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Department of Anesthesia and Perioperative Medicine, University of California, San Francisco, California
Address correspondence and reprint requests to Dr. Talke, Department of Anesthesia and Perioperative Medicine, University of California, San Francisco, CA 94143-0648. Address e-mail to talkep{at}anesthesia.ucsf.edu
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Abstract |
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IMPLICATIONS: IV clonidine, at doses that decrease blood pressure, causes arterial vasoconstriction in awake subjects. These data suggest that an 
-2 agonist with a high -2a/-2b selectivity should provide more profound sedative and analgesic effects with less undesirable vasoconstrictive effects.
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Introduction |
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-2 Agonists have sympatholytic, sedative, analgesic, and vasoconstrictive effects (1–3). These multiple, but distinct, effects are mediated at various anatomical sites and/or by specific -2 receptor subtypes (-2a, -2b, and -2c). There is evidence suggesting that -2a adrenoceptors located in the central nervous system are responsible for the blood pressure-decreasing sympatholytic effects, and that -2b adrenoceptors located at the peripheral vascular smooth muscle are responsible for the vasoconstrictive effects (4,5). It is these vasoconstrictive properties now being attributed to the -2b adrenoceptors that limit the clinical use of large concentrations of -2 agonists to provide profound sedation/anesthesia (1). However, if we could quantify the peripheral -2b receptor function (vasoconstriction), we would (perhaps) be able to characterize -2 agonists for their different pharmacologic activities, thereby aiding in the development of subtype-selective -2 agonists and antagonists.
Studies of the peripheral vasoconstrictive effects of -2 agonists in vivo usually are masked by the simultaneous sympatholytic effects. Recently, we succeeded in studying vasoconstriction without concurrent sympatholytic activity. That is, we attenuated sympathetic nervous system tone in volunteers by using propofol/alfentanil/nitrous oxide anesthesia, and found that an IV dose of clonidine, which decreases blood pressure in awake volunteers, increased blood pressure and caused vasoconstriction in the presence of anesthesia (3). However, our previous study was limited in part by studying the subjects under anesthesia, which per se produced some undesirable effects, specifically hypotension and attenuation of sympathetic nervous system responses in response to changing blood pressure.
Our goal was to evaluate the vasomotor effects of clonidine in awake subjects with an intact central cardiovascular regulatory system. Peripheral vasomotor responses to clonidine were investigated with and without sympathetic denervation achieved by a unilateral axillary nerve block.
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Methods |
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Volunteers fasted 8 h before arriving at the study laboratory site. They rested supine in a 22°–23°C room during the protocol. All studies were conducted in the morning, starting at 8 AM. On the morning of study, after application of lidocaine local anesthesia, a catheter was inserted into a vein of the foot to permit the administration of IV fluids and the study drug. Before the study began, 7 mL/kg of lactated Ringer’s solution was administered and 1.0 mL · kg-1 · h-11 thereafter until the end of study. After application of lidocaine local anesthesia, a right radial arterial catheter was placed to permit continuous measurement of arterial blood pressure. Monitors (photo-plethysmography, laser Doppler flowmetry, and finger temperature) were attached to both hands as described below. To avoid locally mediated vasomotor activity throughout the protocol, volunteers were covered with blankets to prevent active warming and cooling.
Approximately 15 min after application of all monitors, hemodynamic, finger plethysmographic, laser Doppler, and temperature measurements were obtained. To block the sympathetic fibers of the left arm, an axillary perivascular brachial plexus block was administered by using 30 mL of 1% mepivacaine. Successful axillary block was verified approximately 25 min later by testing motor and sensory function of the left hand. Thirty minutes after the administration of axillary block, baseline hemodynamic, finger plethysmographic, laser Doppler, and temperature measurements were obtained. We then determined hemodynamic and vasomotor responses before and during four progressively increasing IV doses of clonidine (Roxane Laboratories Inc., Deerfield, IL).
The infusion solution was prepared by adding 2 mL of clonidine (100 µg/mL) to 48 mL of 0.9% NaCl. Clonidine (4 µg/mL) was infused, targeting plasma concentrations of 0.30, 0.45, 0.68, and 1.0 ng/mL, by using a computer-controlled infusion pump. The duration of each infusion step was at least 15 min. The infusion pump (Harvard Apparatus 22; Harvard Apparatus, South Natick, MA) was controlled using STANPUMP software (obtained from Steven Shafer, MD, Department of Anesthesia, Stanford University), which adjusted and recorded the infusion rate every 10 s based on current weight-adjusted pharmacokinetic data for clonidine (6).
Arterial blood pressure (systolic [SBP], diastolic, and mean) (Propaq 106; Protocol Systems, Beaverton, OR) was measured continuously via the right radial arterial catheter, which was connected to a Transpac II transducer (Abbott Laboratories, North Chicago, IL). Heart rate (HR) was measured noninvasively by using electrocardiography (Propaq 106). The hemodynamic data were recorded at 10-s intervals using an automated data acquisition system. Hemoglobin oxygen saturation (SpO2) was monitored using pulse oximetry (Nellcor N200; Nellcor Inc., Hayward, CA).
