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Departments of *Anesthesiology (Sections of Critical Care and Cardiothoracic Anesthesiology) and Radiology, Wake Forest University School of Medicine, Winston-Salem, North Carolina
Address correspondence and reprint requests to Dr. Prielipp, Department of Anesthesiology, Wake Forest University School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157-1009. Address e-mail to prielipp{at}wfubmc.edu
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Abstract |
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2-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]).
IMPLICATIONS: Dexmedetomidine-induced sedation decreased cerebral blood flow (CBF) by 
33%, which could be due to direct 2-receptor cerebral smooth muscle vasoconstriction or to compensatory CBF changes caused by dexmedetomidine-induced decreases in the cerebral metabolic rate.
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Introduction |
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2-agonist with sedative, anxiolytic, and analgesic properties, with recent regulatory approval for sedation of critically ill, initially mechanically ventilated, intensive care unit (ICU) patients. Dexmedetomidine is especially noteworthy for its ability to produce a state of patient tranquility without depressing respiration. Although 2-adrenoreceptors are located throughout the body, they are present in larger concentrations in vascular smooth muscle and in key arousal areas of the central nervous system (CNS), such as the locus ceruleus. Activation of 2-adrenoreceptors in the CNS decreases centrally mediated sympathetic activity and induces sedation (1–3). Activation of presynaptic 2-adrenoreceptors on cortical blood vessels decreases norepinephrine release, whereas postsynaptic 2-adrenoreceptors may directly increase vascular smooth muscle tone. Thus, infusions of dexmedetomidine may have both direct (i.e., 2-agonist-mediated increases in calcium flux, triggering vascular smooth muscle constriction) and indirect (changes in central sympathetic activity and decreased cerebral metabolic rate) effects on cerebral blood flow (CBF).
Given the frequent occurrence of cerebral trauma, injury, infections, or other CNS metabolic derangements in the very ICU patients who require sedation, clinicians should be aware of the potential effects of sedative drugs on CBF, CBF velocities, and intracranial hemodynamics. Furthermore, drug actions on CBF, if they exist, could vary in different regions of the human brain, depending on the concentration of 2-adrenergic receptors in the cerebral vasculature of the cortical, white matter, and thalamic areas of the brain. Currently, there is a paucity of data to document the effects of dexmedetomidine administration on cerebral vasculature or CBF during IV infusion in humans. Because experimental studies identify 2-adrenergic receptors on both large and small cerebral vessels (4) and because dexmedetomidine is a selective 2-adrenoreceptor agonist with an 2/1 ratio of 1300:1 (1), we hypothesized that therapeutic doses of dexmedetomidine would decrease global and regional CBF in healthy, supine, normotensive volunteers.
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Methods |
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2-agonists or 2-antagonists for 30 days before the study. Women were required to have a negative pregnancy test just before study enrollment. Subjects were studied sequentially without randomization. Four men and five women, aged 24–48 yr and weighing 61–84 kg, completed the study. Volunteers ate a light breakfast and then fasted for 4 h before the study. After local 1% lidocaine anesthesia, all subjects underwent placement of the following catheters: 1) an 18-gauge IV catheter in the antecubital vein of the right arm, dedicated for H215O injections during dynamic positron emission tomography (PET) scans; 2) a 20-gauge IV catheter in the right forearm for the administration of dexmedetomidine; and 3) a 20-gauge intraarterial catheter in the left radial artery for continuous arterial blood pressure (BP) monitoring and for blood sampling after H215O injections. Additional monitoring included standard oscillometric BP determination (Dinamap®) at 10-min intervals, cardiac output (CO) measurement via thoracic bioimpedance (CIC-1000; Sorba, Milwaukee, WI), lead II electrocardiogram, and peripheral digital pulse oximetry.
