Kulka, Peter J. MD; Tryba, Michael MD; Zenz, Michael MD
Clonidine and other alpha2-adrenoceptor agonists are under intense investigation as an adjunct to anesthesia . These drugs reduce anesthetic requirements, attenuate adrenergic, hormonal, and hemodynamic stress responses to surgery, reduce anxiety, and lead to sedation. Several studies confirm that reduction of stress responses in patients undergoing cardiac surgery improves postoperative morbidity [2-5]. However, little information is available about the use of clonidine in this special group of patients. This is especially true for the intravenous (IV) route of administration which provides the advantage of easier control of the pharmacodynamic drug effects. Data concerning the appropriate dose of clonidine vary considerably between 0.625 micro gram/kg and 600 micro gram [6-8]. No dose-response studies of different clonidine doses in coronary artery bypass grafting (CABG) patients are available. Therefore, this study was designed to evaluate dose-response effects of patients' reactions to stressful stimuli after different IV doses of clonidine.
After approval of the local ethics committee and after obtaining informed written consent, 48 patients scheduled to undergo CABG surgery were randomly assigned in a double-blind manner to one of four groups. One group received placebo (Group C0) and served as control. The other groups received IV clonidine in a dose of 2, 4, or 6 micro gram/kg body weight (Groups C2, C4, and C6, respectively). Patients who were extremely obese, >75 yr of age, with neurologic or severe metabolic diseases, hypotension, impaired myocardial function (ejection fraction <45%, disturbances of wall motion), main stem coronary artery stenoses, or unstable angina were excluded from the study. Patients scheduled for emergency or reoperations were also excluded.
In all patients anesthesia was performed by the same experienced anesthesiologist. The observation period started with the administration of clonidine or placebo and included the induction of anesthesia with special regard to the patients' reactions to laryngoscopy and tracheal intubation.
Patients were premedicated with 2 mg flunitrazepam per os the evening prior to the operation and received another 1 mg approximately 1 h before departure to the anesthesia induction room. The left radial artery (G18) and a forearm vein (G14) were cannulated. A flow-directed pulmonary artery catheter was placed via the right internal jugular vein. All painful procedures were performed under local anesthesia. Fifteen minutes after the end of preparation, clonidine or placebo diluted in 100 mL NaCl 0.9% was infused IV over a 15-min period. During the preinduction period pulse oximetry was measured continuously. All patients were prepared by an anesthesiologist not involved in the study.
Fifteen minutes after the end of the infusion of the test drug, anesthesia was induced by administration of etomidate 0.3 mg/kg, fentanyl 5-7 micro gram/kg, and pancuronium 0.1 mg/kg. The patients' tracheas were intubated; gastric tubes and oral temperature probes were inserted. The entire intubation procedure had to be performed within 120 s.
Increases of mean arterial pressure (MAP) > or=to100 mm Hg, increases of heart rate (HR) > or=to100 bpm, and signs of inadequate anesthesia were defined as criteria for intervention. Intervention consisted of bolus administration of 5 mg etomidate. If the dose proved to be ineffective after 30 s another dose of etomidate was administered combined with 0.25 mg fentanyl.
Sedation was scored prior to and 15 min after the end of clonidine or placebo infusion according to a scale: 0 = patient awake; 1 = patient sedated, but awake; 2 = patient asleep, reacting immediately to verbal command; 3 = patient asleep, reacting to verbal command with delay; 4 = patient asleep, not reacting to verbal command.
HR, MAP, pulmonary artery pressure (PAP), and central venous pressure were measured continuously and recorded every minute (Hewlett Packard HP M 1810 A). At predefined intervals cardiac output and pulmonary capillary wedge pressure (PCWP) were measured. From these data total peripheral resistance (TPR), pulmonary vascular resistance, cardiac index (CI), and stroke volume index were calculated.
Times for hemodynamic measurement were defined as follows: T0 = baseline, 15 min after the end of preparation for induction of anesthesia, prior to the start of infusion of clonidine or placebo; T1 = immediately after the infusion of clonidine or placebo; T2 = 15 min after the end of clonidine or placebo infusion; T3 = after the injection of the induction drugs; T4 = 30 s after the start of laryngoscopy; T5 = 60 s after the end of laryngoscopy; T6 = 5 min after the end of laryngoscopy. At T0, T2, and T4, arterial blood samples were collected for determination of catecholamine plasma levels by high-pressure liquid chromatography.
For intergroup comparison analysis of variance was performed. A two-tailed paired t-test was used (P < 0.05) for comparison of variables with baseline values. Fisher's exact test was used for the statistical analysis of the number of interventions.
Demographic data were similar in all groups Table 1. No patient was excluded from the study. Baseline hemodynamic data, catecholamine plasma levels, and sedation scores were not different. During and after the infusion of clonidine all patients remained arousable Table 2. In patients treated with placebo or clonidine 2 micro gram/kg there was a trend (P = not significant) to higher sedation scores. Significant increases of sedation scores were observed in patients in the C4 and C6 groups.