Finger blood volume was assessed by using photoelectric plethysmography, which measures infrared light transmitted through a fingertip (LTF). The absolute level of transmitted light was determined by using pulse oximetry (Nellcor N200; Nellcor Inc.), for which we placed a sensor (Nellcor D25; Nellcor Inc.) on the ring finger of each hand. The pulse oximeter consists of an electro-optical sensor that is applied to the subject’s finger and a microprocessor-based monitor that processes the measurements. The electro-optical sensor contains a low-voltage, low-intensity light-emitting diode (LED) as a light source, and one photodiode as a light receiver. The LED emits infrared light (approximately 920 nm) and is supplied with constant drive current. When the light from the LED is transmitted through the tissue at the sensor site, a portion of the light is absorbed by the finger. The detector photodiode generates a current proportional to the amount of light it receives (7). The pulse oximeter photo-detector current data were transmitted to a computer, sampled every 10 s, and written onto a disk file. The photo-detector current measurement (in nanoAmps) served as the qualitative measure of the arterial blood volume in the fingertip. An increase in transmitted light reflects a decrease in finger volume (vasoconstriction). While the volunteer lay supine, to maximize arterial contribution to the LTF measurements, and to minimize venous contribution to the blood volume in the fingertip, the monitored hand was elevated 4–8 cm above the heart to drain venous blood from the limb.
Skin blood flow was recorded from a laser Doppler probe (PeriFlux 4001 Master; Perimed AB, Järfälla, Sweden) attached to the pulp of the middle finger using double-sided adhesive tape and connected to a laser Doppler flowmeter (PeriFlux System 5000; Perimed AB). This system emits 780-nm wavelength light, has 0.25-mm fiber separation, and 0.5–1-mm measuring depth. Doppler values were expressed in arbitrary perfusion units (PU). We used a 3.0-s time constant and recorded peak flow before axillary block, immediately before clonidine infusion (baseline), and at the end of each infusion step.
Finger temperature was recorded bilaterally from thermocouples attached to the pulp of the ring finger of each hand connected to Iso-Thermax thermometers having an accuracy of 0.1°C (Columbus Instruments, Columbus, OH). Finger temperature was recorded before axillary block, immediately before clonidine infusion (baseline), and at the end of each infusion step.
Fifteen minutes after the end of clonidine infusion, motor and sensory blocks of the left hand were verified. After study, the volunteers rested in the postoperative care unit for 3 h before returning home after the brachial plexus block had resolved completely.
For analysis, SBP, HR, and plethysmography data were reduced to 1-min median values. Baseline values for continuously measured variables (SBP, HR, LTF) were defined as the median value obtained over 1 min before clonidine infusion. The values present at the end of each clonidine infusion step were determined. In the anesthetized hand, every infusion step produced an initial rapid change in transmitted light. Therefore, peak values during each clonidine infusion step in the anesthetized hand also were determined. The effect of clonidine on SBP, HR, and LTF, skin blood flow, and temperature in both hands was determined by repeated measures analysis of variance followed by Dunnett’s post hoc test. The effect of axillary block on all variables was determined by paired Student’s t-test. Values obtained from the right and left hand were compared by using a paired Student’s t-test with Bonferroni correction for multiple comparisons. Data were reported as the mean ± SD. P < 0.05 identified statistical significance.
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Results |
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Clonidine decreased SBP (P < 0.004) from 135 ± 8 to 115 ± 8 mm Hg (Table 1). The decrease was significant for the 0.45, 0.68, and 1.0 ng/mL target concentrations relative to control values before infusion. Clonidine decreased HR (P = 0.0017) from 68 ± 7 to 61 ± 10 bpm. The decrease was significant only for the 1.0 ng/mL target concentration (Table 1).
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Finger skin temperatures before axillary block were 31.4° ± 4.3°C and 31.9° ± 3.9°C for the middle fingers of the right and left hands, respectively (P = not significant). Axillary nerve block increased temperature in the left hand to 35.2° ± 0.7°C, but had no effect on temperature of the right hand. Clonidine had no further effect on finger temperature in the left hand (sympathectomy) (Table 1), but increased temperature more than (P < 0.0001) preinfusion values at the 0.68 and 1.0 ng/mL target concentrations of the right hand. The maximal increase in temperature was to 34.5° ± 0.9°C.
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Discussion |
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-2 agonists in humans. The finding that clonidine vasodilated (as indicated by LTF measurement) the neurally intact hand by 12% is consistent with previous results we obtained using an identical clonidine protocol in a similar volunteer study population (3). Also consistent with previous work is our finding that clonidine increased LTF vasoconstriction in the sympathetically denervated hand as it did in our previous study in anesthetized subjects. However, the increase in LTF vasoconstriction in the present study is twofold more than we previously observed in the presence of anesthesia (3). This difference could be explained, in part, by our use of propofol anesthesia in our previous volunteer study population. In addition to having central sympatholytic effects, propofol may have had direct effects on vascular smooth muscle cells that attenuated maximal clonidine-induced vasoconstriction. This may also explain why we found a lower threshold for clonidine-induced vasoconstriction in our present volunteers (0.3 vs 1.0 ng/mL in our previous study).