Subjects were studied in the supine position in the PET scan gantry after 2 sequential 15-min periods of stabilization and monitoring. The environmental conditions were controlled with room temperature set at 72°F, ambient light reduced by 50%, and extraneous noise minimized. Subjects wore a light hospital gown, comfortable pants, and light cotton stockings. Their arms were abducted comfortably at 10°–20°, resting on two pillows atop the scanner gantry. Hemodynamic profiles were determined at the end of study intervals, and each profile included the determination of the following:
During the study period, HR and CO were collected at intervals by using the CIC-1000. The CIC-1000 is a Food and Drug Administration-approved, automated, real-time, noninvasive CO monitor (based on the technology of impedance cardiography) that has been tested and validated (6). Compared with Fick, Doppler, and thermodilution determinations of CO, bioimpedance technology provides acceptable estimates of CO, especially in healthy patients or volunteers. The system uses R-wave triggering and ensemble averaging (which improves the signal/noise ratio by reducing respiratory and motion artifacts). Impedance electrodes are placed on the forehead, at the base of the neck, at the left midaxillary line at the level of the xiphoid, and at the crest of the left hip. A phonograph microphone is placed over the left second parasternal region to assist with determination of left ventricular ejection time. The system generates a 50-kHz, 500-µA signal, which is applied to the outer 2 electrodes, and impedance wave forms are continuously recorded and ensemble averaged over 10-s intervals across the inner 2 electrodes. Stroke volume (SV) is determined by a computer algorithm based on the equation of Kubicek et al. (7). CO is then calculated as the product of SV and mean HR (bpm) during the 10-s interval.
Oxygen-15 was produced by using a Siemens/CTI RDS 112 11-MeV negative ion (H-) cyclotron. The PET scans were acquired on a General Electric Advance scanner (General Electric Systems, Milwaukee, WI). The Advance provides 35 transaxial slices over a 15.2-cm axial field of view (4.3-mm center-to-center slice spacing), producing approximately 4.8-mm spatial resolution in all 3 dimensions, and has a system sensitivity of approximately 220 kcps · µCi-1 · mL-1. The subject was placed in the scanner and positioned with all of the cortex included within the field of view. A laser system was used to mark the subject so that the same positioning could be maintained throughout the study.
Six H215O emission scans were acquired for each of the first five subjects: two for baseline studies, two during the administration of small-dose dexmedetomidine, and two after the infusion of large-dose dexmedetomidine for 45 min. The data from these five subjects were used to confirm the function, reliability, and reproducibility of CBF data acquisition. Satisfied with our new PET scan methodology, we studied the final five subjects with the acquisition of only one H215O CBF emission scan at each time point. This permitted the addition of a final study time point 30 min after the dexmedetomidine infusion was terminated in the last five volunteers, while still maintaining subjects below the radiation limit set by the IRB. The IRB approved this amendment to the protocol. Approximately 50 mCi of H215O was delivered to the subject for each scan. Before each group of 1 (or 2) emission scans, a 4-min transmission scan was acquired to be used for segmented photon attenuation compensation (8). Each emission scan was acquired as a 9-min, two-dimensional dynamic study (6 5-s frames, 3 20-s frames, 3 30-s frames, 2 60-s frames, and 2 120-s frames). The data were reconstructed by filtered backprojection with a Hanning filter with an 8-mm cutoff frequency. Arterial blood sampling was performed with an automated sampler (240/3; Ole Dich Instruments, Hvidovre, Denmark) that drew the blood through a line past opposing bismuth germinate scintillation detectors that operate in coincidence. However, the sampled blood was not available for arterial gas tension measurements. The automated blood sampler was calibrated on each day before study. Quantitative transaxial images of regional CBF (mL · min-1 · 100 g of tissue-1) were generated from these data by using the method described by Koeppe et al. (9).
To analyze the PET scan data, we drew 14 predetermined spherical (1.5-cm-diameter) regions of interest (ROIs). Eight of the ROIs sampled cortical brain, two were located in the thalamus, two represented the caudate nucleus, and two sampled deep-brain white matter (see Fig. 1 and Appendix 1). This ROI technique is identical to that which we previously used for regional and global determination of CBF (10). For each region, the maximal pixel counts at each ROI were determined from paired measurements and used in the standard calculation of CBF by PET (8,9). We calculated global CBF for each patient by examination of the maximum CBF from all 14 brain ROIs.
