Sedation In Volunteers Research Articles

Brain functional connectivity differentiates dexmedetomidine from propofol and natural sleep

BackgroundWe used functional connectivity measures from brain resting state functional magnetic resonance imaging to identify human neural correlates of sedation with dexmedetomidine or propofol and their similarities with natural sleep. MethodsConnectivity within the resting state networks that are proposed to sustain consciousness generation was compared between deep non-rapid-eye-movement (N3) sleep, dexmedetomidine sedation, and propofol sedation in volunteers who became unresponsive to verbal command. A newly acquired dexmedetomidine dataset was compared with our previously published propofol and N3 sleep datasets. ResultsIn all three unresponsive states (dexmedetomidine sedation, propofol sedation, and N3 sleep), within-network functional connectivity, including thalamic functional connectivity in the higher-order (default mode, executive control, and salience) networks, was significantly reduced as compared with the wake state. Thalamic functional connectivity was not reduced for unresponsive states within lower-order (auditory, sensorimotor, and visual) networks. Voxel-wise statistical comparisons between the different unresponsive states revealed that thalamic functional connectivity with the medial prefrontal/anterior cingulate cortex and with the mesopontine area was reduced least during dexmedetomidine-induced unresponsiveness and most during propofol-induced unresponsiveness. The reduction seen during N3 sleep was intermediate between those of dexmedetomidine and propofol. ConclusionsThalamic connectivity with key nodes of arousal and saliency detection networks was relatively preserved during N3 sleep and dexmedetomidine-induced unresponsiveness as compared to propofol. These network effects may explain the rapid recovery of oriented responsiveness to external stimulation seen under dexmedetomidine sedation. Trial registry numberCommittee number: ‘Comité d’Ethique Hospitalo-Facultaire Universitaire de Liège’ (707); EudraCT number: 2012-003562-40; internal reference: 20121/135; accepted on August 31, 2012; Chair: Prof G. Rorive. As it was considered a phase I clinical trial, this protocol does not appear on the EudraCT public website.

Evaluation of Transcutaneous and End-Tidal Carbon Dioxide During Intravenous Sedation in Volunteers

Objective: During intravenous sedation, end-tidal carbon dioxide (ETCO2) is usually measured with a nasal cannula or mouth-nose cannula. We compared the measurement accuracy of ETCO2 between these two devices and TC-CO2 and assessed which device is more useful during intravenous sedation in volunteers. Methods: Eight male volunteers aged 25 to 35 years were evaluated in this single-institution blinded observational trial. After they lay quietly for 5 min without supplemental oxygen, the volunteers received supplemental oxygen by means of each device at a flow rate of 3 L/min for 15 min. Next, midazolam (0.05 mg/kg) was intravenously injected, flumazenil (20 mg) was injected 30 min later, and the ETCO2 and TC-CO2 waveform were recorded. Results: The differences between ETCO2 and TC-CO2 significantly increased after midazolam injection and decreased after flumazenil injection. The difference between ETCO2 and TC-CO2 using the nasal cannula was greater than that using the mouth-nose cannula. The mean difference between TC-CO2 and ETCO2 ranged from 3 to 9 mmHg after midazolam injection using a nasal mask, and the mean difference ranged from 3 to 6 mmHg after midazolam injection using a mouth-nose cannula. Conclusions: The difference between ETCO2 and TC-CO2 against TC-CO2 was within the clinically acceptable range. Both the nasal and mouth-nose cannula were useful for ETCO2 measurement with supplemental oxygen by means of each device at flow rate of 3 L/min during intravenous sedation in volunteers.

Forced-air warming effectively prevents midazolam-induced core hypothermia in volunteers

Midazolam is a commonly used sedative and anaesthetic adjuvant and the agent is known to decrease core temperature by core-to-periphery redistribution of heat. We tested the hypothesis that forced-air warming could effectively prevent midazolam-induced hypothermia. Six healthy male volunteers were studied over 3 days. On the first day, the volunteers were alert during a 30 min control period with forced-air warming. On the second day, after the volunteers were vasoconstricted, 75 microg kg(-1) midazolam was injected intramuscularly and they were covered with a cotton blanket. On the third day, after the volunteers were vasoconstricted, 75 microg kg(-1) midazolam was again administered and they were given forced-air warming. Tympanic temperature was measured as the core temperature. Four adhesive skin-surface probes with thermocouples were fixed on the chest, upper right arm, lateral calf and thigh, and both mean skin and body temperatures were calculated. Fingertip perfusion was evaluated using forearm minus fingertip and calf minus toe skin-surface temperature gradients. Thirty minutes after the intramuscular injection of midazolam, the level of sedation in volunteers was measured by a blinded observer according to the alertness/sedation scale. Core temperature significantly decreased by midazolam premedication in a time-dependent manner. Although forced-air warming did not prevent the midazolam-induced transient decrease in core temperature, it increased the temperature to the control level thereafter. We conclude that forced-air warming can effectively prevent midazolam-induced redistribution hypothermia.

