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The Effects of Clonidine on Desflurane-Mediated Sympathoexcitation in Humans

Devcic, Ante MD; Muzi, Michael MD; Ebert, Thomas J. MD, PhD

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Desflurane is a new inhaled anesthetic which has been associated with a more frequent incidence of tachycardia, hypertension, and myocardial ischemia when compared to other anesthetics [1-3]. For example, a previous study from our laboratory demonstrated a marked activation of the sympathetic nervous system during the initial titration of desflurane into the inspired gas after intravenous induction of anesthesia [1]. This sympathetic activation led to heart rates (HRs) exceeding 100 bpm and substantial increases in arterial blood pressure. Similar responses were triggered when the anesthetic level was rapidly deepened from 1.0 to 1.5 minimum alveolar anesthetic concentration (MAC). Thus, the morbidity associated with the administration of desflurane could be improved if methods to attenuate these hyperdynamic responses were described.

The present study examined the effect of clonidine pretreatment on the hemodynamic and sympathetic nervous system responses to desflurane. The alpha2 agonists have been extensively studied and, as anesthetic adjuvants, they cause sedation, reduce the hemodynamic response to laryngoscopy and endotracheal intubation, and result in better perioperative hemodynamic stability with reduced requirements for other anesthetics [4]. Because the tachycardia, hypertension, and myocardial ischemia observed during desflurane administration have been attributed to the activation of the sympathetic nervous system, the possibility that pretreatment of patients undergoing desflurane anesthesia with clonidine might attenuate or abolish these sympathoexcitatory responses seemed promising.


The protocol was approved by our Human Research Reviow Committee, and informed consent was obtained from 19 young (20-31 yr) male volunteers who were free of systemic illness, were not receiving medications or taking drugs, had fasted for at least 12 h prior to testing, and were studied supine in a quiet, warm room. HR was monitored from leads II and V5 of the electrocardiogram. A 20-gauge catheter was inserted in the right radial artery for continuous mean blood pressure (MAP) measurements. An 18-gauge catheter was inserted into a forearm vein and 7 mL/kg of saline was administered before the initiation of the study. An 18-gauge, 5-in, catheter was inserted into the right jugular vein and advanced into the superior vena cava to monitor central venous pressure (CVP).

Forearm blood flow was calculated by Hg-in-Silastic strain gauge plethysmography. A double-stranded strain gauge was wrapped around the forearm at the area of greatest circumference just distal to the elbow. The arm was raised above heart level and a blood pressure cuff wrapped around the upper arm was used to produce intermittent venous outflow obstruction by inflating the cuff to 60 mm Hg. The venous outflow from the hand was occluded with a second cuff wrapped around the wrist. Forearm vascular resistance (FVR) was calculated as the ratio of MAP to forearm blood flow.

The right leg was slightly raised, cushioned, and passively rotated toward the midline to expose the area of the peroneal nerve where it passes under the head of the fibula on the lateral aspect of the leg, just distal to the knee. Initially, the location of the nerve was mapped by using an external stimulator connected to a blunt probe applied to the skin surface. The skin was then cleansed and two epoxy-coated, tungsten needles with exposed tips were inserted through the skin. One needle was placed in the region near the peroneal nerve and the second needle was used to directly record from the peroneal nerve. A ground electrode was placed nearby on the upper leg. The peroneal nerve was located by repeatedly advancing and withdrawing the needle under the skin while applying a small electrical current to the needle (0.2 mA, 9V, 1 Hz). When the needle reached the nerve, a pulsing parasthesia was felt by the volunteer if a nerve fascicle supplying skin was entered, whereas a distinct muscular contraction was noted if a nerve fascicle directed to skeletal muscle was entered. For the purpose of this study, skin nerves were excluded because they regulate only approximately 4% of the cardiac output, are not under baroreceptor control, and have mixed effector sites (skin blood flow, pseudomotor and piloerector muscles). Once a muscle contraction was observed, the stimulator was halted and the signal was amplified 100,000 times after filtering and cancellation of signals common to both needles (e.g., noise and artifact). Characteristic, spontaneous bursts of sympathetic neural activity were sought by subtle advancement or withdrawal of the needle within the muscle nerve fascicle. Once an acceptable recording was obtained, the subject remained relaxed and quiet with a completely immobile leg to avoid altering the location of the needle within the nerve. Characteristic sympathetic nerve activity (SNA) directed to skeletal muscle blood vessels demonstrated spontaneous and pulse-synchronous groupings that were augmented during Phases II and III of Valsalva's maneuver and during prolonged breath holding. Neural activity was not augmented by startle maneuvers or painful stimuli that are common activators of skin sympathetic activity.