Within a few minutes after the start of clonidine infusion, MAP increased slightly but significantly in a dose-related manner for a period of 1-3 min Figure 1. Maximum increases ranged between 7 (Group C0) and 12 (Group C6) mm Hg Figure 2. During the further course of infusion HR, MAP, PAP, PCWP and CI decreased in all clonidine groups compared with placebo. Changes of these hemodynamic variables were dose-related for Groups C0-C4. Increasing the dose to 6 micro gram/kg did not further enhance the effect. On an average, HR decreased by 10-15 bpm and MAP by approximately 20-25 mm Hg. Maximum HR decreases were 14 bpm in Group C0, 22 bpm in Group C2, 29 bpm in Group C4, and 41 bpm in Group C6. Maximum decreases of MAP were 14 mm Hg in Group C0, 31 mm Hg in Group C2, 38 mm Hg in Group C4, and 47 mm Hg in Group C6. The lowest HR was 44 bpm (Group C6). The lowest MAP was 67 mm Hg in Group C4 and 69 mm Hg in Group C6.
After induction of anesthesia, HR decreased slightly in all groups Figure 1. During laryngoscopy and intubation HR increased significantly compared with baseline values in placebo-treated patients from 73 +/- 8 to 80 +/- 11 bpm. In one patient of the C0 group, 96 bpm were noted and in one patient of the C2 group, 116 bpm were recorded. In Groups C4 and C6 tachycardia was attenuated in all patients. During intubation mean HR in Groups C4 (67 +/- 12 bpm) and C6 (67 +/- 12 bpm) was significantly lower compared with placebo (80 +/- 11 bpm).
After administration of the induction drugs MAP decreased in all groups between 25 and 30 mm Hg below baseline values Figure 1. The maximum decreases of MAP were almost identical in all groups (53, 44, 51, and 54 mm Hg in Groups C0 to C6, respectively). No differences were observed between the groups. During laryngoscopy and intubation MAP increased significantly to 120 +/- 15 mm Hg in the placebo group. In two placebo patients values as high as 150 mm Hg were observed Figure 3. The blood pressure response to laryngoscopy and intubation was attenuated in all clonidine groups. Nevertheless, in two patients in Group C2, maximal values of 150 mm Hg occurred whereas in Groups C4 and C6, MAP reached 120 mm Hg in two patients.
After administration of the induction drugs CI decreased in all groups in a dose-related manner: 2.5 L centered dot min-1 centered dot m-2 (C0); 2.35 L centered dot min-1 centered dot m-2 (C2); 2.13 L centered dot min (-1) centered dot m-2 (C4); and 2.03 L centered dot min-1 centered dot m-2 (C6) Figure 1. However, no differences were observed after completion of laryngoscopy. TPR was not different between the groups Figure 1. PAP and PCWP significantly increased during laryngoscopy and intubation in the C0 groups compared with Groups C4 and C6, to 24 +/- 7 mm Hg and 12 +/- 3 mm Hg, respectively. Both variables were lowest in the C6 group Figure 1.
Epinephrine plasma levels were not influenced by clonidine or placebo. However, after induction of anesthesia epinephrine plasma levels decreased in all groups Table 3. After infusion of clonidine, norepinephrine plasma levels significantly decreased in the C4 and C6 groups compared with baseline values and compared with placebo. During laryngoscopy and intubation, norepinephrine concentrations remained suppressed in the C4 and C6 groups.
Additional bolus doses of etomidate and fentanyl were required more often in patients treated with placebo and clonidine 2 micro gram/kg compared with patients in Groups C4 and C6 Table 4. In the latter groups the number of additional bolus administrations was almost identical. Increases of MAP were observed in six patients in the C0 group, five patients in the C2 group, and one patient in the C4 group that led to 9, 5, and 2 therapeutic interventions, respectively. No patient sustained bradycardia requiring treatment. Throughout the study no other clonidine-related adverse effects were observed.
Adrenergic reactions frequently occur in association with anesthesia and surgery . In patients undergoing CABG surgery, tachycardia and hypertension increase the risk of perioperative myocardial ischemia and infarction [3,5]. Laryngoscopy and endotracheal intubation are stressful stimuli resulting in increased catecholamine blood levels, tachycardia, and hypertension . alpha2-Adrenergic drugs, such as clonidine or dexmedetomidine, attenuate these potentially harmful cardiovascular reactions during induction of anesthesia.
In noncardiac ASA physical status I patients, Carabine et al.  demonstrated that 0.625 and 1.25 micro gram/kg clonidine IV 15 min prior to induction of anesthesia attenuates the pressor response to laryngoscopy and intubation. In contrast, Wright et al.  observed in noncardiac ASA physical status I patients that under almost identical conditions 1.25 micro gram/kg clonidine IV was not effective. Furthermore, 4 micro gram/kg clonidine orally in patients undergoing general surgery was not sufficient to blunt the reaction to laryngoscopies that exceed 15 s duration .
The maximum dose of clonidine is limited by its action at peripheral alpha2-adrenoceptors . In dogs IV doses of more than 3 micro gram/kg clonidine increased arterial blood pressure and peripheral resistance and decreased cardiac output .
