A Pharmacokinetic and Pharmacodynamic Study of Oral Dexmedetomidine.

BACKGROUND: Dexmedetomidine is only approved for use in humans as an intravenous medication. An oral formulation may broaden the use and benefits of dexmedetomidine to numerous care settings. The authors hypothesized that oral dexmedetomidine (300 mcg to 700 mcg) would result in plasma concentrations consistent with sedation while maintaining hemodynamic stability. METHODS: The authors performed a single-site, open-label, phase I dose-escalation study of a solid oral dosage formulation of dexmedetomidine in healthy volunteers (n = 5, 300 mcg; followed by n = 5, 500 mcg; followed by n = 5, 700 mcg). The primary study outcome was hemodynamic stability defined as lack of hypertension, hypotension, or bradycardia. The authors assessed this outcome by analyzing raw hemodynamic data. Plasma dexmedetomidine concentrations were determined by liquid chromatograph-tandem mass spectrometry. Nonlinear mixed effect models were used for pharmacokinetic and pharmacodynamic analyses. RESULTS: Oral dexmedetomidine was associated with plasma concentration-dependent decreases in heart rate and mean arterial pressure. All but one subject in the 500-mcg group met our criteria for hemodynamic stability. The plasma concentration profile was adequately described by a 2-compartment, weight allometric, first-order absorption, first-order elimination pharmacokinetic model. The standardized estimated parameters for an individual of 70 kg was V1 = 35.6 [95% CI, 23.8 to 52.8] l; V2 = 54.7 [34.2 to 81.7] l; CL = 0.56 [0.49 to 0.64] l/min; and F = 7.2 [4.7 to 14.4]%. Linear models with effect sites adequately described the decreases in mean arterial pressure and heart rate associated with oral dexmedetomidine administration. However, only the 700-mcg group reached plasma concentrations that have previously been associated with sedation (>0.2 ng/ml). CONCLUSIONS: Oral administration of dexmedetomidine in doses between 300 and 700 mcg was associated with decreases in heart rate and mean arterial pressure. Despite low oral absorption, the 700-mcg dose scheme reached clinically relevant concentrations for possible use as a sleep-enhancing medication.

Cryptic sexual dimorphism in spatial memory and hippocampal oxytocin receptors in prairie voles (Microtus ochrogaster).

Sex differences are well documented and are conventionally associated with intense sex-specific selection. For example, spatial memory is frequently better in males, presumably due to males' tendency to navigate large spaces to find mates. Alternatively, monogamy (in which sex-specific selection is relatively relaxed) should diminish or eliminate differences in spatial ability and the mechanisms associated with this behavior. Nevertheless, phenotypic differences between monogamous males and females persist, sometimes cryptically. We hypothesize that sex-specific cognitive demands are present in monogamous species that will influence neural and behavioral phenotypes. The effects of these demands should be observable in spatial learning performance and neural structures associated with spatial learning and memory. We analyzed spatial memory performance, hippocampal volume and cell density, and hippocampal oxytocin receptor (OTR) expression in the socially monogamous prairie vole. Compared to females, males performed better in a spatial memory and spatial learning test. Although we found no sex difference in hippocampal volume or cell density, male OTR density was significantly lower than females, suggesting that performance may be regulated by sub-cellular mechanisms within the hippocampus that are less obvious than classic neuroanatomical features. Our results suggest an expanded role for oxytocin beyond facilitating social interactions, which may function in part to integrate social and spatial information.

Dexmedetomidine promotes biomimetic non-rapid eye movement stage 3 sleep in humans: A pilot study.

OBJECTIVES: Sleep, which comprises of rapid eye movement (REM) and non-REM stages 1-3 (N1-N3), is a natural occurring state of decreased arousal that is crucial for normal cardiovascular, immune and cognitive function. The principal sedative drugs produce electroencephalogram beta oscillations, which have been associated with neurocognitive dysfunction. Pharmacological induction of altered arousal states that neurophysiologically approximate natural sleep, termed biomimetic sleep, may eliminate drug-induced neurocognitive dysfunction. METHODS: We performed a prospective, single-site, three-arm, randomized-controlled, crossover polysomnography pilot study (n = 10) comparing natural, intravenous dexmedetomidine- (1-µg/kg over 10 min [n = 7] or 0.5-µg/kg over 10 min [n = 3]), and zolpidem-induced sleep in healthy volunteers. Sleep quality and psychomotor performance were assessed with polysomnography and the psychomotor vigilance test, respectively. Sleep quality questionnaires were also administered. RESULTS: We found that dexmedetomidine promoted N3 sleep in a dose dependent manner, and did not impair performance on the psychomotor vigilance test. In contrast, zolpidem extended release was associated with decreased theta (∼5-8 Hz; N2 and N3) and increased beta oscillations (∼13-25 Hz; N2 and REM). Zolpidem extended release was also associated with increased lapses on the psychomotor vigilance test. No serious adverse events occurred. CONCLUSIONS: Pharmacological induction of biomimetic N3 sleep with psychomotor sparing benefits is feasible. SIGNIFICANCE: These results suggest that α2a adrenergic agonists may be developed as a new class of sleep enhancing medications with neurocognitive sparing benefits.

Minimizing ICU Neurological Dysfunction with Dexmedetomidine-induced Sleep (MINDDS): protocol for a randomised, double-blind, parallel-arm, placebo-controlled trial.