The rapid increase in LTF approximately 60 seconds after the beginning of clonidine infusion supports the hypothesis that clonidine-induced vasoconstriction is mediated peripherally by the vascular smooth muscle. Our results suggest that the clonidine-induced decrease in SBP had a negligible effect on the LTF values, because at the smallest clonidine target plasma concentration, there were no significant hemodynamic changes whereas LTF values increased, and the time course of the vasoconstrictive and hemodynamic changes were different (Fig. 2).
The shape of the LTF curve over time (rapid increase followed by a slow decline, Fig. 1) is identical to that found in previous studies with clonidine and dexmedetomidine in anesthetized subjects (8). The reason for the slow decline in LTF values over time is not known, but differences in the design of the studies may help to eliminate some possible causes. For example, our initial finding that clonidine caused vasoconstriction and a simultaneous increase in BP in the presence of anesthesia led us to speculate that the increase in BP might have caused reflex changes to decrease vasoconstriction (3). However, this hypothesis fails with our present data, which demonstrate a similar slow decline in LTF values despite a reduction in BP. Thus, we are left to consider that the slow decline in LTF is caused by pharmacokinetic factors, receptor desensitization, or endothelium-derived vasodilatory prostaglandins.
As measured by laser Doppler flowmetry, -2 agonists mediate vasodilation in innervated human cutaneous vascular beds (9). In contrast, in the present study, clonidine did not cause a statistically significant increase in skin blood flow in the innervated arm. However, in the presence of initially low skin blood flow (n = 2), clonidine infusion increased skin blood flow substantially. Results obtained in the denervated arm also differed. That is, laser Doppler flowmetry indicated a transient decrease in skin blood flow that was not sustained throughout infusion.
The total effect of -2 agonists on BP is a combination of their sympatholytic, vagomimetic, and vasoconstrictive effects. Our present data show that the peripheral vasoconstrictive effect already appears at a plasma clonidine concentration of 0.3 ng/mL. The profound sedative and vasoconstrictive effects associated with large clonidine doses limit the ability to study the complete vasoconstriction dose-response curve in humans. However, data from the present and previous studies show that, at clinically useful doses, clonidine and dexmedetomidine cause a peripheral vasoconstriction that becomes significant enough to overcome the BP decreasing effect of both drugs (>10 ng/mL clonidine and >1.9 ng/mL dexmedetomidine) (1,10). These data suggest that an -2 agonist with a higher -2a/-2b selectivity than that of clonidine and dexmedetomidine should provide more profound sedative and analgesic effects before producing unwanted vasoconstrictive effects.
During the study, the subject’s hands were elevated to facilitate emptying of the hand veins. By emptying the hand veins of blood, we attempted to maximize the arterial and minimize the venous contribution to the LTF measurements. However, this part of our study was limited by the potential contribution of venoconstriction to our LTF measurements. Our study was also limited by the potential contribution of systemically absorbed mepivacaine on vascular responsiveness.
Because the present study required invasive procedures, we did not study a group that did not receive clonidine. Each subject acted as his or her own control. Previous data show that axillary nerve block with mepivacaine lasts more than two hours (11). Therefore, our clonidine infusion protocol was designed to be completed within 1.5 hours after the administration of axillary nerve block, well within the 2-hour time frame. Sympathectomy of the left arm after axillary nerve block was indirectly confirmed by elimination of LTF and laser Doppler oscillations, increased finger temperature in the left hand, and vasodilation in the left, but not right, hand. Sympathectomy at the end of clonidine infusion was confirmed by verifying that these changes, and motor and sensory block, were sustained throughout the study.
We have demonstrated that IV clonidine, at doses that decrease BP, causes arterial vasoconstriction in awake subjects. The hemodynamic effects of -2 agonists are a combination of their centrally mediated sympatholytic and peripherally mediated vasoconstrictive properties. At large doses, the vasoconstrictive effects predominate with increasing BP, thus limiting their use at large doses. These data suggest that an -2 agonist with a high -2a/-2b selectivity should provide more profound sedative and analgesic effects with less unwanted vasoconstrictive effects.
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Acknowledgments |
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We thank the subjects for their time, Dr. John Severinghaus for his contributions to the study design, and Winifred von Ehrenburg, PhD, for her editorial assistance.
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This article has been cited by other articles:
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  G. Weigert, H. Resch, A. Luksch, H. A Reitsamer, G. Fuchsjager-Mayrl, L. Schmetterer, and G. Garhofer Intravenous administration of clonidine reduces intraocular pressure and alters ocular blood flow Br. J. Ophthalmol., October 1, 2007; 91(10): 1354 - 1358. [Abstract] [Full Text] [PDF]
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 R. C. Prielipp, M. H. Wall, J. R. Tobin, L. Groban, M. A. Cannon, F. H. Fahey, H. D. Gage, D. A. Stump, R. L. James, J. Bennett, et al. Dexmedetomidine-Induced Sedation in Volunteers Decreases Regional and Global Cerebral Blood Flow Anesth. Analg., October 1, 2002; 95(4): 1052 - 1059. [Abstract] [Full Text] [PDF]
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