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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 α2 adrenoceptor agonist, could safely decrease the incidence of delirium in elderly patients after non-cardiac surgery. 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. 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. 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. 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.

Purpose The aim of this proof-of-concept study was to characterize the pharmacokinetics and pharmacodynamics of intranasal dexmedetomidine compared with its intravenous administration in a small number of healthy volunteers. Methods Single doses of 84 μg of dexmedetomidine were given once intravenously and once intranasally to seven healthy men. Plasma dexmedetomidine concentrations were measured for 10 h, and pharmacokinetic variables were calculated with standard noncompartmental methods. Heart rate, blood pressure, concentrations of adrenaline and noradrenaline in plasma, and central nervous system drug effects (with the Maddox wing, Bispectral Index, and three visual analog scales) were monitored to assess the pharmacological effects of dexmedetomidine. Results Six individuals were included in the analyses. Following intranasal administration, peak plasma concentrations of dexmedetomidine were reached in 38 (15–60) min and its absolute bioavailability was 65% (35–93%) (medians and ranges). Pharmacological effects were similar with both routes of administration, but their onset was more rapid after intravenous administration. Conclusions Dexmedetomidine is rather rapidly and efficiently absorbed after intranasal administration. Compared with intravenous administration, intranasal administration may be a feasible alternative in patients requiring light sedation.

In this trial, clonidine, an α2-adrenergic agonist, did not reduce the rate of death or MI among patients undergoing noncardiac surgery. Clonidine did increase the risk of perioperative hypotension, bradycardia, and nonfatal cardiac arrest. Myocardial infarction is the most common major vascular complication of surgery and is associated with substantial mortality. 1 During and after noncardiac surgery, there is marked activation of the sympathetic nervous system, which can lead to a mismatch between the supply of and demand for myocardial oxygen and to subsequent myocardial infarction. 2 – 4 We previously reported that perioperative administration of a high-dose, long-acting beta-blocker (initiated 2 to 4 hours before surgery and continued after surgery) reduced the risk of myocardial infarction but increased the risk of death, stroke, and clinically important hypotension. 5 Clonidine, an α 2 -adrenergic agonist, blunts central sympathetic . . .

Dexmedetomidine, a highly selective central α2-agonist, undergoes mainly biotransformation in the liver. The pharmacokinetics of dexmedetomidine were significantly affected by hepatic insufficiency. The clearance of dexmedetomidine in patients with severe hepatic failure decreased by 50% compared with controls. We tested the hypothesis that the pharmacokinetics of dexmedetomidine would be affected by obstructive jaundice. The prospective registration number of clinical trial is ChiCTR-IPR-15007572. 18 patients with obstructive jaundice and 12 non-jaundiced patient controls received dexmedetomidine, 1 μg/kg, over 10 min. Arterial blood samples were drawn before, during, and up to 5 h after the infusion. Plasma dexmedetomidine concentrations were determined by 1290 infinity high performance liquid chromatography coupled with 6470 tandem mass spectrometry. The relevant pharmacokinetic parameters were calculated by non-compartmental analysis using Phoenix WinNonlin 7.0. Plasma clearance of dexmedetomidine was decreased by 33.3% in the obstructive jaundice group as compared with the control group (0.0068±0.0017 vs. 0.0102±0.0033 L/kg/min; P = 0.002). Volume of distribution was decreased by 29.2% in the obstructive jaundice group as compared with the control group (1.43±0.58 vs. 2.02±0.84 L/kg; P = 0.041). This study demonstrates that the clearance and distribution volume of dexmedetomidine were decreased in patients with obstructive jaundice. It may be advisable to adjust the dose of dexmedetomidine in those patients.

PurposeDexmedetomidine increases sleep and reduces delirium in postoperative patients, but it is expensive and requires a monitored environment. Clonidine, another α2-agonist, is cheaper and is used safely for other purposes in wards. We assessed whether clonidine would improve sleep in postoperative high-dependency unit (HDU) patients.MethodsThe Clonidine at Low dosage postoperatively to Nocturnally Enhance Sleep (CLONES) study was a double-blind, placebo-controlled, parallel-group pilot effectiveness randomised trial involving adult elective surgery HDU patients in a single academic hospital. Patients received clonidine 0.3 μg/kg/h or saline placebo on the night of surgery. The primary outcome was total sleep time measured using a consumer actigraphy/photoplethysmography device.ResultsOf the 83 randomised patients, three had no data available, leaving 80 (39 clonidine, 41 placebo) in the intention-to-treat analysis, modified for missing data. Median patient ages of the groups were similar (61 and 59 years), as were other baseline characteristics. Clonidine patients had a mean of 100.8 (95% confidence interval [CI] 38.2–163.4) minutes (p = 0.002) longer total sleep time (mean 497.2 vs. 396.4 min) and reported better sleep overall. Delirium was only observed in one patient prior to study drug infusion, and none at the end of the study. Safety outcomes were not different. Four clonidine patients had their medication ceased due to bradycardia and hypotension that required no additional treatment.ConclusionAmong postoperative elective surgical patients admitted to HDU, low-dose non-titrated clonidine, compared to placebo, was associated with longer and subjectively better-quality sleep.

