Thomas J. Ebert

The effects of increasing plasma concentrations of dexmedetomidine in humans

Background This study determined the responses to increasing plasma concentrations of dexmedetomidine in humans. Methods Ten healthy men (20–27 yr) provided informed consent and were monitored (underwent electrocardiography, measured arterial, central venous [CVP] and pulmonary artery [PAP] pressures, cardiac output, oxygen saturation, end-tidal carbon dioxide [ETCO2], respiration, blood gas, and catecholamines). Hemodynamic measurements, blood sampling, and psychometric, cold pressor, and baroreflex tests were performed at rest and during sequential 40-min intravenous target infusions of dexmedetomidine (0.5, 0.8, 1.2, 2.0, 3.2, 5.0, and 8.0 ng/ml; baroreflex testing only at 0.5 and 0.8 ng/ml). Results The initial dose of dexmedetomidine decreased catecholamines 45–76% and eliminated the norepinephrine increase that was seen during the cold pressor test. Catecholamine suppression persisted in subsequent infusions. The first two doses of dexmedetomidine increased sedation 38 and 65%, and lowered mean arterial pressure by 13%, but did not change central venous pressure or pulmonary artery pressure. Subsequent higher doses increased sedation, all pressures, and calculated vascular resistance, and resulted in significant decreases in heart rate, cardiac output, and stroke volume. Recall and recognition decreased at a dose of more than 0.7 ng/ml. The pain rating and mean arterial pressure increase to cold pressor test progressively diminished as the dexmedetomidine dose increased. The baroreflex heart rate slowing as a result of phenylephrine challenge was potentiated at both doses of dexmedetomidine. Respiratory variables were minimally changed during infusions, whereas acid–base was unchanged. Conclusions Increasing concentrations of dexmedetomidine in humans resulted in progressive increases in sedation and analgesia, decreases in heart rate, cardiac output, and memory. A biphasic (low, then high) dose–response relation for mean arterial pressure, pulmonary arterial pressure, and vascular resistances, and an attenuation of the cold pressor response also were observed.

Sedative, amnestic, and analgesic properties of small-dose dexmedetomidine infusions.

This research determined the safety and efficacy of two small-dose infusions of dexmedetomidine by evaluating sedation, analgesia, cognition, and cardiorespiratory function. Seven healthy young volunteers provided informed consent and participated on three occasions with random assignment to drug or placebo. Heart rate, blood pressure, respiratory rate, ETCO2, O2 saturation, and processed electroencephalogram (bispectral analysis) were monitored. Baseline hemodynamic measurements were acquired, and psychometric tests were performed (visual analog scale for sedation; observer’s assessment of alertness/sedation scale; digit symbol substitution test; and memory). The pain from a 1-min cold pressor test was quantified with a visual analog scale. After a 10-min initial dose of saline or 6 &mgr;g · kg−1 · h−1 dexmedetomidine, volunteers received 50-min IV infusions of saline, or 0.2 or 0.6 &mgr;g · kg−1 · h−1 dexmedetomidine. Measurements were repeated at the end of infusion and during recovery. The two dexmedetomidine infusions resulted in similar and significant sedation (30%–60%), impairment of memory (approximately 50%), and psychomotor performance (28%–41%). Hemodynamics, oxygen saturation, ETCO2, and respiratory rate were well preserved throughout the infusion and recovery periods. Pain to the cold pressor test was reduced by 30% during dexmedetomidine infusion. Small-dose dexmedetomidine provided sedation, analgesia, and memory and cognitive impairment. These properties might prove useful in a postoperative or intensive care unit setting. Implications: The &agr;2 agonist, dexmedetomidine, has sedation and analgesic properties. This study quantified these effects, as well as cardiorespiratory, memory and psychomotor effects, in healthy volunteers. Dexmedetomidine infusions resulted in reversible sedation, mild analgesia, and memory impairment without cardiorespiratory compromise.

Sympathetic Responses to Induction of Anesthesia in Humans with Propofol or Etomidate