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After baseline determinations were completed, dexmedetomidine administration was initiated with a loading dose of 1.0 µg/kg (per the manufactur-er’s package insert recommendations) infused over 20 min. A dexmedetomidine infusion was immediately initiated at 0.2 µg · kg-1 · h-1 (LOW DEX) and continued for 30 min; repeat hemodynamic, CBF, and plasma (dexmedetomidine) measurements were completed (which required approximately 15 min to accomplish). The dexmedetomidine infusion was increased to 0.6 µg · kg-1 · h-1 (HIGH DEX) for an additional 45 min, and data collection was repeated. These dexmedetomidine doses were chosen to duplicate those of Hall et al. (11) and Khan et al. (12) so that comparisons could be drawn to similar sets of study subjects. This infusion regimen targets dexmedetomidine plasma concentration in the range of 400 pg/mL (LOW DEX) to 700 pg/mL (HIGH DEX) (11–13). All patients received 1 L of IV normal saline during the course of the study to help maintain hemodynamic variables (HR and MAP) within 25% of baseline values. In addition, if necessary, bradycardia was treated with 0.4 mg of IV atropine (one patient had an HR of >33 bpm), and hypotension was treated with incremental boluses of IV phenylephrine (30–60 µg) (one patient). One patient required both atropine and phenylephrine for an HR of 42 bpm with a mean MAP of 
60 mm Hg. After the dexmedetomidine infusion was discontinued, a final set of hemodynamic and CBF measurements was completed for the last five study subjects. After all measurements were complete, subjects were transported to a postanesthesia recovery unit, where BP and other vital signs were observed for 2 h. All invasive catheters and noninvasive monitors were removed, and the subjects were medically discharged to home with a responsible adult. There were no serious adverse events.
The effect of drug treatment on CBF was analyzed by using mixed-effects analysis of variance (ANOVA) with random effects for the volunteers and fixed effects for ROIs, drug dose, and the interaction. Residual analysis showed CBF to best fit a log-normal model; thus, the analysis was performed by using log-transformed CBF values. Because of log transformation, geometric least squares means, 95% confidence intervals, and difference ratios are reported. Bonferroni corrections were made for post hoc multiple comparisons only when the ANOVA’s main effect and interactions were not significant (with Fisher’s protected least-significant difference approach). The effects of treatment on global CBF, HR, MAP, and CO were each analyzed by using mixed-effects ANOVA with fixed effects for treatments and random effects for the volunteers. Finally, because the values for the hemodynamic indices were stable between the first two baseline periods, these two time points were averaged for subsequent analyses. All statistical analyses were performed with SAS (Version 8.0; SAS Institute, Inc., Cary, NC). P values <0.05 were considered significant, unless otherwise corrected for multiple comparisons.
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Results |
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Discussion |
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15%–20%, and increased PaCO2 no more than 5 mm Hg. We believe that these findings are consistent with the known 2-receptor-mediated anxiolytic and sympatholytic effects of dexmedetomidine, as well as with our hypothesis that dexmedetomidine activates vascular 2B-receptors, producing cerebral vasoconstriction (despite a small, but significant, increase in PaCO2) and decreasing CBF in most of the cortical and subcortical brain regions we examined.
