Intense noxious stimuli such as laryngoscopy and endotracheal intubation activate the sympathetic nervous system, inducing tachycardia and hypertension. Studies show that approximately 50% of patients with coronary artery disease experience episodes of myocardial ischaemia during intubation when no specific preventive measures are taken . Although multiple drugs have been used for this purpose [2,3], opioids seem to attenuate the haemodynamic changes induced by intubation most effectively. However, due to their potent analgesic effect and their synergistic interaction with the hypnotic and anxiolytic drugs commonly used during induction of anaesthesia, opioids may induce severe hypotension, especially in geriatric and ASA III-IV patients . Clonidine is an α2-adrenergic agonist with sympatholytic, analgesic and sedative effects that has been shown to attenuate the increase in arterial pressure and heart rate (HR) during endotracheal intubation [5,6] and to reduce the requirements of hypnotics . In recent years, several studies have reported that esmolol, a β1-adrenergic antagonist, reduces intraoperative anaesthetic requirements during balanced anaesthesia  and enhances the hypnotic component of inhalational anaesthetics .
In the present report we compared the effects of alfentanil, esmolol or clonidine administered by intravenous (i.v.) infusion on blood pressure (BP) and HR and the depth of hypnosis using the bispectral index (BIS) during induction of general anaesthesia. The results would help to establish the best drug regimen to be used in geriatric or hypovolaemic patients during induction of general anaesthesia.
After our institution's Human Ethics Committee approved the study protocol, written informed consent was obtained from 45 ASA I-III unselected, sequential patients scheduled for elective surgery under general anaesthesia. Patients were visited the night before surgery by an attending anaesthesiologist and assigned randomly to one of three groups, according to a predefined randomization list. Patients were given diazepam 5 mg sublingually the night before, and again 1 h before surgery. ASA I-III patients over 18 yr of age were eligible to participate. Exclusion criteria were a history of allergic reactions to any of the study drugs, advanced hepatic, renal, or cardiac dysfunction, intracardiac blocks, poorly controlled bronchial asthma, long-term administration of opioids, sedatives, or β-adrenoreceptor blocking agents, and gross obesity (> 150% of ideal body weight).
Monitoring of arterial pressure, HR, oxygen saturation (SPO2) and BIS (2000® electroencephalograph (EEG); Aspect Medical Systems, Natick, MA, USA) were continuously monitored when the patient arrived in the operating room. Each patient had a code number that indicated the assigned treatment group. The study drugs and dosages were alfentanil 3 μg kg−1 min−1, esmolol 1 mg kg−1 min−1 or clonidine 3 μg kg−1. The appropriate doses of the study drugs were diluted in 200 mL of saline 0.9% and infused over a period of 10 min. Both the patient and the investigator who was responsible for the induction of anaesthesia were unaware of the assigned drug.
At the end of the 10 min infusion, the patients were given oxygen to breathe by mask. After 1 min of oxygen, anaesthesia was induced with midazolam 2 mg followed by thiopental in a dose just sufficient to abolish the eyelash reflex. This end-point was achieved by giving bolus injections of thiopental 50 mg every 10 s (Fig. 1). Muscle relaxation was achieved with atracurium 0.5 mg kg−1. In the alfentanil and esmolol groups, the infusion of the study drug was maintained at the same rate during induction until completion of the study 3 min after endotracheal intubation, while in the clonidine group, the study drug was stopped after the 10 min infusion and a saline infusion was substituted.
The cardiovascular variables - mean arterial pressure (MAP) and HR - and BIS values were recorded at the following time points (Fig. 1): at arrival in the operating room (baseline), at the end of the study drug infusion (PREM), 1 min after midazolam (MID), 3 min after thiopental and atracurium (THP) and 1 and 3 min after endotracheal intubation (ETI-1 and ETI-3, respectively). The times of evaluation were selected to establish the cumulative effects of the drugs and the noxious stimuli on cardiovascular variables and the BIS index.
In the present study, ΔBIS and ΔMAP are defined as the difference between the values of BIS and MAP, respectively, at the time points ETI-1 and THP. They reflect or indicate the response to the noxious stimulus of ETI. Overall haemodynamic stability is assessed by the change in MAP from baseline (OT) to after intubation (ETI-1).