Once an acceptable sympathetic recording was obtained, a 10-min quiet rest period was observed followed by blood sampling for baseline blood gas and collection of a 5-min sample of control hemodynamic data and muscle SNA. Volunteers randomly received 0.3 mg oral clonidine (n = 9) or placebo (n = 10) pretreatment and were then asked to rest quietly for 60 min. Neurocirculatory recordings and blood sampling were then repeated to determine the effects of clonidine. After 5 min of 100% oxygen administration by face mask, a priming dose of vecuronium (0.01 mg/kg) was given followed 2 min later by 2.5 mg/kg of propofol and 0.15 mg/kg of vecuronium intravenously (IV). Ventilation was controlled by mask without an oral airway. Exactly 2 min after propofol administration (75 min after clonidine or placebo), the desflurane vaporizer was activated at a setting of 3.6% (0.5 MAC). In the two subsequent 1-min periods, the vaporizer was increased to 7.2% (1.0 MAC) followed by 11% (1.5 MAC), while mask ventilation continued and end-tidal CO2 concentrations were maintained at conscious baseline levels. Desflurane at 11% via a mask was continued for 7 min, the trachea was intubated, the desflurane concentration was decreased to 5.4% (0.75 MAC), and ventilation was controlled to maintain end-tidal CO2 at the awake level. FVR data were not included in the data collection during the induction period because the direct effects of propofol and desflurane on the arterial vasculature would have made data interpretation strained.

After 20 min (30 min from propofol induction), 0.75 MAC steady-state data were collected. After the steady-state readings, hemodynamic and muscle SNA responses were recorded during the first 5 min after increasing the vaporizer from 5.4% to 11% desflurane. Fresh gas flow was 6 L/min. An over-pressure paradigm, i.e., advancing the vaporizer beyond the desired concentration to increase the speed of the transition, was not used. The steady-state responses at 1.5 MAC were recorded 10 min after achieving an end-tidal concentration of 11%. The concentrations of the inspired and expired. CO2 and desflurane were monitored continuously. End-tidal CO2 concentrations were maintained constant throughout the experiment and subsequently confirmed by arterial blood gas analysis at each steady-state measurement period. Neuromuscular function was evaluated by train-of-four stimulation at the ulnar nerve. At the completion of the experimental session, neuromuscular block was reversed with IV glycopyrrolate and neostigmine, the desflurane was discontinued, and the time to home discharge from the recovery area was recorded by an assistant who was blinded to the experimental treatment. Discharge criteria included stable vital signs, ease of arousability, ability to sit and visually focus without symptoms of nausea, and ability to ambulate with a normal gait.

Consecutive hemodynamic and neural measurements were compared with analysis of variance for repeated measures with Bonferroni correction. Specific time points were compared between groups with Dunnett's t-tests. Probability values less than 0.05 were considered sufficient to reject the null hypothesis.


There were no differences in age, height, weight, or health status of the young subjects randomized to receive either placebo or clonidine. Neurocirculatory recordings at conscious baseline revealed no differences between groups Table 1. The administration of clonidine followed by a 60-min absorption period resulted in significant decreases in SNA, MAP, CVP, and FVR, but did not significantly alter resting HR Table 1. Neurocirculatory responses recorded 2 min after the IV administration of 2.5 mg/kg of propofol demonstrated significant increases in HR (from the clonidine baseline) and further decreases in MAP and SNA. The magnitude of change in response to propofol was not different between treatment groups except for a significantly larger decrease in MAP in the clonidine group after propofol administration Table 1. Positive pressure ventilation by mask contributed to the increases in the CVP noted after propofol administration.

Table 1
Table 1:
Neurocirculatory Responses to Clonidine or Placebo and Propofol Induction

Responses to the administration of desflurane in three incremental steps beginning 2 min after the administration of propofol are shown in Figure 1. The first 5 min of desflurane administration were associated with significant increases in HR, MAP, and SNA in both treatment groups. Although HR and MAP responses in the clonidine-pretreated group at comparable time points were, in general, less than the placebo-treated group, the majority of this difference could be accounted for by the effects of propofol. The peak changes from the propofol baseline in response to the initial administration of desflurane are shown in Table 2. Clonidine did not significantly alter the maximum hemodynamic responses to desflurane. CVP showed a progressive but gradual increase in the placebo-treated group and this change was significant over the 10-min induction period. A similar CVP response was noted in the clonidine-pretreated subjects. The SNA increases, triggered by desflurane, were not significantly attenuated by the pretreatment with clonidine.

