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Abstract |
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The neuromuscular effects of dexmedetomidine in humans are unknown. We evaluated the effect of dexmedetomidine on neuromuscular block and hemodynamics during propofol/alfentanil anesthesia. During propofol/alfentanil anesthesia, the rocuronium infusion rate was adjusted in 10 volunteers to maintain a stable first response (T1) in the train-of-four sequence at 50% ± 3% of the pre-rocuronium value. Dexmedetomidine was then administered by computer-controlled infusion, targeting a plasma dexmedetomidine concentration of 0.6 ng/mL for 45 min. The evoked mechanical responses of the adductor pollicis responses (T1 response and T4/T1 ratio), systolic blood pressure (SBP), heart rate (HR), and transmitted light through a fingertip were measured during the dexmedetomidine infusion and compared with pre-dexmedetomidine values using repeated-measures analysis of variance and Dunnett’s test. Plasma dexmedetomidine levels ranged from 0.68 to 1.24 ng/mL. T1 values decreased during the infusion, from 51% ± 2% to 44% ± 9% (P < 0.0001). T4/T1 values did not change during the infusion. Plasma rocuronium concentrations increased during the infusion (P = 0.02). Dexmedetomidine increased SBP (P < 0.001) and decreased HR (P < 0.001) (5-min median values) during the infusion compared with values before the infusion. Dexmedetomidine increased the transmitted light through the fingertip by up to 41% ± 8% during the dexmedetomidine infusion (P < 0.001).We demonstrated that dexmedetomidine (0.98 ± 0.01 µg/kg) increased the plasma rocuronium concentration, decreased T1, increased SBP, and decreased finger blood flow during propofol/alfentanil anesthesia. We conclude that dexmedetomidine-induced vasoconstriction may alter the pharmacokinetics of rocuronium.
Implications: We studied the effect of an 
2-agonist (dexmedetomidine) on rocuronium-induced neuromuscular block during propofol/alfentanil anesthesia. We found that the rocuronium concentration increased and the T1 response decreased during the dexmedetomidine administration. Although these effects were statistically significant, it is unlikely that they are of clinical significance.
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Introduction |
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Dexmedetomidine is a highly selective, nonsubtype-specific, investigational
2-agonist. In healthy volunteers and in surgical patients, it has sedative, analgesic, and anesthetic-sparing effects, and it decreases heart rate (HR), blood pressure, and cardiac output in a dose-dependent manner (1–3). The neuromuscular effects of dexmedetomidine are unknown in humans. Accordingly, we evaluated the effect of dexmedetomidine on neuromuscular block during propofol/alfentanil anesthesia.
2-Agonists decrease blood pressure by centrally mediated sympatholytic effects and by decreasing norepinephrine release via peripheral presynaptic 2 receptor stimulation (4). In addition, 2-agonists induce peripheral vasoconstriction by directly activating vascular smooth muscle 2 receptors (5,6). The hemodynamic effects of 2-agonists therefore should be a combination of their sympatholytic and vasoconstrictive effects. Most clinical studies show that dexmedetomidine decreases blood pressure and HR. However, the hemodynamic effects of dexmedetomidine have not been studied in humans during the administration of anesthetics that decrease sympathetic tone. Therefore, we also measured the hemodynamic effects of dexmedetomidine during propofol/alfentanil anesthesia.
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Methods |
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With approval from our institutional review board and written, informed consent, we studied six male and four female volunteers with the following morphometric characteristics: age 31 ± 7 yr, height 175 ± 10 cm, and weight 74 ± 12 kg. Volunteers who had a history of cardiac, pulmonary, hepatic or renal disease; those with a history of alcohol or drug abuse, taking prescription medication, >45 yr of age, or with a body weight >130% of normal were excluded.
Volunteers fasted for 8 h before arriving at the study laboratory site and rested supine during the protocol. On the morning of study, a catheter was inserted into a hand vein for fluid and study drug administration. Lactated Ringer’s solution (10 mL/kg) was administered before the induction of anesthesia, and 1.5 mL · kg-1 · h-1 was administered thereafter until the end of the study. Throughout the protocol, volunteers were covered with blankets; during anesthesia, forced-air warming was used to maintain esophageal temperature at 36–37°C.