The results are expressed as mean and standard error of the mean (SEM). Qualitative data were evaluated by the χ2-test and quantitative parameters by one-way ANOVA. For each variable (MAP, HR and BIS), the differences between the treatment groups over time and their interaction were compared using a two-way ANOVA for repeated measurements. If an interaction was present, differences between groups were established by one-way ANOVA. For each variable and treatment group (alfentanil, esmolol and clonidine), the changes observed over the different times of evaluation (OT, PREM, MID, THP, ETI-1 and ETI-3) were established using a one-way ANOVA followed by the Student-Newman-Keuls test; in the Tables, significant differences between the values are indicated by different letters (a, b and c), while the same letter (a and a) indicates no significant differences between the two values. In all instances, P < 0.05 was considered significant.
Power analysis for ΔMAP and ΔBIS using the sample size of 15 patients per group showed that the β-error for detecting statistically significant differences in MAP in the range of 13-16 mmHg, and in BIS index values between 10 and 13 was 20% (power = 80%).
Forty-five patients aged 28-85 yr were enrolled in the study: 15 in the alfentanil group, 16 in the esmolol group and 14 in the clonidine group. The groups were comparable regarding biometric data and ASA distribution (Table 1). In all groups, thiopental requirements were within the normal range required for intubation, but patients in the esmolol group required 21% more thiopental than those in the other groups (one-way ANOVA; P < 0.014).
Table 2 shows MAP and HR registered at the different time points. Baseline values were similar in all groups, and HR remained unchanged throughout the study. Changes in MAP over time were evaluated by two-way ANOVA (time and treatment). The results demonstrated that the treatment had no significant effect, while the time of evaluation (P < 0.001) and the interaction of the two were significant (P < 0.001). The significant effect of the interaction is related to the lower values of MAP in the alfentanil group after thiopental administration (THP) and after intubation (ETI-1 and ETI-3) (P < 0.04).
None of the drugs alone had a significant effect on BP (PREM, Table 2). Midazolam reduced MAP below baseline values in the alfentanil and clonidine groups, but this was not significantly altered in the esmolol group. After thiopental, MAP decreased significantly from baseline by approximately 30% and 20% in patients who received alfentanil or esmolol, respectively, but none required BP support. The decrease in BP was only 9% in the patients treated with clonidine. Significant differences were observed between the study groups (P < 0.008, one-way ANOVA).
MAP was 15% lower than baseline (P < 0.05) immediately after intubation (ETI-1) in the alfentanil group, but 20% higher than baseline in the clonidine group (P < 0.05). The 7% increase in the esmolol group was not significant. Three minutes after intubation (ETI-3), MAP had not changed in patients receiving alfentanil or esmolol, but had decreased slightly (− 14%) in the clonidine group. One-way ANOVA showed significant differences between the groups of the study at time points ETI-1 (P < 0.001) and ETI-3 (P < 0.04).
Immediately after intubation (ETI-1), MAP increased similarly in all groups from pre-intubation values (THP). This increase was the same in all three groups: alfentanil 20 ± 4 mmHg; esmolol 32 ± 5 mmHg and clonidine 30 ± 6 mmHg (ANOVA; P < 0.21). Thus based on ΔMAP, all treatments had a similar attenuating effect on haemodynamic changes induced by intubation. If the results are considered overall one can infer that esmolol provided better haemodynamic stability than the other treatments.
BIS values were registered at the same time points as the cardiovascular variables. Baseline values were similar in all groups. Two-way ANOVA showed a significant effect of time (P < 0.001), but not of treatment or their interaction. The study drugs did not alter the BIS index in any of the study groups (PREM, Table 3, Fig. 2); indicating that they did not induce significant sedation. After midazolam, the BIS index did not change in the alfentanil or esmolol groups, but it decreased in the clonidine group by approximately 17% (P < 0.05). Following the injection of thiopental, the BIS index was significantly reduced in all groups, but the decrease was more prominent in the esmolol group (P < 0.02). The BIS index increased to a similar extent in all groups after ETI.