Figure 1
Figure 1:
Neurocirculatory responses recorded during the initial administration of desflurane beginning 2 min after anesthetic induction with propofol. Desflurane triggered significant increases in all variables in both treatment groups. The absolute level of heart rate (HR) and mean arterial pressure (MAP) in the clonidine pretreated group, in general, was lower than in the placebo-treated groups. However, the response trends triggered by desflurane for HR, MAP, central venous pressure, and sympathetic nerve activity did not differ (nonsignificant interaction by analysis of variance). All variables in each treatment group were significantly changed by desflurane over time compared to conscious baseline. *P < 0.05 vs placebo. Total activity = (burst frequency centered dot mean burst amplitude [mu V])/100 cardiac cycles.
Table 2
Table 2:
Peak Responses to Desflurane at Induction of Anesthesia

In both groups, increasing steady-state concentrations of desflurane resulted in progressively decreasing MAP and increasing HR and CVP. There were no changes in SNA at 5.4% desflurane but significant increases at steady-state 11% desflurane Figure 2. Although FVR decreased from conscious baseline at 5.4% desflurane, there was no further decrease at 11% desflurane. This response is best explained by counter-opposing effects of a more potent direct vasodilation coincident with a heightened SNA response at 11% desflurane. Clonidine did not alter any of the neurocirculatory responses recorded at the two steady-state concentrations of desflurane.

Figure 2
Figure 2:
Responses at conscious baseline and during steady-state periods of desflurane administration at either 5.4% (0.75 minimum alveolar anesthetic concentration [MAC]) or 11% (1.5 MAC). *Significant change from conscious baseline (P < 0.05); dagger significant change from 5.4% (P < 0.05). Total activity = (burst frequency centered dot mean burst amplitude [mu V])/100 cardiac cycles.

The neurocirculatory responses recorded during the first 5 min after advancing the desflurane vaporizer from 5.4% to 11% are demonstrated in Figure 3. Clonidine attenuated the increases in HR and MAP associated with this stimulating event, as demonstrated by the significant interaction term in the analysis of variance. There were no differences in SNA, CVP, or FVR between the clonidine- and placebo-treatment groups.

Figure 3
Figure 3:
Transition responses recorded during the first 5 min after advancing the desflurane vaporizer from 5.4% to 11%. In the placebo group, there were significant increases in all variables measured during this 5-min sampling period. Pretreatment with clonidine attenuated the increases in heart rate and mean arterial pressure as noted by a significant interaction term in the analysis of variance (dagger P < 0.05), *P < 0.05 vs placebo. Total activity = (burst frequency centered dot mean burst amplitude [mu V])/100 cardiac cycles.

The time to discharge in placebo-treated subjects was 45 +/- 3 min whereas the time to discharge in the clonidine-treated subjects was 105 +/- 6 min (P < 0.05 vs placebo). The majority of the discharge delay was related to excessive somnolence.


The present study explored the effect of clonidine pretreatment on the sympathoexcitatory responses elicited by desflurane anesthesia. The major findings of this study are: 1) clonidine significantly reduced the tachycardia and hypertension triggered by the initial administration of desflurane into the inspired gas and reduced similar responses elicited by the rapid increase in the inspired desflurane concentration from 5.4% to 11%; 2) despite the ability of clonidine to reduce basal levels of SNA prior to induction of anesthesia, it did not significantly attenuate the activation of muscle SNA provoked by desflurane administration; 3) clonidine pretreatment did not result in excessive or unfavorable reductions in blood pressure during steady-state periods of desflurane administration; and 4) clonidine administration led to a prolongation in the time to discharge from the anesthesia recovery area.

In a recently published study from our laboratory, we demonstrated a consistent and profound activation of the sympathetic nervous system in healthy human volunteers anesthetized with desflurane [1]. Introduction of desflurane into the inspired gas after thiopental induction of anesthesia resulted in marked sympathetic activation that led to hypertension and tachycardia. There was frequent reddening of the face, tearing, and mild upper airway obstruction [1]. A quantitatively similar hemodynamic response mediated by the sympathetic nervous system was observed during the rapid increase of the desflurane concentration from 7.2% to 11%. The placebo-treated subjects in the present study demonstrated responses consistent with this earlier work, but there appeared to be a 1-2 min delay in the activation of the sympathetic nervous system. This difference may be a result of the use of propofol (versus thiopental) in the present study since we have previously observed a marked sympathoinhibition after the administration of propofol [5].