Volunteers breathed 100% oxygen while anesthesia was induced with IV alfentanil (30 µg/kg) and propofol (3 mg/kg). After tracheal intubation, anesthesia was maintained with 70% nitrous oxide in oxygen, IV propofol (100 µg · kg-1 · min-1), and alfentanil (0.5 µg · kg-1 · min-1) infusions. A radial artery cannula was placed to permit measurement of arterial blood pressure and collection of blood samples. Ventilation was adjusted to maintain end-tidal CO2 between 35 and 40 mm Hg.
Supramaximal stimuli (duration 0.2 ms) in a train-of-four (TOF) sequence were applied every 12 s via surface electrodes (Digistim II®; Neuro Technology Inc., Houston, TX) to the ulnar nerve at the right wrist. The resulting evoked mechanical responses of the adductor pollicis (preload 200–300 g) were measured by using a calibrated force transducer (Myotrace; Life-Tech Inc., Houston, TX) and amplified. The evoked responses (T1 response and T4/T1 ratio) were digitized, displayed, and recorded on a Macintosh computer.
Approximately 30 min after the induction of anesthesia, once blood pressure and HR varied <5% over a 5-min period, the twitch tension was measured, and the value of the T1 response was taken as 100%. Rocuronium was then administered as a bolus (200 µg/kg), followed by an infusion (200 µg · kg-1 · h-1). The rocuronium administration was adjusted to target a stable T1 response within the range of 50% ± 3% of the pre-rocuronium value by administering additional rocuronium bolus doses and by changing the infusion rate. When the T1 response was stable (<2% variation) and within the range of 47%–53% and the rocuronium infusion rate had been constant for at least 10 min, the dexmedetomidine infusion was begun. The rocuronium infusion rate sustaining the target T1 response was unchanged for the remainder of the study.
The dexmedetomidine infusion was prepared by adding 1 mL of dexmedetomidine (200 µg/mL) in 49 mL of 0.9% NaCl. Volunteers received an IV infusion of dexmedetomidine starting 55 ± 10 min after the beginning of the rocuronium administration and continuing for 45 min. Targeting plasma dexmedetomidine concentrations of 0.6 ng/mL, dexmedetomidine (4 µg/mL) was administered using a computer-controlled infusion pump. 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, Stanford, CA); the software adjusted and recorded the infusion rate every 10 s based on the current pharmacokinetic data for dexmedetomidine.
Finger blood volume was assessed by measuring transmitted light through the finger using photoelectric plethysmography. To measure the absolute level of infrared light transmitted through a fingertip, we placed a pulse oximeter sensor (Nellcor D25; Nellcor Inc., Pleasanton, CA) on the ring finger of the left hand and connected it to a pulse oximeter (Modified Nellcor N200; Nellcor Inc.). The internal pulse oximeter light level data were transmitted to a computer, sampled every 10 s, and written onto a disk file. With the volunteer in the supine position, the hand was elevated 4–8 cm above the heart to drain venous blood from the limb. The photodetector current measurement from the infrared light channel served as the qualitative measure of the arterial blood volume in the fingertip. We interpreted an increase in transmitted light (decreased absorbance) to provide a measure of arteriolar vasoconstriction accompanied by a decrease in volume of blood in the fingertip.
Arterial blood pressure (systolic, diastolic, and mean) and HR were measured noninvasively from 5 min before the induction of anesthesia until the introduction of an arterial cannula. Thereafter, arterial blood pressure was measured continuously via the radial artery cannula, which was connected to a Transpac II transducer (Abbott Laboratories, North Chicago, IL). Hemoglobin oxygen saturation (SpO2) was measured noninvasively using a pulse oximeter (Propaq 106; Protocol Systems, Beaverton, OR) with the probe placed on a distal phalanx. The hemodynamic and SpO2 data were recorded at 10-s intervals using an automated data acquisition system.