Dexmedetomidine is the d-enantiomer of medetomidine, a potent imidazole compound often used as a veterinary anesthetic. Dexmedetomidine is a highly selective 2-agonist and activates 2-adrenergic receptors in the CNS, spinal cord, and autonomic ganglia and in the postsynaptic region of vascular smooth muscle. Central sedation and anxiolysis are likely mediated by the 2A-receptor subtype, which may also modulate working memory (2). All our subjects were tranquil and sleepy, though they could be easily aroused throughout the investigation by a voice command or a light touch. However, it was not our intent or desire to quantify the depth of sedation in these healthy volunteers, because in the judgment of the investigators, extensive and repeated verbal arousal and neuropsychiatric testing might alter the systemic and cerebral hemodynamics—those essential variables that were the focus of this pharmacodynamic study. In addition, the psychoactive effects of dexmedetomidine infused in this fashion, which targets plasma concentrations in the range of 400 pg/mL (LOW DEX) to 700 pg/mL (HIGH DEX), are already well described (2,3,11–15). For instance, the Observer Assessment of Alertness/Sedation score (which uses a variety of categories, including response to verbal stimuli, speech, facial expression, and so forth) decreased 31% and 37% with dexmedetomidine infusions of 0.2 and 0.6 µg · kg-1 · h-1, respectively (11). In these subjects, the bispectral index scores decreased 31% and 36%, respectively (11). Examined another way, infusion of dexmedetomidine produced a significant anesthetic-sparing effect (12). With use of a supramaximal tetanic stimulation of 50 Hz for five seconds over the ulnar nerve to assess isoflurane requirements, dexmedetomidine plasma concentrations of 350 and 730 pg/mL decreased the end-tidal isoflurane concentration requirements from 1.05% to 0.72% and 0.52%, respectively (12). Ebert et al. (13) studied even larger doses of dexmedetomidine, in which plasma concentrations of larger than 1900 pg/mL rendered some subjects unarousable.
The 2A-receptors that inhibit CNS sympathetic activity (especially at the locus ceruleus in the brainstem) likely decrease BP and HR. Our subjects manifested a 15% decrease in BP and HR, along with a similar decrease in CO. In previous studies in young, healthy volunteers, Ebert et al. (13) found similar hemodynamic changes during dexmedetomidine administration. BP decreased 13%, HR decreased 29%, and CO decreased 35% during their dose-titration phase, which achieved plasma dexmedetomidine concentrations similar to ours (500–1000 pg/mL). However, SV did not decrease until very large plasma concentrations were achieved (
3200 pg/mL). In another volunteer study that used the same dexmedetomidine administration protocol that we used, Hall et al. (11) found significant decreases in MAP (-12%) and HR (-16%), similar to ours. Thus, the effects of dexmedetomidine on the cardiovascular system appear consistent and predictable in these healthy study subjects, producing modest decreases in HR, BP, and CO, whereas SV is well maintained.
2B-Receptors may also produce a vasoconstrictive, hypertensive action (2). Indeed, the subjects studied by Ebert et al. (13) manifested a steady increase in BP at doses that achieved larger dexmedetomidine plasma concentrations. Activation of the 2B-receptors located directly on vascular smooth muscle cells in the resistance vessels appears to mediate vasoconstriction via the L-type calcium channels. This specific arterial vasoconstrictive action has been identified with doses of clonidine that decrease BP in awake, healthy subjects (16). We believe that this mechanism is also consistent with the effects of dexmedetomidine that we observed on CBF in this study. The vascular smooth muscle cells of cerebral arteries normally contain only a small active pool of intracellular calcium (17), and consequently, these vessels are dependent on the receptor-mediated influx of extracellular calcium for the regulation of cerebral vasomotor tone. Thus, the dexmedetomidine-induced decrease in regional and global CBF that we observed is consistent with 2B-adrenergic receptor-induced vasoconstriction and is also consistent with the known distribution and activity of 2-adrenergic receptors in the cerebral vasculature (4,18–24). It is possible that the dexmedetomidine loading dose maximally stimulated the receptors mediating cerebral vasoconstriction, and therefore we were unable to discriminate a CBF difference during our LOW DEX and HIGH DEX infusion periods. In addition, preliminary information suggests that dexmedetomidine exhibits no specificity toward any particular subfamily (2A, 2B, or 2C) of the 2-adrenergic receptor (Victor Jorden MD, MPH, Abbott Laboratories, personal communication, 2001).
