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CARDIOVASCULAR ANESTHESIA

The Effects of Clonidine on Human Digital Vasculature

Department of Anesthesia and Perioperative Medicine, University of California, San Francisco, California

Address correspondence and reprint requests to Pekka O. Talke, Department of Anesthesia and Perioperative Medicine, University of California, San Francisco, CA 94143-0648. Address e-mail to talkep{at}anesthesia.ucsf.edu

	Abstract

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Large concentrations of ₂ agonists cause vasoconstriction. However, the threshold of the vasoconstrictive effect in humans is not known. We studied seven volunteers to determine the lower limit of the vasoconstrictive effect of clonidine. Subjects were studied while they were awake, and they were anesthetized with propofol/alfentanil/N₂O. Arterial blood pressure was continuously monitored via radial arterial catheter and vasoconstriction via finger volume plethysmography measuring infrared light transmitted through a fingertip (LTF). Clonidine was administered, targeting plasma clonidine concentrations of 0.3, 0.45, 0.68, 1.0, 1.5, and 2.25 ng/mL. The maximum change from preclonidine values for systolic blood pressure (SBP) and LTF was analyzed by using repeated measures analysis of variance. In awake subjects, clonidine (2.25 ng/mL) decreased LTF by 14% ± 13% and SBP from 141 ± 7 to 110 ± 15 mm Hg (P < 0.0001). In contrast, clonidine (2.25 ng/mL) increased LTF in anesthetized subjects by 21% ± 16% and SBP from 91 ± 7 to 106 ± 19 mm Hg (P < 0.0001). We conclude that the same dose of clonidine that decreased blood pressure and caused vasodilation in awake subjects had the opposite effect in anesthetized subjects with reduced sympathetic tone, increasing blood pressure and causing vasoconstriction in human digital vasculature. Our findings suggest that the lower threshold for clonidine-induced vasoconstriction in human digital vasculature is 1.0 ng/mL.

Implications: At clinically relevant doses, clonidine produced vasoconstriction in digital vasculature and increased blood pressure in anesthetized volunteers, while producing the opposite effect in the awake state.

	Introduction

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In humans, there are three known ₂ adrenoceptor subtypes, _2a, _2b, and _2c. The hemodynamic effects of ₂ agonists are mediated by the _2a and _2b subtypes (1,2). The _2a adrenoceptors are located in the central nervous system and are responsible for the blood pressure-decreasing sympatholytic effects of ₂ agonists (1). The _2b adrenoceptors are located at the peripheral vascular smooth muscle and are responsible for the vasoconstrictive effects (2). The total effect of the ₂ agonists on blood pressure therefore combines sympatholytic and vasoconstrictive actions mediated by the _2a and _2b adrenoceptors respectively.

Although all known ₂ agonists have vasoconstrictive properties, the lower limit of this vasoconstrictive effect in humans has not yet been determined. Yet, the ability to characterize the range of the vasoconstrictive effect of the ₂ agonists would be useful in understanding function of the _2b adrenoceptor, hemodynamic profiles of ₂ agonists, as well as their interaction with other vasoactive drugs.

Study of the vasoconstrictive effects of ₂ agonists in vivo is complicated by their concomitant sympatholytic effects. We found that, by attenuating the sympathetic nervous system tone using propofol/alfentanil/N₂O anesthesia, we can study the vasoconstrictive effect of ₂ agonists without interference from their sympatholytic effect (3). Accordingly, we evaluated the vasomotor effects of the ₂ agonist clonidine in healthy volunteers while they were awake and while they were anesthetized with propofol/alfentanil/N₂O.

	Methods

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With approval from the institutional review board of the University of California, San Francisco, and written, informed consent, we studied three male and four female volunteers having the following morphometric characteristics: age 29 ± 6 yr, height 170 ± 11 cm, and weight 67 ± 12 kg. We excluded from the study volunteers who had a history of cardiac, pulmonary, hepatic, or renal disease, or a history of alcohol or drug abuse, and those taking prescription medication, those older than 45 yr, or those with body weight exceeding 130% of normal.

