood vessels. However, the effects of dexmedetomidine on ICP are controversial and have not been evaluated during RALP under the establishment of pneumoperitoneum in the steep Trendelenburg position. Therefore, we evaluated the effect of dexmedetomidine on optic nerve sheath diameter (ONSD) as a surrogate for assessing ICP during RALP.Methods:Patients were randomly allocated to receive dexmedetomidine (n = 63) (loading dose, 1 μg/kg for 10 minutes and continuous infusion, 0.4 μg/kg/hr) or normal saline (n = 63). The ONSD was measured at 10 minutes after induction of anesthesia in the supine position (T1), 30 minutes (T2) and 60 minutes (T3) after establishment of pneumoperitoneum in the steep Trendelenburg position, and at closing the skin in the supine position (T4). Hemodynamic and respiratory variables were measured at every time point.Results:ONSDs at T2, T3, and T4 were significantly smaller in the dexmedetomidine group than in the control group (5.26 ± 0.25 mm vs 5.71 ± 0.26 mm, 5.29 ± 0.24 mm vs 5.81 ± 0.23 mm, and 4.97 ± 0.24 mm vs 5.15 ± 0.28 mm, all P <.001). ONSDs at T2, T3, and T4 were significantly increased compared to T1 in both groups. Hemodynamic and respiratory variables, except heart rate, did not significantly differ between the 2 groups. The bradycardia and atropine administration were not significantly different between the 2 groups.Conclusion:Dexmedetomidine attenuates the increase of ONSD during RALP, suggesting that intraoperative dexmedetomidine administration may effectively attenuate the ICP increase during pneumoperitoneum in the Trendelenburg position.

Identification of Candidate Genes and Pathways in Dexmedetomidine-Induced Cardioprotection in the Rat Heart by Bioinformatics Analysis.

Dexmedetomidine (DEX), a highly selective alpha2 adrenergic receptor agonist, directly protects hearts against ischemia/reperfusion (I/R) injury. However, the detailed mechanism has not been fully elucidated. We studied differentially expressed mRNAs and miRNAs after DEX administration in rat hearts by comprehensive analysis. Additionally, bioinformatics analysis was applied to explore candidate genes and pathways that might play important roles in DEX-induced cardioprotection. The results of microarray analysis showed that 165 mRNAs and 6 miRNAs were differentially expressed after DEX administration. Through bioinformatics analysis using differentially expressed mRNAs, gene ontology (GO) terms including MAP kinase tyrosine/serine/threonine phosphatase activity and pathways including the p53 pathway were significantly enriched in the down-regulated mRNAs. Dusp1 and Atm were associated with the GO term of MAP kinase tyrosine/serine/threonine phosphatase activity and the p53 pathway, respectively. On the other hand, no significant pathway was found in the target mRNAs of deregulated miRNAs. The results indicated some possible key genes and pathways that seem to be of significance in DEX-induced cardioprotection, although miRNAs seem to be unlikely to contribute to cardioprotection induced by DEX.