ΔBIS is the difference between the BIS index values obtained at the time points THP and ETI-1. It was significantly higher in the esmolol group than in the alfentanil or clonidine groups (one-way ANOVA; P < 0.002). The results are shown in Figure 2.
The present study evaluates and compares the effects of esmolol, clonidine and alfentanil as adjuvants to thiopental on haemodynamics and depth of anaesthesia during induction of anaesthesia and ETI. The drugs used in the present study have all been shown to have sedative effects [8,10,11] and enhance the effects of hypnotics such as thiopental and propofol. The study drugs were given by continuous infusion, since we wanted to prevent sudden haemodynamic changes that can occur when they are given as rapid injections . In the present investigation, we assessed the effects of the study drugs in order to determine an optimal induction protocol for elderly or critically ill patients. The mean age of our patients was approximately 50 yr, with a range from 28 to 85 yr.
After thiopental, MAP was significantly reduced (compared to baseline) in the alfentanil (31%) and esmolol (20%) groups, and was unaltered in the clonidine group (9%, non statistically significant); however the hypotension induced by alfentanil and esmolol was not clinically relevant and did not require pharmacological treatment. When MAP after intubation (ETI-1) was compared to basal values (OT), the alfentanil group showed a 15% decrease while MAP in the esmolol and clonidine groups increased by 7 and 20% respectively. Thus our results suggest that esmolol may provide better haemodynamic stability than either alfentanil or clonidine during induction of general anaesthesia. The highest increase of arterial pressure from baseline was observed in the clonidine group (20%). Although clonidine has been shown to have analgesic properties, acute administration can also induce vasoconstriction and this could explain the increase in MAP after ETI .
ETI caused a similar increase of MAP in all groups (24-33.3%) suggesting that all study drugs had similar attenuating effects on intubation-induced haemodynamic changes. ΔMAP was largest in the esmolol group with a 33.3% increase. Esmolol is reported to enhance the analgesic effects of opioids , but no analgesic effect has been reported when the drug is given alone. Thus, the lesser degree of analgesia in the groups of patients treated with esmolol could explain the large ΔMAP.
The standard dose of alfentanil for induction of anaesthesia lies between 30 and 50 μg kg−1. We used a similar dose in our study, but administered it by infusion over a period of 20 min (3 μg kg−1 min−1) . The dose and rate of infusion for esmolol (1 mg kg−1 min−1) were selected according to the doses used in children to treat hypertensive emergencies . Clonidine was infused at 3 μg kg−1 for 10 min before, but not during the induction of general anaesthesia. This dose has been shown to be effective to attenuate the stress response to ETI . However, we were concerned that during a continuous infusion of clonidine, a painful stimulus such as intubation could induce vasoconstriction with an increase in arterial pressure  and the higher clonidine dose could also cause excessive sedation in the postoperative period. Thus, after the 10 min infusion, clonidine was replaced by saline in our protocol. However, the rapid distribution (t(1/2)α = 10.8 ± 4.7 min) and long elimination half-life (t(1/2)β = 8.5 ± 0.9 h) of the clonidine ensured an adequate effect during ETI .
The initial infusion of alfentanil, clonidine, or esmolol before induction did not cause changes in arterial pressure, BIS index or oxygen saturation, a fact that could be related to the administration by continuous infusion, without a previous loading dose. All patients were awake but calm, and followed verbal commands. Thus, the study drugs did not induce clinically relevant adverse effects. A significant decrease of the BIS value of 17% from baseline (P < 0.03) was observed after the administration of midazolam in the clonidine group, suggesting that the sedative effects of these drugs could be more than additive . Thiopental administration reduced the BIS value in all groups; the more pronounced effect observed in the esmolol group could be related to the higher doses of thiopental required by these patients (P < 0.014). After ETI, all groups returned to a similar BIS value, which remained below those at which recall is unlikely (∼60). In clinical practice, depth of anaesthesia is the end result of the balance between the intensity of the painful stimulus and the concentrations of anaesthetic drugs (hypnotics and analgesics) at target sites in the central nervous system. In our study, since the stimulus induced by ETI was similar in all groups, the results suggest an interaction (synergy) between thiopental, alfentanil and clonidine, as shown by the lower requirements of the hypnotic in the presence of an adequate BIS value [17,18]. Patients receiving alfentanil or clonidine had similar ΔBIS values, which were significantly lower than those of the esmolol group (Fig. 2). One explanation could be that the analgesic properties of alfentanil or clonidine, not present in esmolol, might attenuate the variation of the BIS value after intubation. Iselin-Chaves and colleagues  demonstrated that the change in the BIS index following a painful stimulus can be reduced either by increasing the dose of the hypnotic or by giving opioids. However in our study, ΔBIS decreased only when an analgesic (opioid or α2-adrenergic agonist) was given, but not when larger doses of the hypnotic were administered.