Using a cross-over protocol, we randomly (awake versus anesthesia study day) compared the effects of six progressively increasing IV doses of clonidine while volunteers were either awake or anesthetized. At least 7 days were allowed between treatments. Blood pressure and vasomotor responses were determined.

Volunteers fasted 8 h before arriving at the laboratory. They rested supine during the protocol. On the morning of study, a catheter was inserted into a vein of the left hand to permit administration of IV fluids and the study drug. Lactated Ringer’s solution 7 mL/kg was administered before study began and 1.5 ml · kg^-1 · h^-1 thereafter until the end of study. A left radial artery catheter was placed to permit continuous measurement of arterial blood pressure. To avoid locally mediated vasomotor activity throughout the protocol, volunteers were covered with blankets to prevent active warming and cooling; during the administration of anesthesia, forced air warming was used to maintain esophageal temperature at 36°–37°C.

On the anesthesia study day, volunteers breathed 100% oxygen while general anesthesia was induced with IV alfentanil (30 µg/kg) and propofol (3 mg/kg). Rocuronium (600 µg/kg) was administered to facilitate tracheal intubation. After intubation, anesthesia was maintained throughout study with 70% N₂O in oxygen and IV infusion of propofol (100 µg · kg^-1 · min^-1) and alfentanil (0.5 µg · kg^-1 · min^-1). Ventilation was adjusted to maintain ETCO₂ between 35 and 40 mm Hg.

Approximately 30 min after the induction of anesthesia or a period of quiet rest (awake study day), once blood pressure and heart rate varied <5% for a 5-min period, baseline hemodynamic and finger plethysmography measurements were obtained. The clonidine protocol was then begun.

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 0.3, 0.45, 0.68, 1.0, 1.5, and 2.25 ng/mL, by using a computer-controlled infusion pump. The duration of each infusion step was 15 min. The infusion pump (Harvard Apparatus 22^TM; Harvard Apparatus, South Natick, MA) was controlled by using STANPUMP^TM software (obtained from Steven Shafer, MD, Department of Anesthesia, Stanford University); the software adjusted and recorded the infusion rate every 10 s based on current pharmacokinetic data for clonidine (Vc = 0.51 L/kg, K10 = 0.008 min^-1, K12 = 0.105 min^-1, K21 = 0.022 min^-1) (4).

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^TM; Nellcor Inc, Hayward, CA), for which we placed a sensor (Nellcor D25^TM; Nellcor Inc, Pleasanton, CA) on the ring finger of the right 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 (5). The pulse oximeter photodetector current data were transmitted to a computer, sampled every 10 s, and written on a disk file. The photodetector current measurement (in nanoAmps) served as the qualitative measure of the arterial blood volume in the fingertip. While the volunteer lay supine, the monitored hand was elevated 4–8 cm above the heart to drain venous blood from the limb.

Arterial blood pressure (systolic [SBP], diastolic, and mean) (Propaq 106^TM; Protocol Systems, Beaverton, OR) was measured continuously via the radial artery catheter, which was connected to a Transpac II^TM transducer (Abbott Laboratories, North Chicago, IL). Hemoglobin oxygen saturation (SpO₂) and heart rate (HR) were measured noninvasively by using a pulse oximeter (Propaq 106) with the probe placed on a distal phalanx. The hemodynamic and SpO₂ data were recorded at 10-s intervals by using an automated data acquisition system. After study, the volunteers rested in the postoperative care unit for 3 h before returning home accompanied by an adult.

For analysis, blood pressure, 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 2 min before clonidine infusion. For each study day, the values present at the end of each clonidine infusion step were determined. In anesthetized volunteers, every infusion step produced in initial rapid change in transmitted light and SBP. Therefore, in anesthetized volunteers, peak values during each clonidine infusion step were also determined. For each study day, the effect of clonidine on SBP, HR, and LTF was determined by using repeated measures analysis of variance followed by Dunnett’s post hoc test. Values obtained in anesthetized and awake volunteers were compared by using a paired Student’s t-test with Bonferroni correction for multiple comparisons. Linear least squares regression was used to correlate changes in SBP and changes in LTF in anesthetized volunteers. Data were reported as the mean ± SD. P < 0.05 identified statistical significance.