Anesthetic induction with propofol commonly results in hypotension. This study explored potential mechanisms contributing to hypotension by recording cardiovascular responses including sympathetic neural activity from patients during induction of anesthesia with propofol (2.5 mg.kg-1 plus 200 micrograms.kg-1.min-1) or, for comparison, etomidate (0.3 mg.kg-1 plus 15 micrograms.kg-1.min-1). Twenty-five consenting, nonpremedicated, ASA physical status 1 and 2, surgical patients were evaluated. Measurements of R-R intervals (ECG), blood pressure (radial artery), forearm vascular resistance (plethysmography), and efferent muscle sympathetic nerve activity ([MSNA] microneurography: peroneal nerve) were obtained at rest and during induction of anesthesia. In addition, a sequential bolus of nitroprusside (100 micrograms) followed by phenylephrine (150 micrograms) was used to obtain data to quantitate the baroreflex regulation of cardiac function (R-R interval) and sympathetic outflow (MSNA) in the awake and anesthetized states. Etomidate induction preserved MSNA, forearm vascular resistance, and blood pressure, whereas propofol reduced MSNA by 76 +/- 5% (mean +/- SEM), leading to a reduction in forearm vascular resistance and a significant hypotension. Both cardiac and sympathetic baroslopes were maintained with etomidate but were significantly reduced with propofol, especially in response to hypotension. These findings suggest that propofol-induced hypotension is mediated by an inhibition of the sympathetic nervous system and impairment of baroreflex regulatory mechanisms. Etomidate, conversely, maintains hemodynamic stability through preservation of both sympathetic outflow and autonomic reflexes.

The efficacy of dexmedetomidine versus morphine for postoperative analgesia after major inpatient surgery.

Thirty-four patients scheduled for elective inpatient surgery were randomized equally to receive either dexmedetomidine (initial loading dose of 1-&mgr;g/kg over 10 min followed by 0.4 &mgr;g · kg−1 · h−1 for 4 h) or morphine sulfate (0.08 mg/kg) 30 min before the end of surgery. We determined heart rate (HR), mean arterial blood pressure (MAP), respiratory rate (RR), sedation and analgesia (visual analog scale), and use of additional morphine in the postanesthesia care unit (PACU) and up to 24 h after surgery. Groups were similar for patient demographics, ASA physical status, surgical procedure, baseline hemodynamics, and intraoperative use of drugs and fluids. Dexmedetomidine-treated patients had slower HR in the PACU (by an average of 16 bpm), whereas MAP, RR, and level of sedation were similar between groups. During Phase I recovery, dexmedetomidine-treated patients required significantly less morphine to achieve equivalent analgesia (PACU dexmedetomidine group, 4.5 ± 6.8 mg; morphine group, 9.2 ± 5.2 mg). Sixty minutes into recovery only 6 of 17 dexmedetomidine patients required morphine in contrast to 15 of 17 in the morphine group. The administration of dexmedetomidine before the completion of major inpatient surgical procedures significantly reduced, by 66%, the early postoperative need for morphine and was associated with a slower HR in the PACU.

Sympathetic Hyperactivity during Desflurane Anesthesia in Healthy Volunteers: A Comparison with Isoflurane

Background:Desflurane has been reported to produce more tachycardia and hypertension on induction than isoflurane. The present study employed microneurography to determine whether these cardiovascular effects were related to sympathetic outflow. Methods:In 14 healthy, young (age 20–31 yr) volunteers, arterial pressure was measured from the radial artery, forearm blood flow was derived by strain gauge plethysmography, and sympathetic nerve activity (SNA) directed to skeletal muscle blood vessels was recorded from a tungsten needle placed percutaneously into the peroneal nerve. Heart rate, blood pressure, muscle SNA, respiration, tidal volume, end-tidal carbon dioxide, and desflurane or isoflurane concentrations (infrared spectroscopy) were continuously monitored before and during anesthesia. Two minutes after administering thiopental (5 mg/kg) and vecuronium (0.2 mg/kg), desflurane (n = 7) or isoflurane (n = 7) was titrated gradually to the inspired gas over several minutes to 1.5 MAC. Results:The initiation of desflurane anesthesia resulted in significant changes that included a 2.5-fold increase in SNA, hypertension (peak mean arterial pressure 114 ± 3 mmHg), tachycardia (peak heart rate 102 ± 6 beats/min), facial flushing, and tearing. Moderate upper airway obstruction developed in three subjects approximately 4 min after initiating desflurane, despite neuromuscular blockade. These responses were not observed in subjects receiving isoflurane. After tracheal intubation, the anesthetic concentration was maintained at 0.5 MAC for 30 min. Steady-state measurements of hemodynamics and SNA were obtained. Similar steady-state measurements were obtained 15 min after establishing 1.0 and 1.5 MAC. Both anesthetics produced a progressive reduction in blood pressure and forearm vascular resistance, and muscle SNA gradually increased. In subjects receiving desflurane, heart rate remained unchanged until the 1.5-MAC level was reached, at which time tachycardia (a 10-beat/min increase) was noted. The transition from 1.0 to 1.5 MAC desflurane resulted in significant heart rate increases (>30 beats/min), hypertension (>30 mmHg), and a doubling of SNA that persisted for several minutes. These responses did not occur in the isoflurane group. Conclusions:Titration of desflurane following thiopental induction and increasing the concentration of desflurane from 1.0 to 1.5 MAC result in sympatho-excitation, hypertension and tachycardia in healthy, young volunteers. Until methods are determined to attenuate these responses, desflurane should be administered with great caution to patients who may be placed at risk by these responses.