Selective Phosphodiesterase 5 Inhibition Does Not Reduce Propofol Sedation Requirements but Affects Speed of Recovery and Plasma Cyclic Guanosine 3???,5???-Monophosphate Concentrations in Healthy Volunteers

Cyclic guanosine 3',5'-monophosphate (cyclic GMP) has been implicated in modulating the effects of anesthesia. We hypothesized that limiting the breakdown of cyclic GMP through selective phosphodiesterase inhibition would influence propofol sedation requirements and plasma cyclic GMP concentrations. Ten volunteers received 100 mg of sildenafil or placebo orally in this placebo-controlled, double-blind, randomized crossover pilot study. Propofol sedation was achieved using a target-controlled infusion system until loss of verbal contact (LVC). Plasma cyclic GMP concentrations were determined at baseline, LVC, and 30 min after LVC. There was no difference in the amount of propofol used, predicted plasma concentration, or duration of sedation in volunteers after sildenafil compared with placebo treatment. Return of spontaneous verbal contact was faster after sildenafil (4 [3-8] min versus 6 [3-5] min, median [range], P = 0.019). Cyclic GMP concentrations were reduced during propofol sedation in the placebo group compared with baseline (P < 0.004). The plasma cyclic GMP concentrations were larger (P = 0.004) at LVC in the sildenafil group compared with placebo. We have shown that selective phosphodiesterase 5 inhibition decreases recovery time from propofol sedation without affecting propofol requirements. The decrease of plasma cyclic GMP concentrations during propofol sedation in the placebo group indicates a potential role of cyclic GMP in propofol anesthesia in humans. Plasma cyclic guanosine 3',5'-monophosphate (cyclic GMP) concentrations are reduced during propofol sedation. Selective phosphodiesterase 5 inhibition, however, does not reduce propofol sedation requirements or plasma cyclic GMP concentrations but affects speed of recovery in healthy volunteers.

Dexmedetomidine-Induced Sedation in Volunteers Decreases Regional and Global Cerebral Blood Flow

Dexmedetomidine is a selective α2-agonist approved for sedation of critically ill patients. There is little information on the effects of dexmedetomidine on cerebral blood flow (CBF) or intracranial hemodynamics, despite considerable other pharmacodynamic data. We hypothesized that therapeutic doses of dexmedetomidine would decrease CBF. Therefore, nine supine volunteers, aged 24–48 yr, were infused with a 1 μg/kg IV loading dose of dexmedetomidine, followed by an infusion of 0.2 μg · kg−1 · h−1 (LOW DEX) and 0.6 μg · kg−1 · h−1 (HIGH DEX). Hemodynamic and CBF (via positron emission tomography) measurements were determined at each experimental time point. Dexmedetomidine decreased both cardiac output and heart rate during and 30 min after drug administration. Blood pressure decreased from 12% to 16% during and after the dexmedetomidine administration. Global CBF was decreased significantly from baseline (91 mL · 100 g−1 · min−1 [95% confidence interval, 72–114] to 64 mL · 100 g−1 · min−1 [51–81] LOW DEX and 61 mL · 100 g−1 · min−1 [48–76] HIGH DEX). This decrease in CBF remained constant for at least 30 min after the dexmedetomidine infusion was discontinued, despite the plasma dexmedetomidine concentration decreasing 40% during this same time period (628 pg/mL [524–732] to 380 pg/mL [253–507]).

Target Controlled Infusion (TCI) of AQUAVANTM, a Watersoluble Prodrug of Propofol, for Conscious Sedation in Volunteers

Target Controlled Infusion (TCI) of AQUAVANTM, a Watersoluble Prodrug of Propofol, for Conscious Sedation in Volunteers