	Results

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The cumulative doses of clonidine administered at the end of each of the six infusion steps were 0.40 ± 0.03, 0.76 ± 0.02, 1.27 ± 0.03, 1.94 ± 0.03, 3.00 ± 0.04, and 4.53 ± 0.04 µg/kg in awake volunteers, and 0.39 ± 0.01, 0.76 ± 0.02, 1.28 ± 0.04, 1.98 ± 0.06, 3.02 ± 0.09, and 4.55 ± 0.10 µg/kg in anesthetized volunteers.

LTF, SBP, mean arterial pressure, and HR values during clonidine infusion are shown in Table 1. The initial LTF values were 8482 ± 3865 nA and 7766 ± 2263 nA for the awake and anesthesia (preinduction) days, respectively. In awake volunteers, clonidine decreased LTF significantly below (P < 0.0001) preclonidine values at the 0.68-ng/mL target concentration. The maximum decrease in LTF was to 6997 ± 2993 nA (-14% ± 13%) at the 2.25-ng/mL target concentration (Fig. 1). After the induction of anesthesia, the preclonidine LTF value was 5112 ± 1903 nA. In anesthetized volunteers, clonidine increased LTF significantly above (P < 0.0001) preclonidine values at the 1.0-ng/mL target concentration. Maximum increase in LTF was to 6286 ± 1870 nA (28 ± 22%) at the 2.25-ng/mL target concentration (Fig. 1). Every infusion step in anesthetized volunteers produced an initial rapid increase in LTF and SBP, followed by a gradual decline (Fig. 2). The LTF values obtained at the end of each infusion step in awake versus anesthetized volunteers differed significantly (P < 0.001) at the 1.0-, 1.5-, and 2.25-ng/mL target concentrations.

View larger version (20K): [in this window] [in a new window]   Figure 1. Transmitted light through finger data during stepwise clonidine infusion in subjects while they were awake and anesthetized. Data are means from all subjects. Increase in transmitted light reflects decrease in finger volume (vasoconstriction). The vertical lines mark the beginning of each clonidine infusion step.

View larger version (35K): [in this window] [in a new window]   Figure 2. Data collected from a subject receiving clonidine while he was anesthetized (left) and awake (right). The top panels illustrate transmitted light through the finger during each consecutive 15-min clonidine infusion step. Increase in transmitted light reflects decrease in finger volume (vasoconstriction). The bottom panels illustrate systolic blood pressure. The vertical line marks the beginning of the 1.5-ng/ml infusion step to illustrate the simultaneous increase in transmitted light through finger and systolic blood pressure.

Clonidine decreased HR (P < 0.0001) at all target plasma concentrations in anesthetized volunteers and at all but the 0.3-ng/mL target concentration in awake volunteers relative to control values before the infusion (Table 1). HR values did not differ in awake and anesthetized volunteers.

	Discussion

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Our data suggest that we have identified the lower threshold of vasoconstrictive effect for the ₂ agonist, clonidine, in anesthetized humans. That is, over the clinically relevant dose range of 0.3, 0.45, 0.68, 1.0, 1.5, and 2.25 ng/mL, we found that doses of 1.0–2.25 ng/mL clonidine caused vasoconstriction in human digital vasculature and increased blood pressure in anesthetized volunteers with reduced sympathetic tone. This effect is in direct opposition to that of the same doses in awake volunteers, in which, like previous investigators, we found that clonidine decreases blood pressure and causes vasodilation (5–7).

Clonidine has a biphasic effect on blood pressure (6,7). At plasma concentrations of 0.4–2 ng/mL, clonidine dose-dependently decreases blood pressure (7,8). At larger doses, its hypotensive effects are attenuated: for example, at plasma concentrations larger than 10 ng/mL, clonidine increases blood pressure (7). For the present study, we targeted a dose range that, based on previous reports in awake subjects, should have resulted in no effect on blood pressure at the smaller doses and a dose-dependent hypotensive effect at larger doses. Our results in awake volunteers confirm these effects. In the presence of anesthesia, however, these effects were reversed, and clonidine increased blood pressure (from 91 ± 7 to 102 ± 19 mm Hg) at the 2.25-ng/mL dose that decreased blood pressure in subjects with an intact sympathetic nervous system. Moreover, this increase in blood pressure was associated with vasoconstriction in the fingertip, suggesting that the increase in blood pressure is secondary to increased vascular resistance.