Arterial blood samples for determination of plasma dexmedetomidine and plasma rocuronium concentrations were collected just before the start of the rocuronium and dexmedetomidine infusions and 15, 30, and 45 min after the start of the dexmedetomidine infusion. Blood samples were iced immediately, and plasma was separated by centrifugation. Plasma was stored at -70°C until analysis. The plasma clearance (Cl) of rocuronium at the beginning and end of the dexmedetomidine infusion was calculated by dividing the infusion rate by the plasma concentration.
Dexmedetomidine concentrations were assayed by using gas chromatography-mass spectrometry. This combined method has a lower limit of detection of 20 pg/mL and a coefficient of variation of 5.7% in the relevant concentration range (Dr. Hrusowsky, personal communication, Abbott Laboratories, 1997). Plasma concentrations of rocuronium were determined by using a capillary gas chromatographic assay with a coefficient of variation of 15% at concentrations of 15 ng/mL and a sensitivity of 10 ng/mL (7). All drugs and fluids administered were recorded.
For analysis, blood pressure and HR data were reduced to 5-min median values. For continuously measured variables (SBP, HR, transmitted light through fingertip), baseline values were defined as the median value obtained over 2 min before the dexmedetomidine infusion. For analysis of transmitted light through the fingertip, we used 1-min median data values from 5 min before the dexmedetomidine infusion to 10 min after the beginning of the dexmedetomidine infusion. Measured dexmedetomidine concentrations were compared with target concentrations (600 pg/mL) during the infusion. For each concentration, the percent error ([predicted measured]/predicted, expressed in percentages) was determined.
If the twitch response and/or plasma concentration of rocuronium changed during the administration of dexmedetomidine, then the Hill equation with an assumed value of 5 for the power function was used to determine whether changes in plasma rocuronium concentration might account for the changes in twitch tension (8,9).
The effect of dexmedetomidine on blood pressure, HR, T1, T4/T1, transmitted light, and plasma rocuronium concentrations was determined by using repeated-measures analysis of variance followed by Dunnett’s post hoc test. Data are reported as the mean ± SD. P < 0.05 identified statistical significance.
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Results |
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The average dose of dexmedetomidine administered was 0.98 ± 0.01 µg/kg (range 0.95–0.99 µg/kg). Plasma dexmedetomidine concentrations exceeded the target concentration of 0.6 ng/mL in all patients at all measured time points (Table 1). The percent error ranged from 36% to 107% at 15 min, from 24% to 103% at 30 min, and from 13% to 92% at 45 min.
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The T1 and T4/T1 values during dexmedetomidine infusion are illustrated in Figure 1. Inspection of the results showed that T1 values decreased over time (P < 0.0001), becoming significantly lower than pre-dexmedetomidine values 30 min after the beginning of infusion. T4/T1 values did not change during the dexmedetomidine infusion.
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The final rocuronium infusion rates were 914 ± 288 µg · kg-1 · h-1 (range 545–1488 µg · kg-1 · h-1). Rocuronium plasma concentrations increased over time (P < 0.05), becoming significantly higher than pre-dexmedetomidine values 45 min after the beginning of the infusion (Table 1). The initial Cl of rocuronium was 9.0 ± 1.6 mL · kg-1 · min-1. The Cl was altered, with a significant reduction (6%) occurring at the final time point of 45 min. The percent increase in plasma rocuronium concentration was 7.6% and was associated with a mean decrease in twitch tension (from 51% to 44%) after 45 min of the dexmedetomidine infusion. The mean final twitch tension predicted (Hill equation) by this change in rocuronium concentration is 41%, compared with the value of 44% that we observed.
Dexmedetomidine increased SBP (P < 0.001) and decreased HR (P < 0.001) at all time points (5-min median) during the infusion relative to control values before the infusion (Table 1). SBP increased from 97 ± 9 mm Hg to a maximum of 117 ± 10 mm Hg 5 min after the beginning of the dexmedetomidine infusion. HR decreased from 60 ± 11 bpm to a minimum of 54 ± 10 bpm 5 min after the beginning of the dexmedetomidine infusion.