Purpose We aimed to identify a safe and effective method to assist older adults with pneumonia in tolerating the prone position for a longer duration. Methods This was a randomized, controlled, double-blinded study performed at the Shanghai Fourth People's Hospital. Eighty patients with pneumonia aged ≥ 65 years were included. The patients were able to spontaneous breath in the prone position and were administered intravenous dexmedetomidine or an isotonic sodium chloride solution. The cumulative daily durations of prone positioning for all patients in the two groups were recorded. The primary outcome was the percentage of patients who completed ≥ 9 h/day in the prone position. The secondary outcomes included the incidence of complications in the prone position and patient outcomes. Results Eighty patients were included (average age: 79.6 ± 8.9 years). The percentage of patients who completed ≥ 9 h/day in the prone position was significantly higher in the dexmedetomidine group than in the placebo group ( P  = 0.011). The percentage of patients who completed ≥ 12 h/day in the prone position was also significantly greater in the dexmedetomidine group than in the placebo group ( P  = 0.008). There were no significant differences in other variables between the two groups. Conclusions The results of this study demonstrate that intravenous dexmedetomidine injection can significantly prolong the duration of spontaneous breathing in the prone position in elderly pneumonia patients without obvious adverse events. We provide a safe and effective method to help patients with pneumonia, especially those with delirium or cognitive impairment, who cannot tolerate the length of time needed for spontaneous breathing in the prone position to be effective. Trial registration: The study was registered with the Chinese Clinical Trial Center (registration number: ChiCRT2300067383) on 2023-01-05.

Objective: This is a feasibility study evaluating the safety, tolerability, and potential anxiolytic efficacy of the α2 agonist guanfacine extended-release (GXR) in children and adolescents with generalized anxiety disorder (GAD), separation anxiety disorder (SAD), or social phobia/social anxiety disorder. Methods: Youth aged 6–17 years with a primary diagnosis of GAD, SAD, and/or social anxiety disorder were treated with flexibly dosed GXR (1–6 mg daily, n = 62) or placebo (n = 21) for 12 weeks. The primary aim of this study was to determine the safety and tolerability of GXR in youth with anxiety disorders, which involved the analysis of treatment-emergent adverse events (TEAEs), the emergence of suicidal ideation and behaviors, vital signs, and electrocardiographic/laboratory parameters. Exploratory efficacy measures included dimensional anxiety scales (Pediatric Anxiety Rating Scale [PARS] and Screen for Child Anxiety Related Emotional Disorders [SCARED]), as well as the Clinical Global Impression–Improvement (CGI-I) scale. As this was an exploratory study, no inferential statistical analyses were performed. Results: GXR was safe and well tolerated. Treatment-related mean ± standard deviation changes in heart rate (GXR: 1.8 ± 12 beats per minute [bpm] decrease; placebo: 0.5 ± 11 bpm decrease), systolic blood pressure (GXR: 2.3 ± 11 mm Hg decrease; placebo: 1.7 ± 11 mm Hg decrease), or diastolic blood pressure (GXR: 1.3 ± 9 mm Hg decrease; placebo: 0.9 ± 7 mm Hg increase) were similar between treatment groups. TEAEs, including headache, somnolence/fatigue, abdominal pain, and dizziness, were consistent with the known safety profile of GXR. No differences were observed between treatment groups for PARS and SCARED scores, although at endpoint, a higher proportion of subjects receiving GXR versus placebo demonstrated CGI-I scores ≤2 (54.2% vs. 31.6%), as rated by the clinician investigator. Conclusions: GXR was well tolerated in pediatric subjects with GAD, SAD, and/or social anxiety disorder. ClinicalTrials.gov Identifier: NCT01470469.