The Efficacy, Side Effects, and Recovery Characteristics of Dexmedetomidine Versus Propofol When Used for Intraoperative Sedation

We evaluated the cardio-respiratory effects of equi-sedative doses of dexmedetomidine and propofol for intraoperative sedation. Secondary comparison end points were time to achieve and terminate sedation and postoperative analgesia and psychomotor performance. Forty patients scheduled for elective surgery provided informed consent and were randomized equally to receive either dexmedetomidine (1 &mgr;g/kg initial loading dose for 10 min; maintenance, 0.4–0.7 &mgr;g · kg−1 · h−1) or propofol (75 &mgr;g · kg−1 · min−1 × 10 min; maintenance, 12.5–75 &mgr;g · kg−1 · min−1). Hemodynamic variables (heart rate and mean arterial blood pressure), sedation (visual analog scale and Observer Assessment of Alertness/Sedation), bispectral index score of sedation, ventilation (respiratory rate, O2 sat, and ETco2), psychomotor performance (digital symbol substitution test), and pain (visual analog scale) were determined during surgery and up to 95 min after surgery. Intraoperative sedation levels were targeted to achieve a bispectral index score of 70–80. Patient demographics, ASA class, surgical procedure, and baseline cardio-respiratory variables were similar between groups. Sedation was achieved more rapidly with propofol but was similar between groups 25 min after initiating infusions. The average infusion rate for dexmedetomidine was 0.7 &mgr;g · kg−1 · h−1 and 38 &mgr;g · kg−1 · min−1 for propofol. There were no differences between groups in psychomotor performance and respiratory rate during recovery. The previous use of dexmedetomidine resulted in more sedation, lower blood pressure, and improved analgesia (less morphine use) in recovery.

Mechanisms whereby propofol mediates peripheral vasodilation in humans : Sympathoinhibition or direct vascular relaxation ?

Background Anesthetic induction and maintenance with propofol are associated with decreased blood pressure that is, in part, due to decreased peripheral resistance. Several possible mechanisms whereby propofol could reduce peripheral resistance include a direct action of propofol on vascular smooth muscle, an inhibition of sympathetic activity to the vasculature, or both. This study examined these two possibilities in humans by measuring the forearm vascular responses to infusions of propofol into the brachial artery (study 1) and by determining the forearm arterial and venous responses to systemic (intravenous) infusions of propofol after sympathetic denervation of the forearm by stellate blockade (study 2). Methods Bilateral forearm venous occlusion piethysmography was used to examine forearm vascular resistance (FVR) and forearm vein compliance (FVC). Study 1 used infusion of intralipid (time control) and propofol at rates between 83 and 664 micro gram/min into the brachial artery of 11 conscious persons and compared responses to arterial infusions of sodium nitroprusside (SNP) at 0.3, 3.0, and 10 micro gram/min. Venous blood from the infusion arm was assayed for plasma propofol concentrations. In study 2, after left stellate block (12 ml 0.25% bupivacaine + 1% lidocaine), six participants were anesthetized and maintained with propofol infusions of 125 and 200 micro gram [centered dot] kg sup ‐1 [centered dot] min sup ‐1. Simultaneous right forearm (unblocked) blood flow dynamics served as the time control. In three additional conscious participants, intrabrachial artery infusions of SNP and nitroglycerin, both at 10 micro gram/min, were performed before and after stellate blockade of the left forearm to determine whether the sympathetically denervated forearm vessels could dilate beyond the level produced by denervation alone. Results In study 1, infusion of intralipid or propofol into the brachial artery did not change FVR or FVC. Sodium nitroprusside significantly decreased FVR in a dose‐dependent manner by 22 +/‐ 5%, 65 +/‐ 3%, and 78 +/‐ 2% (mean +/‐ SEM) but did not change FVC. During the incremental propofol infusions, plasma propofol concentrations increased from 0.2 to 10.1 micro gram/ml and averaged 7.4 +/‐ 1.1 micro gram/ml during the highest infusion rate. In study 2, stellate ganglion blockade decreased FVR by 50 +/‐ 6% and increased FVC by 58 +/‐ 10%. Propofol anesthesia at 125 and 200 micro gram [centered dot] kg sup ‐1 [centered dot] min sup ‐1 progressively reduced mean arterial pressure. In the arm with sympathetic denervation, FVR and FVC showed no further changes during propofol anesthesia, whereas in the control arm FVR significantly decreased by 41 +/‐ 9% and 42 +/‐ 7%, and FVC increased significantly by 89 +/‐ 27% and 85 +/‐ 32% during 125 and 200 micro gram [centered dot] kg sup ‐1 [centered dot] min sup ‐1 infusions of propofol, respectively. In the three additional conscious participants, intraarterial infusion of SNP and nitroglycerin (TNG) after the stellate blockade resulted in a further decrease of FVR and a further increase of FVC. Conclusions In contrast to SNP infusions, propofol infusions into the brachial artery of conscious persons caused no significant vascular responses, despite the presence of therapeutic plasma concentrations of propofol within the forearm. The effects of propofol anesthesia on FVR and FVC are similar to the effects of sympathetic denervation by stellate ganglion blockade. Thus the peripheral vascular actions of propofol appear to be due primarily to an inhibition of sympathetic vasoconstrictor nerve activity.