Since, in most human studies, 4 micro gram/kg clonidine was applied without relevant signs of peripheral alpha stimulation, we chose this dose as mid-dose. Because our study was designed to evaluate the effect of different clonidine doses in patients endangered by the deleterious sequelae of stress-induced hemodynamic reactions, an additional premedication was obligatory. This implies the disadvantage that our data reflect the combined effects of flunitrazepam premedication, clonidine, and the different anesthetics. However, this study design has the advantage that the results can be related directly to clinical practice in CABG patients.
As bioavailability after oral intake varies between 70% and 90%, we chose the IV route of administration to relate pharmacodynamic effects more precisely to a certain dose [15,16]. The IV infusion of clonidine was demonstrated to be safe in our patients. In early investigations the fast injection of clonidine increases blood pressure and, as a consequence, decreases CI . These effects can be attributed to peripheral alpha2 stimulation by high clonidine plasma levels. Despite the lack of adverse side effects, even this slow IV infusion obviously affected peripheral alpha2-adrenoceptors because blood pressure increased slightly but significantly during the 5 min after the start of infusion. However, the resulting blood pressure increase of 10 mm Hg for 1 or 2 min is clinically irrelevant Figure 2. During the further course of our study we did not observe any hemodynamic effects attributable to peripheral alpha stimulation, indicating that in humans receiving up to 6 micro gram/kg clonidine the centrally mediated depressor effects are predominant.
After the infusion of clonidine (T1-2) changes of HR, MAP, PAP, and CI were dose-related up to a dose of 4 micro gram/kg. Increasing the dose to 6 micro gram/kg did not further enhance the hemodynamic effects. We did not observe a marked decrease of TPR, which is most probably due to the fact that TPR was already low at baseline. MAP decreased to the same level in all groups after the administration of the induction drugs Figure 3. This indicates that the additional administration of clonidine did not enhance the maximal decrease of blood pressure after induction of anesthesia.
Our study confirms several others which observed no differences in blood pressure between placebo- and clonidine-treated patients after anesthesia induction with etomidate, sufentanil, fentanyl, or benzodiazepines [8,12,18,19].
Carabine et al.  using etomidate, isoflurane, and nitrous oxide as induction drugs described a "trend for a decrease in systolic pressure" after an oral dose of 300 micro gram clonidine. This and the fact that "two patients required IV fluids as treatment of hypotension in the recovery ward" led to the recommendation not to use a dose of 300 micro gram clonidine for premedication. However, we believe that the cause of hypotension after clonidine is usually hypovolemia, unmasked by the reduction of sympathetic tone. This can be treated easily by the administration of IV fluids providing both normotonia and normovolemia in the postoperative period.
In patients of the C0 group a significant increase of MAP occurred during laryngoscopy and intubation Figure 3. Mean values of MAP may lead to the impression that even 2 micro gram/kg clonidine effectively attenuated this reaction Figure 1. However, looking upon our data as percentiles Figure 3 demonstrates that after 2 micro gram/kg clonidine, an unacceptable increase of MAP to laryngoscopy still occurred in some patients. In contrast, MAP values > 110 mm Hg were not observed in any patient in Groups C4 or C6.
Carabine et al.  suggested that cardiovascular reactions caused by short-lasting laryngoscopies can be attenuated with very low doses of clonidine. However, after analyzing their data it became obvious that mean MAP increased to more than 100 mm Hg and mean HR to 110 bpm. As no further information is given, the number of patients who had extreme increases of blood pressure and HR remains questionable. There is evidence that even the administration of 0.1 mg fentanyl usually can attenuate the pressor response to intubation . However, in many individuals this dose will prove insufficient. Our study demonstrates that even a five times greater dose of fentanyl, together with 2 micro gram/kg clonidine, was poorly effective. On the other hand, 4 micro gram/kg clonidine attenuated not only the average response to laryngoscopy but in all individuals as well.
Catecholamine plasma levels reflect sympathetic activity [8,9,22]. A dose of 300 micro gram clonidine per os, which is equivalent to approximately 4 micro gram/kg IV, or higher doses have been shown to reduce sympathetic activity [19,22-26]. We were able to confirm this finding. After the infusion of 4 and 6 micro gram/kg clonidine, norepinephrine plasma levels decreased significantly and remained suppressed during intubation whereas the infusion of clonidine 2 micro gram/kg was not more effective than placebo. Our data show that administration of 4 micro gram/kg clonidine significantly blunts catecholamine release and that higher clonidine doses were not more effective.
The number of interventions was significantly reduced in patients treated with 4 and 6 micro gram/kg clonidine. The difference between Groups C4 and C6 was negligible. This finding again indicates that increasing the dose to 6 micro gram/kg does not lead to a clinically relevant increase of efficacy.
In summary, we have shown that the IV administration of clonidine up to a dose of 6 micro gram/kg proved to be safe even in CABG patients. The effects on hemodynamic variables, sedation, catecholamine plasma levels, and anesthetic requirements were dose-related up to a dose of 4 micro gram/kg. Increasing the dose did not further enhance efficacy.
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