Intrusive memories of traumatic events are a core feature of post-traumatic stress disorder but little is known about the neurobiological formation of intrusions. The aim of this study was to determine whether the activity of the noradrenergic system during an intrusion-inducing stressor would influence subsequent intrusive memories. We conducted an experimental, double-blind, placebo-controlled study in 118 healthy women. Participants received a single dose of either 10 mg yohimbine, stimulating noradrenergic activity, or 0.15 mg clonidine, inhibiting noradrenergic activity, or placebo. Subsequently, they watched an established trauma film which induced intrusions. The number of consecutive intrusions resulting from the trauma film, the vividness of the intrusions, and the degree of distress evoked by the intrusions were assessed during the following 4 days. Salivary cortisol and α-amylase were collected before and after the trauma film. A significant time × treatment interaction for the number of intrusions and the vividness of intrusions indicated a different time course of intrusions depending on treatment. Post-hoc tests revealed a delayed decrease of intrusions and a delayed decrease of intrusion vividness after the trauma film in the yohimbine group compared with the clonidine and placebo groups. Furthermore, after yohimbine administration, a significant increase in salivary cortisol levels was observed during the trauma film. Our findings indicate that pharmacological activation of the noradrenergic system during an emotionally negative event makes an impact on consecutive intrusive memories and their vividness in healthy women. The noradrenergic system seems to be involved in the formation of intrusive memories.

Currently, no FDA-approved medication exists for the treatment of cocaine use disorder. Furthermore, as women become increasingly more at risk for the consequences of cocaine addiction, the need to establish better-tailored treatment medications is paramount. We examine the effects of the alpha2 adrenergic agonist, guanfacine HCl, on responses to stress and drug cue in a group of cocaine-dependent men and women who also abuse alcohol and nicotine. Forty early abstinent treatment-seeking cocaine-dependent males and females were randomly assigned to receive either daily placebo (12 M/7 F) or guanfacine (2 or 3 mg) (15 M/6 F) for 3 weeks. In week 4, they participated in a laboratory experiment and were exposed to three 10-min guided imagery conditions (stress/stress, cue/cue, and stress/cue), one per day, consecutively in a random, counterbalanced order. Craving, negative emotion, anxiety, and cardiovascular function were assessed at baseline, immediately following imagery exposure, and at various recovery time points. Guanfacine significantly attenuated cocaine craving, alcohol craving, anxiety, and negative emotion following exposure to all three imagery conditions in females, but not males. Guanfacine did, however, reduce sympathetic tone as well as stress and cue-induced nicotine craving and systolic blood pressure (SBP) in both males and females. These findings highlight sex-specific effects of guanfacine on drug craving, anxiety, and negative mood with significant effects in women and not men. The findings suggest further evaluation of guanfacine in the treatment of cocaine use disorder with a specific focus on sex differences in treatment response.

Adrenergic receptors (ARs) have gained attention for their involvement in breast cancer (BC) progression. Dexmedetomidine, a selective α2‐AR agonist, has been reported to increase the malignancy of BC cells in vitro or stimulate tumor growth in mice. However, clinical evidence is lacking. Clinical research in this area is important as dexmedetomidine is widely used in BC surgery patients. Here we allocated 24 women with primary BC to the dexmedetomidine group (who received a total dose of 2 μg kg−1 dexmedetomidine perioperatively) or to the control group (who received the same volume of normal saline). Venous blood was obtained from all patients immediately upon entering the operating room and 24 hours postoperatively. Serum was then exposed to MCF‐7 cells at a concentration of 10% for 24 hours. Cell proliferation, migration, and invasion were analyzed using EdU, Transwell, and Matrigel methods, respectively. We found that postoperative serum from those who received dexmedetomidine was associated with significantly increased cell proliferation, migration, and invasion compared with preoperative serum when used to culture MCF‐7 cells. The mean percentage change from post to preoperative values in these cell functions was significantly larger in the dexmedetomidine group than in the control group (proliferation, 30.44% vs 8.45%, P = .0024; migration, 15.90% vs 3.25%, P = .0015; invasion, 8.17% vs 2.13%, P = .04). In conclusion, these findings suggest that in patients undergoing surgery for primary BC, perioperative administration of dexmedetomidine might influence the serum milieu in a way that favors the malignancy of MCF‐7 cells. Clinical trial registration: NCT03108937. Exposure of MCF‐7 cells to postoperative serum from patients receiving dexmedetomidine during surgery, but not control saline, had significantly higher proliferation, invasion, and migration than preoperative serum. The mean percentage changes from post to preoperative values in all these cellular malignant properties were also significantly larger in the Dex group compared with the control group. These findings suggest that the utilization of Dex during breast cancer surgery may modulate the patients' serum milieu to a direction that favors the malignancy of MCF‐7 cells.