Dexmedetomidine increased the transmitted light through the fingertip (P < 0.001). The maximal increase in transmitted light was 41% ± 8% during the dexmedetomidine infusion compared with pre-dexmedetomidine values (Fig. 2). Transmitted light and blood pressure increased simultaneously within 30–90 s of the beginning of the dexmedetomidine infusion.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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There are two new findings in our study of the neuromuscular effects of dexmedetomidine. First, after the administration of dexmedetomidine in a clinically relevant dose, plasma rocuronium concentrations increased and T1 decreased. Second, during the dexmedetomidine infusion, there was a sustained decrease in finger blood volume and a sustained increase in systemic blood pressure, which suggests a persistent dexmedetomidine-induced peripheral vasoconstriction.
We administered dexmedetomidine for 45 min to a target plasma concentration of 0.6 ng/mL. This concentration is effective in decreasing postoperative hypertension and tachycardia and is the highest dexmedetomidine concentration presently used in perioperative clinical trials. We considered the 45-min infusion long enough to observe potential centrally mediated effects because these effects are maximal 30–45 min from the time of drug administration (10). The direct, peripherally mediated vascular effect (vasoconstriction) occurs immediately after administration (2).
Although clonidine has been available for perioperative use for several years, very little has been published on the perioperative neuromuscular effects of 2-agonists. In a study of perioperative clonidine (11), the oral administration of 5 µg/kg clonidine had no effect on the onset or duration of vecuronium-induced neuromuscular relaxation. The authors concluded that clonidine did not interact with neuromuscular relaxation. In contrast, we found that T1 decreased during a dexmedetomidine infusion.
The decrease in twitch tension during the dexmedetomidine infusion was probably due to the increased plasma concentration of rocuronium. The twitch tension of 41% predicted by the change in rocuronium concentration was almost exactly the value we observed, 44%. Although a combination of other mechanisms might be invoked to explain our results, we believe that the change in twitch tension was the result of the increased rocuronium concentration.
The reason for the increase in plasma rocuronium concentration in the presence of dexmedetomidine is not clear. Perhaps we did not actually reach steady state before the dexmedetomidine infusion began. If so, then we would have expected the plasma concentration to increase in some subjects and to decrease in others. We did not see this, and plasma rocuronium concentrations in all subjects increased after the dexmedetomidine infusion was begun.
Alternatively, dexmedetomidine may have altered the biodisposition of rocuronium. The Cl of rocuronium decreased by 6% over the course of dexmedetomidine infusion, which suggests that dexmedetomidine influences the pharmacokinetics of rocuronium. Dexmedetomidine decreases both renal and hepatic blood flow (12) and decreases thiopental distribution volume and distribution Cls (13). Thus, the pharmacokinetic mechanisms may, in part, explain the increase the plasma rocuronium concentration.
In designing the neuromuscular study, we had two principal requirements—we needed a system that produced stable conditions throughout the dexmedetomidine infusion and one that was sensitive enough to detect small dexmedetomidine-related effects on neuromuscular function. We performed the study in volunteers to ensure stable experimental conditions and to allow sufficient time to achieve stable neuromuscular block.
Neuromuscular block was maintained at 50% before the administration of dexmedetomidine, because this level of block is on the steepest part of the concentration-activity curve. Thus, changes in the concentration of rocuronium or sensitivity of the neuromuscular junction have most effect on twitch tension; i.e., the system is maximally sensitive.
We used rocuronium to produce neuromuscular block for two reasons. First, its principal metabolite does not reach a pharmacologically active concentration, which may have caused difficulty in obtaining a stable level of block (8). Second, it is eliminated by both renal and hepatic mechanisms, which suggests that Cl may be affected by dexmedetomidine-related changes in perfusion of these organs (14).
2-Agonists decrease blood pressure by centrally mediated sympatholytic effects and by decreasing norepinephrine release via peripheral presynaptic 2 receptor stimulation (4). In addition, 2-agonists induce peripheral vasoconstriction by directly activating vascular smooth muscle 2 receptors (5,6). The hemodynamic effects of 2-agonists are therefore thought to be a combination of their central sympatholytic and peripheral vasoconstrictive effects. The present study is the first to report that dexmedetomidine (at the same dose found to decrease blood pressure and HR in healthy, awake volunteers) has a sustained peripheral vasoconstrictive effect in volunteers anesthetized with propofol and alfentanil.