The time course of the increases in blood pressure and decreases in digital blood volume (as measured by continuous plethysmographic monitoring of changes in transmitted infrared light) in our volunteers is consistent with a direct vascular effect. At the beginning of each clonidine infusion step, blood pressure and digital blood volume changed simultaneously within 30–60 seconds. This initial decrease in digital blood volume was followed by a gradual increase (Fig. 1), although digital blood volume remained below baseline values at the end of the 15-minute infusion step. Several factors can explain the decline in blood pressure and increase in digital blood volume over time, including the inability of the pharmacokinetic data to estimate plasma clonidine levels accurately during the first few minutes of infusion when plasma levels rapidly fluctuate, rapidly desensitize the ₂ adrenoceptors, or vasodilate by intact vascular reflexes.

Data obtained in animal models (awake and pithed rats) demonstrate that all ₂ agonists possess both hypo- and hypertensive properties and that the hypotensive effect appears at smaller doses than the hypertensive effect (9). However, these effects are species-specific, and relating these hemodynamic responses in animals to humans should be done with caution. For example, to achieve similar hypotensive effects, clonidine dose requirements are approximately 20-fold higher in rats and nearly 8-fold higher in dogs than in humans (7). Our findings suggest that we have developed a method that can be used to study the vasoconstrictive effects of ₂ agonists in humans. As current research focuses on developing ₂ subtype-selective drugs for human use, our model may also prove useful in characterizing pharmacologic profiles of new ₂ agonists.

In humans, the vasoconstrictive effect of ₂ agonists has been demonstrated previously by direct infusion of clonidine into the brachial artery (10). However, these studies were performed by using systemically subtherapeutic doses which had no effect on blood pressure. In our stepwise model, we found no effect of clonidine on blood pressure at the smaller doses and a dose-dependent hypotensive effect at larger doses in awake subjects, in contrast to no decrease in blood pressure with any dose and an increase in blood pressure with the largest dose (2.25 ng/mL) in anesthetized volunteers. We therefore interpret the blood pressure data in the awake state to reflect a combination of the central sympatholytic and peripheral vasoconstrictive effects of clonidine.

Our study has several limitations: 1) We did not study clonidine doses larger than 2.25 ng/mL. However, studies using larger clonidine doses may be limited by profound prolonged sedation, as well as potentially dangerous increases in vascularresistance. 2) We studied only healthy subjects. (A similar study in hypertensive patients is underway.) 3) We did not measure sympathetic nervous system activity during propofol/alfentanil/N₂O anesthesia administration. Our anesthetic included nitrous oxide, which may have increased sympathetic nervous system activity. However, the effects (reduced sympathetic nervous system activity) of propofol anesthesia on forearm vascular responses are similar to the effects of sympathetic denervation by stellate ganglion blockade (11). 4) We did not measure plasma clonidine concentrations. Plasma clonidine concentrations were estimated by using pharmacokinetic data. 5) We studied changes in blood volume via transmitted light only at the finger and therefore cannot comment on the effects of clonidine on other vascular beds.

Sedation is considered an undesirable side effect of ₂ agonists when they are used as antihypertensive drugs, but a desirable therapeutic effect perioperatively. Given that the degree of therapeutic sedation may in part be limited by the vasoconstrictive effect of the ₂-agonists, knowing the upper and lower thresholds for vasoconstriction can help to determine appropriate perioperative therapeutic dose ranges. In the present study, we determined the lower limit of the vasoconstrictive effect of the clonidine in human digital vasculature. Our results also suggest that we have developed a method that can be used to determine the vasoconstrictive potencies of ₂ agonists in humans.

	Acknowledgments

 
Supported by departmental and university funds.

We thank the subjects for volunteering their time, and Winifred von Ehrenburg for editorial assistance.

	References

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