INTRODUCTION: Delirium, which is prevalent in postcardiac surgical patients, is an acute brain dysfunction characterised by disturbances in attention, awareness and cognition not explained by a pre-existing neurocognitive disorder. The pathophysiology of delirium remains poorly understood. However, basic science and clinical studies suggest that sleep disturbance may be a modifiable risk factor for the development of delirium. Dexmedetomidine is a α-2A adrenergic receptor agonist medication that patterns the activity of various arousal nuclei similar to sleep. A single night-time loading dose of dexmedetomidine promotes non-rapid eye movement sleep stages N2 and N3 sleep. This trial hypothesises dexmedetomidine-induced sleep as pre-emptive therapy for postoperative delirium. METHODS AND ANALYSIS: The MINDDS (Minimizing ICU Neurological Dysfunction with Dexmedetomidine-induced Sleep) trial is a 370-patient block-randomised, placebo-controlled, double-blinded, single-site, parallel-arm superiority trial. Patients over 60 years old, undergoing cardiac surgery with planned cardiopulmonary bypass, will be randomised to receive a sleep-inducing dose of dexmedetomidine or placebo. The primary outcome is the incidence of delirium on postoperative day 1, assessed with the Confusion Assessment Method by staff blinded to the treatment assignment. To ensure that the study is appropriately powered for the primary outcome measure, patients will be recruited and randomised into the study until 370 patients receive the study intervention on postoperative day 0. Secondary outcomes will be evaluated by in-person assessments and medical record review for in-hospital end points, and by telephone interview for 30-day, 90-day and 180-day end points. All trial outcomes will be evaluated using an intention-to-treat analysis plan. Hypothesis testing will be performed using a two-sided significance level (type I error) of α=0.05. Sensitivity analyses using the actual treatment received will be performed and compared with the intention-to-treat analysis results. Additional sensitivity analyses will assess the potential impact of missing data due to loss of follow-up. ETHICS AND DISSEMINATION: The Partners Human Research Committee approved the MINDDS trial. Recruitment began in March 2017. Dissemination plans include presentations at scientific conferences, scientific publications and popular media. TRIAL REGISTRATION NUMBER: NCT02856594.

Lack of Responsiveness during the Onset and Offset of Sevoflurane Anesthesia Is Associated with Decreased Awake-Alpha Oscillation Power.

Anesthetic drugs are typically administered to induce altered states of arousal that range from sedation to general anesthesia (GA). Systems neuroscience studies are currently being used to investigate the neural circuit mechanisms of anesthesia-induced altered arousal states. These studies suggest that by disrupting the oscillatory dynamics that are associated with arousal states, anesthesia-induced oscillations are a putative mechanism through which anesthetic drugs produce altered states of arousal. However, an empirical clinical observation is that even at relatively stable anesthetic doses, patients are sometimes intermittently responsive to verbal commands during states of light sedation. During these periods, prominent anesthesia-induced neural oscillations such as slow-delta (0.1-4 Hz) oscillations are notably absent. Neural correlates of intermittent responsiveness during light sedation have been insufficiently investigated. A principled understanding of the neural correlates of intermittent responsiveness may fundamentally advance our understanding of neural dynamics that are essential for maintaining arousal states, and how they are disrupted by anesthetics. Therefore, we performed a high-density (128 channels) electroencephalogram (EEG) study (n = 8) of sevoflurane-induced altered arousal in healthy volunteers. We administered temporally precise behavioral stimuli every 5 s to assess responsiveness. Here, we show that decreased eyes-closed, awake-alpha (8-12 Hz) oscillation power is associated with lack of responsiveness during sevoflurane effect-onset and -offset. We also show that anteriorization-the transition from occipitally dominant awake-alpha oscillations to frontally dominant anesthesia induced-alpha oscillations-is not a binary phenomenon. Rather, we suggest that periods, which were defined by lack of responsiveness, represent an intermediate brain state. We conclude that awake-alpha oscillation, previously thought to be an idling rhythm, is associated with responsiveness to behavioral stimuli.

Spatiotemporal Dynamics of Dexmedetomidine-Induced Electroencephalogram Oscillations.

An improved understanding of the neural correlates of altered arousal states is fundamental for precise brain state targeting in clinical settings. More specifically, electroencephalogram recordings are now increasingly being used to relate drug-specific oscillatory dynamics to clinically desired altered arousal states. Dexmedetomidine is an anesthetic adjunct typically administered in operating rooms and intensive care units to produce and maintain a sedative brain state. However, a high-density electroencephalogram characterization of the neural correlates of the dexmedetomidine-induced altered arousal state has not been previously accomplished. Therefore, we administered dexmedetomidine (1mcg/kg bolus over 10 minutes, followed by 0.7mcg/kg/hr over 50 minutes) and recorded high-density electroencephalogram signals in healthy volunteers, 18-36 years old (n = 8). We analyzed the data with multitaper spectral and global coherence methods. We found that dexmedetomidine was associated with increased slow-delta oscillations across the entire scalp, increased theta oscillations in occipital regions, increased spindle oscillations in frontal regions, and decreased beta oscillations across the entire scalp. The theta and spindle oscillations were globally coherent. During recovery from this state, these electroencephalogram signatures reverted towards baseline signatures. We report that dexmedetomidine-induced electroencephalogram signatures more closely approximate the human sleep onset process than previously appreciated. We suggest that these signatures may be targeted by real time visualization of the electroencephalogram or spectrogram in clinical settings. Additionally, these signatures may aid the development of control systems for principled neurophysiological based brain-state targeting.