Previous clinical studies have shown that 2-agonists decrease blood pressure and HR in healthy volunteers and patients during inhaled anesthesia (15,16). An increase in blood pressure with a concomitant decrease in HR and cardiac output has been reported when a large IV dexmedetomidine dose is administered rapidly, resulting in high plasma dexmedetomidine concentrations (2). This increase in blood pressure starts immediately after dexmedetomidine administration but lasts only a few minutes. Ours is the first study to demonstrate that dexmedetomidine has a persisting vasoconstrictive effect in clinically feasible doses.
In the present study, the increase in systemic blood pressure and in transmitted light through the finger started within 30–90 s of the administration of dexmedetomidine. This suggests a direct effect (vasoconstriction) of dexmedetomidine on vascular smooth muscle 2 receptors. That the increase in blood pressure was sustained throughout the dexmedetomidine infusion, whereas plasma dexmedetomidine concentrations remained stable, implies that vasoconstriction was not due to a transient increase in dexmedetomidine plasma levels, but to a sustained direct effect on the vascular smooth muscle cells. This hypothesis is further supported by our method of dexmedetomidine administration, which consisted of a computer-controlled infusion pump driven by the latest dexmedetomidine pharmacokinetic data, theoretically providing stable dexmedetomidine plasma concentrations. The time course of the rapid decrease (3–4 min) in HR we observed during the dexmedetomidine infusion is consistent with reflex bradycardia in response to the increase in blood pressure but is not consistent with the decrease in HR typically observed over 30–45 min secondary to the central sympatholytic effect with similar dexmedetomidine dosing (17).
Propofol relaxes vascular smooth muscle tone by reducing sympathetic nervous system activity (18), and a significant decrease in sympathetic nervous system activity may occur after the induction of anesthesia with propofol (19). Our ability to observe the peripheral vasoconstrictive effect of dexmedetomidine independent of significant central dexmedetomidine-induced sympatholytic effect may partly be due to a propofol-induced decrease in sympathetic nervous system tone and blood pressure.
Our study is limited by use of a single dexmedetomidine dose. Therefore, we cannot comment on the potential neuromuscular and vasoconstrictive effects of dexmedetomidine at smaller doses. We studied the effect of dexmedetomidine on rocuronium-induced neuromuscular relaxation. Thus, we cannot comment on the potential effects of dexmedetomidine on duration of neuromuscular block.
Because we do not have invasive blood pressure data before the induction of anesthesia, it is difficult to compare the blood pressure values during the dexmedetomidine infusion with those before the administration of propofol. However, the invasive SBP values during the dexmedetomidine infusion (maximum of 117 ± 10 mm Hg) were lower than the preanesthesia noninvasive blood pressure values (121 ± 9 mm Hg), which suggests that this dose of dexmedetomidine did not induce hypertension in our volunteers.
The technique of measuring finger blood volume and changes in blood volume is subject to its limitations. Anything that retards venous drainage from the site increases blood volume and reduces the transmitted light. Any changing pressure at the sensor site by touching or resting the fingertip on a surface also changes the blood volume and transmitted light path. However, our subjects were anesthetized, and we maintained the arm and hand in an optimal, constant position for 5 min before and 10 min after drug infusion.
Although statistically significant, the increase in rocuronium concentration and decrease in T1 during dexmedetomidine infusion are not clinically significant. A rocuronium concentration change of a similar magnitude at 90% neuromuscular block would increase the block by <3% (20).
At doses that induce peripheral vasoconstriction, dexmedetomidine may influence its own pharmacokinetics and that of other drugs. Whether this has implications for dosing of medications and is dependent on individual patient differences, baseline sympathetic tone, and responsiveness of peripheral 2 receptors will be studied in the future. Understanding and characterizing the peripheral vasoconstrictive effects of 2-agonists will allow better management and determination of drug dosing regimens to avoid potentially harmful hypertensive episodes.
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Acknowledgments |
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Supported by Abbott Laboratories, Inc. The authors do not consult for, accept honoraria from, or own stock or stock options in Abbott Laboratories, Inc.
We thank the subjects for volunteering their time.
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Footnotes |
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Presented in part at the annual meeting of the American Society of Anesthesiology, San Diego, CA, November 1997.
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References |
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