Venodilation contributes to propofol-mediated hypotension in humans

The present investigation explored the possibility that the commonly observed hypotension that occurs during induction of anesthesia with propofol might be related to its ability to produce venodilation. Thirty-six ASA I and II patients who received no premedication were studied. The first 20 patients were divided into two equal groups. Hemodynamic measurements consisted of heart rate, arterial blood pressure, and forearm venous compliance by occlusive plethysmography. Baseline measurements were made in awake patients while resting in a supine position. Repeat measurements were made during steady-state infusions of propofol (2.5 mg/kg bolus injection, followed by a continuous infusion at 200 μg·kg−1·min−1) or thiopental (4 mg/kg bolus injection, followed by continuous infusion at 200 μg·kg−1·min−1), 10 min after tracheal intubation while patients were artificially ventilated. Both anesthetics resulted in a significant (P <0.05) and similar tachycardia; however, propofol produced significant decreases in systolic (−30 ± 9 mm Hg) and diastolic (−11 ± 4 mm Hg) arterial blood pressure. Forearm venous compliance was significantly increased during propofol administration but unchanged in patients receiving thiopental. In four additional patients receiving smaller consecutive infusions of propofol (50 and 100 μg·kg−1·min−1), significant subtle increases in forearm compliance were also recorded. These increases were not observed in four patients who received placebo infusions. Thus, one mechanism promoting hypotension during propofol anesthesia in humans seems to be related to its direct effects on venous smooth muscle tone and presumably venous return.

Neurocirculatory responses to sevoflurane in humans : a comparison to desflurane

Background Sevoflurane and desflurane are new volatile anesthetics with low blood solubilities that confer properties of rapid anesthetic induction and emergence. Desflurane has been associated with neurocirculatory excitation after the rapid increase in inspired concentrations. The current study evaluated and compared the sympathetic and hemodynamic responses associated with the administration of sevoflurane to those associated with administration of desflurane in humans.

Differential Effects of Nitrous Oxide on Baroreflex Control of Heart Rate and Peripheral Sympathetic Nerve Activity in Humans

Acute regulation of blood pressure in humans is mediated by arterial baroreflex regulation of heart rate, cardiac contractility, and peripheral sympathetic outflow. Brief pharmacologic reductions of blood pressure were employed in 11 healthy volunteers to determine the effects of N2O on baroreflex-mediated increases in heart rate and efferent muscle sympathetic nerve activity. R-R intervals (ECG), blood pressure (radial artery), central venous pressure, respiratory rate (abdominal bellows), and end-tidal gas concentrations (mass spectrometer) were monitored. Efferent sympathetic nerve activity directed to skeletal muscle blood vessels (MSNA) was recorded from an epoxy-coated tungsten needle placed into the peroneal nerve. Data were obtained from six subjects before and during iv bolus administration of sodium nitroprusside (100 micrograms), during control while breathing 40% N2/60% O2, during administration of N2O (40% N2O/60% O2), and during recovery (40% N2/60% O2). Five subjects served as time controls and breathed 40% N2 in O2 throughout the protocol. Nitrous oxide produced a 59 +/- 18% (P less than 0.05) increase in baseline MSNA but did not alter the reflex augmentations in MSNA produced by nitroprusside. In contrast, there was a 39 +/- 14% decrease in the slope of the relationship between systolic pressure and R-R interval (P less than 0.05) in subjects breathing N2O. N2O thus produces activation of the sympathetic nerves directed to skeletal muscle blood vessels, and it decreases baroreflex-mediated tachycardia without diminishing baroreflex-mediated augmentations in sympathetic outflow.