Resting MAP and SNA were reduced 60 min after the oral administration of 0.3 mg clonidine. Subjects demonstrated moderate sedation and consistently reported a dry mouth. The alpha2 agonists have well known properties that have proven to be quite beneficial in anesthesia. As a premedicant, they cause sedation and anhydrosis, and in many cases, decrease systemic blood pressure and HR [4,6]. Peak plasma concentrations of clonidine are achieved 1-3 h after an oral dose and the elimination half-life ranges from 6-12 h [6]. Maximum hemodynamic changes correspond to the peak plasma concentrations of clonidine [6]. After pretreatment with clonidine, the tachycardia and hypertension associated with laryngoscopy and endotracheal intubation are attenuated, and clonidine appears to be more effective in this attenuation than the combination of lidocaine (1 mg/kg) and fentanyl (2 micro gram/kg) [7]. Interestingly, oral clonidine (5 micro gram/kg) has been shown to be effective in blunting the hemodynamic response to a brief 15-s laryngoscopy but was inadequate in blunting the stress response to a more prolonged 45-s laryngoscopy [8]. These data may explain findings in the present study in which clonidine delayed and reduced the hemodynamic responses to desflurane, but did not abolish them. We have previously documented that oral clonidine reduces but does not abolish the sympathetic responses to the cold pressor test and brief periods of hypotension [9].

After clonidine or placebo pretreatment, the induction of anesthesia with propofol resulted in a near complete inhibition of SNA and concomitant reduction in MAP. This response did not differ between the treatment groups. In the placebo-treated individuals, the administration of propofol resulted in a 10-bpm increase in HR, which may have been due to either direct effects of propofol on the SA node or parasympathetic withdrawal mediated through baroreflex mechanisms (in response to the hypotension). Although sympathoinhibition probably accounts for a major part of the hypotensive response to propofol, we also have shown that propofol has direct effects that relax arterial and venous smooth muscle [10].

The gradual titration of desflurane into the inspired anesthetic gas concentration beginning several minutes after propofol administration resulted in significant increases in SNA associated with increases in MAP and HR. As mentioned previously, it is likely that the sympathetic nervous system is not solely responsible for the HR increase because tachycardia occurred at a time when SNA was still reduced due to propofol. Of interest were the effects of clonidine on the sympathetic activation triggered by desflurane. Although there was a tendency for a reduction in SNA, at no time was it significantly different from the placebo-treated individuals. Despite this lack of difference, there was an attenuation of the HR increases mediated by desflurane and this may account for the reduced MAP response. The reduced HR response despite a fairly well preserved sympathetic activation may be due to a vagomimetic effect of clonidine [4]. These data also indicate that peripherally recorded SNA may have little relationship to cardiac SNA. It is well known that sympathetic outflow is not uniform and shows a high degree of differentiation to the various vascular beds [11,12].

The sympathetic activation and concomitant increases in HR and MAP that occurred when acutely increasing the inspired concentration of desflurane from 5.4% to 11% were consistent with our previous observations [1]. Clonidine modestly reduced the HR and MAP responses to this event, but, similar to the induction period, clonidine did not reduce the sympathetic nerve activation. The explanation for this finding remains unclear.

During the two steady-state periods, increasing concentrations of desflurane resulted in decreasing blood pressure. This effect was not enhanced in the group pretreated with clonidine. SNA was significantly higher during 11% desflurane than 5.4% desflurane and clonidine did not significantly alter this activation. The trigger for this activation is unknown at present but may be mediated through the baroreflex response to the lower MAP observed at higher MAC of desflurane. It also could be centrally mediated by an as yet undescribed property of desflurane that activates the sympathetic nervous system. Consistent with either mechanism of sympathetic activation, HRs were higher during 11% desflurane than at 5.4%.

We [13] and others [3,14] have demonstrated that rapid increases in the inspired concentration of isoflurane from 1.3% to 5% trigger increases in HR, MAP, and SNA. This finding suggests the possibility that desflurane and its parent compound, isoflurane, have similar properties at higher concentrations. Again, the mechanism triggering this response currently is unknown, but could be due to the airway irritant properties of these two anesthetics. Since one of the major goals of anesthesia is the attenuation of excessive autonomic activation triggered by laryngoscopy, intubation, and surgical stimulation, it would seem that these responses to desflurane are unwanted, confusing, and potentially dangerous in patients with underlying cardiovascular or neurologic disease. The present study suggests that clonidine premedication may be useful in attenuating the tachycardia and hypertension triggered by the administration of desflurane. One limitation of this approach is our observation that the time to patient discharge from the recovery room was prolonged by 60 min in the group pretreated with clonidine. This delay may be an undesirable side effect in the ambulatory surgery setting when expedient discharge of patients after their anesthesia and surgery is desired. However, one needs to consider that clonidine has antinociceptive properties [4] and that, had our subjects undergone a surgical procedure, the potential reduction in postoperative pain with clonidine pretreatment may have hastened discharge compared to placebo-treated patients.


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