Although the BIS index is mainly an indicator of hypnosis, it is well established that analgesia can modify hypnosis. The fact that the BIS index may vary in the presence of different intensities of noxious stimuli could be taken as an indirect indicator of the degree of analgesia . Thus in agreement with Guignard and colleagues , we suggest that during ETI variations in ΔBIS could reflect changes in the analgesic component of general anaesthesia. Several reports have confirmed that changes in the BIS index correlate with haemodynamic variables, mainly with MAP [20,21]. However, in the present report we showed that while patients in the alfentanil and clonidine groups had similar ΔBIS values, they exhibited different haemodynamic responses. This could be related to the fact that the drugs used in our study modify sympathetic activity (directly or indirectly), and thus alter the cardiovascular response to ETI.
In our study, the patients of the clonidine group had thiopental requirements and ΔBIS values similar to the patients receiving alfentanil. These results suggest that clonidine has analgesic effects, even if the drug was discontinued before beginning the i.v. induction. Thiopental requirements were similar in the alfentanil and clonidine groups, but were significantly higher (21%) in the esmolol group (P < 0.01). In our protocol, thiopental was administered slowly until the eyelash reflex was abolished, and the required dose of thiopental was recorded. We believe that, although this method is rather imprecise, the consistency of the results and the blinded nature of the protocol support the validity of the finding. In a previous investigation, Johansen and colleagues  showed that esmolol reduced the amount of propofol required to prevent response to skin incision in patients who had been premedicated with morphine. The discrepancy with our results could be related to differences in the protocol, since we used higher infusion rates of esmolol, and no opioids were given simultaneously. Thus, from our results we can conclude that esmolol as used in the present study does not have a thiopentalsparing effect. Similar doses of thiopental were required to abolish the eyelash reflex in the alfentanil and the clonidine groups, but their thiopental-sparing effect could not be assessed, since we did not include a control group receiving no premedication. Such a control group using midazolam plus thiopental without other adjuvants was considered unacceptable due to the tachycardia and hypertension we feared might occur.
In conclusion, the study shows that the infusion of alfentanil, esmolol or clonidine given before induction of anaesthesia with thiopental did not have any effect on cardiovascular variables, BIS index or the oxygen saturation. However, the dose of thiopental required to abolish the eyelash reflex was lower in the alfentanil and clonidine groups. All patients had an adequate level of hypnosis and after ETI the ΔBIS was lower in patients treated with alfentanil or clonidine, a fact that could be evidence of their analgesic effects. Thiopental caused MAP to decrease by 30% from baseline in the alfentanil group, a fact that should be taken into account in elderly or critically ill patients. All study drugs had a similar effect on the haemodynamic response to ETI as indicated by ΔMAP, but patients treated with esmolol showed better overall haemodynamic stability. Lowering the dose of alfentanil might reduce the hypotension seen with this drug. In addition, combinations of alfentanil with doses of clonidine or esmolol lower than those used in the present study might provide better haemodynamic conditions during ETI. Further experiments will be required to validate these protocols.
This work was partially supported by a grants from the Generalitat de Catalunya 2001SGR00409, Barcelona, and Instituto de Salud Carlos III, # C03/06, Madrid, Spain. Results were initially presented at the ESA Annual Meeting held in Nice, France, April 6-9, 2002.
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