Regulation of CBF is also coupled with factors such as cerebral metabolic rate, MAP, and arterial carbon dioxide tension. In general, decreasing metabolic demands imposed on the brain by decreased neuronal activity decreases CBF proportionately. Thus, the decrease in CBF that we observed in this study could be the consequence of a concomitant decrease in cerebral metabolic activity (anxiolysis, hypnosis, sedation) induced by the dexmedetomidine infusion. We attempted to directly determine cerebral oxygen consumption concurrent with our PET CBF study but were unable to do so because of technical limitations, as well as limitations imposed by the IRB on total-body radiation. We are aware of data from studies of dogs that suggest that the decrease in CBF associated with the 2-agonist dexmedetomidine is not metabolically mediated and that the cerebral metabolic rate of oxygen is maintained constant during centrally administered dexmedetomidine (20,25). Similarly, the decrease in MAP that we observed could decrease CBF if dexmedetomidine also affected cerebral autoregulation. Finally, PaCO2 increased 5 mm Hg. In general, the cerebral reactivity to hypercapnia is greater than that seen with hypocapnia, and as a general rule, CBF increases 6% per mm Hg change in PaCO2 (26). Thus, on the basis of arterial carbon dioxide tension alone, we might have anticipated an increase in CBF of as much as 30%. Clearly, the effect of PaCO2 either did not predominate or was overwhelmed by the cerebral vasoconstriction induced by dexmedetomidine activation of 2B-receptors.
PET scans of bolus H215O injections are accurate, quantitative, three-dimensional measurements of regional CBF from both superficial and deep structures under normal and pathologic conditions (27,28). Indeed, PET is currently the most accurate and versatile tracer method to measure in vivo physiologic variables in human brain (29). The advantages of PET include high resolution at normal blood flows and the ability to measure regional blood flow differences between brain structures (10,27). One limitation is that CBF in small areas of low reactivity surrounded by areas of high radioactivity is difficult to measure accurately. Our ROIs were selected to minimize this effect. Thus, we believe that PET is the best current technology to measure regional and global CBF in resting humans.
Several other limitations of this study are evident. First, we were studying young, healthy, normotensive volunteers, and it is unclear whether the same findings will be seen in hypertensive patients, older patients, anesthetized patients, patients with traumatic brain injury, or patients with other intracranial or metabolic alterations of cerebral autoregulation. Indeed, in patients without normal cerebral autoregulation, one would expect a decrease in CBF as systemic blood flow decreases. This could also be the case with our study subjects if dexmedetomidine simultaneously altered cerebral vascular autoregulation. We did not determine formal dexmedetomidine pharmacokinetics, but we used the dexmedetomidine concentrations to correlate with previous data collected during identical drug administration protocols. We also need to acknowledge that our global CBF was based on the sum of the multiple preidentified ROIs. Indeed, we have no certain way of knowing what vascular changes may be occurring anywhere other than where we sampled. Furthermore, at the end of the protocol, after all drug infusion was terminated, we were able to determine CBF only in the final five subjects.
In summary, dexmedetomidine is a novel 2-agonist sedative with potent anxiolytic and sedative properties, which appears to produce a significant decrease in both regional and global CBF. Such decreases in CBF might be beneficial while sedating patients with traumatic brain injury or metabolic brain edema but could be detrimental in the setting of cerebral vasospasm. Appropriate selection of sedative drugs for ICU patients should include knowledge of their CBF effects.
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Appendix |
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Acknowledgments |
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We thank Qin Ji at Abbott Laboratories, Inc., Anesthesia and Pain Management Franchise, Abbott Park, IL, for assay of the dex-medetomidine.
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Footnotes |
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References |
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2-adrenergic agonists. Anesthesiology 2000; 93: 1345–9.[ISI][Medline]
1- and 2-adrenoreceptors. Gen Pharmacol 1989; 20: 799–804.[ISI][Medline]
2-Adrenergic agonist effects on normocapnic and hypercapnic cerebral blood flow in the dog are anesthetic dependent. Anesth Analg 1994; 79: 892–8.2-adrenergic agonist, decreases cerebral blood flow in the isoflurane-anesthetized dog. Anesth Analg 1990; 70: 624–30.1-Adrenergic receptor subtypes, inositol phosphates, and sources of cell Ca2+. Pharmacol Rev 1988; 40: 87–119.[ISI][Medline]
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