Anesth Analg 1999;89:843
© 1999 International Anesthesia Research Society
CARDIOVASCULAR ANESTHESIA
Hemodynamic Responses Induced by Dopamine and Dobutamine in Anesthetized Patients Premedicated with Clonidine
Hiroto Ohata, MD,
Hiroki Iida, MD,
Yukinaga Watanabe, MD, and
Shuji Dohi, MD
Department of Anesthesiology & Critical Care Medicine, Gifu University School of Medicine, Gifu City, Japan
Address correspondence and reprint requests to Hiroki Iida, MD, Department of Anesthesiology & Critical Care Medicine, Gifu University School of Medicine, Gifu City, Gifu 500-8705, Japan. Address e-mail to iida{at}cc.gifu-u.ac.jp
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Abstract
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To test the hypothesis that the pharmacological effects of dopamine (DOA) and dobutamine (DOB) are altered when there is inhibition of the release of norepinephrine from nerve endings, we examined the hemodynamic responses to DOA and DOB in anesthetized patients premedicated with oral clonidine. Seventy adult patients were assigned to one of two groups (oral premedication with clonidine 5 µg/kg or no premedication). After the induction of general anesthesia, heart rate and systemic blood pressure (BP) were measured for 10 min after each of five IV infusions (3 and 5 µg · kg-1 · min-1 of DOA; 0.5, 1, and 3 µg · kg-1 · min-1 of DOB) in a randomized, double-blind manner. In patients given clonidine, the mean BP increases induced by DOA 5 µg · kg-1 · min-1 were significantly attenuated (P < 0.01), whereas the mean BP increases induced by DOB-0.5, 1, or 3 µg · kg-1 · min-1 were significantly enhanced (P < 0.01 or 0.05). The heart rate responses to DOA and DOB did not differ between patients with or without clonidine. Premedication with clonidine alters the effects on BP to both DOA and DOB. When small doses of DOA or DOB are used in clonidine-premedicated patients, differences of pharmacological profiles need to be considered for perioperative management.
Implications: Our randomized, double-blind study suggests that premedication with clonidine may enhance the effect on blood pressure response to a small dose of dobutamine (direct-acting) and attenuate that to a small dose of dopamine (mixed direct- and indirect-acting) in patients anesthetized with fentanyl and nitrous oxide.
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Introduction
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Oral clonidine premedication is used in elective surgery because it potentiates the anesthetic action of other drugs (1,2), reduces anesthetic requirements (1,3,4), and improves cardiovascular stability (1,5). Several previous studies have shown that premedication with oral clonidine either augments or attenuates the hemodynamic responses induced by various drugs that modulate cardiovascular functions (6–10). Clonidine activates 
2-adrenergic receptors in the central nervous system, and so reduces the sympathetic outflow and suppresses the release of norepinephrine from peripheral nerve endings (1). Moreover, it acts directly on blood vessels, including those in the central nervous system, and these effects are blocked by yohimbine (11).
Dopamine (DOA) and dobutamine (DOB) are often used to maintain hemodynamic stability during anesthetic and postoperative periods. These drugs have different pharmacological profiles: DOA causes the release of norepinephrine from nerve endings, which contributes to its effect on cardiovascular functions, whereas the action of DOB does not appear to depend on the release of norepinephrine (12). We hypothesized that clonidine would have different effects on the pharmacological actions of DOA and DOB. The administration of DOA and DOB is usually initiated at 3–5 µg · kg-1 · min-1 for stabilizing hemodynamics by increasing cardiac contractility and cardiac output. Therefore, we examined the interactions between clonidine and 1) IV small dose of DOA (which has both direct and indirect actions on adrenergic receptors) and 2) IV small dose of DOB (which has only direct actions) in anesthetized patients premedicated or not premedicated with clonidine.
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Methods
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The study protocol was approved by our Institutional Human Investigation Committee, and informed consent was obtained from each patient. The study was performed on 70 adult patients (ASA physical status I or II) scheduled to undergo general anesthesia for elective surgery. No patient had any cardiopulmonary disorder or was taking any medication affecting cardiovascular function.
The patients were randomly assigned to one of two groups. One group of 35 patients (clonidine group; CLON) was premedicated with clonidine 5 µg/kg orally 90 min before the induction of general anesthesia, whereas the remaining 35 patients (control group; CONT) received no premedication. Patients in the CLON and CONT groups were randomly assigned to receive one of five test infusions (3 µg · kg-1 · min-1 of DOA [DOA-3]; 5 µg · kg-1 · min-1 of DOA [DOA-5]; 0.5 µg · kg-1 · min-1 of DOB [DOB-0.5]; 1 µg · kg-1 · min-1 of DOB [DOB-1]; or 3 µg · kg-1 · min-1 of DOB [DOB-3] [n = 7 in each case]). We chose these doses of DOA and DOB, since our preliminary study showed that 5 µg · kg-1 · min-1 of DOA and 3 µg · kg-1 · min-1 of DOB increased blood pressure (BP) by more than 20% of baseline value at 10 min after treatment in patients without clonidine. The actual dose administered was determined by a study investigator, and the test solution was administered by a second anesthesiologist who was blinded to both the preanesthetic medication and the identity of the test solution.
DOA (Inovan; Kyowa-hakko, Tokyo, Japan) and DOB (Dobutrex; Shionogi, Osaka, Japan) are each marketed in a solution for injection that contains 100 mg/5 mL. This solution was diluted in 15 mL saline, and then 0.3 (DOB-0.5), 0.6 (DOB-1), 1.8 (DOA-3 and DOB-3), or 3.0 (DOA-5) mL of this diluted solution were added to sufficient saline to achieve a final volume of 500 mL. By this method, we were able to administer the chosen dose by infusing the correct diluted solution in each case at a rate of body weight of patient (in kg) x 10 mL/h.
Just before the administration of premedication with the CLON group or 90 min before the induction of general anesthesia in the CONT group, we measured "pretreatment" values of heart rate (HR) and systemic BP by means of an oscillometric BP cuff, whereas the patient was still on the ward. Patients in the CLON group were then given clonidine 5 µg/kg orally. In the operating room, HR was monitored from lead II of the electrocardiogram, and a BP cuff and a pulse oximeter device were fitted for use throughout the operative period. We then measured "posttreatment" values of both HR and systemic BP. IV infusion of lactated Ringer’s solution was started and maintained at a constant rate of 10 mL · kg-1 · h-1 during and after induction of anesthesia, and throughout the study. General anesthesia was induced IV with sodium thiopental (4 mg/kg) and fentanyl (3 µg/kg). Muscle relaxation was obtained by IV administration of vecuronium 0.2 mg/kg. After tracheal intubation, anesthesia was maintained with 50% nitrous oxide in oxygen. The lungs were mechanically ventilated with a tidal volume of approximately 10 mL/kg and end-tidal CO2 maintained between 35 and 40 mm Hg. A 22G catheter was inserted into the radial artery for direct measurement of systemic BP in each patient. After the induction of general anesthesia and when a stable hemodynamic state had been obtained for at least 10 min, "baseline" values of HR and BP were measured in each patient. Then, an IV infusion of one of the test solutions was started, and hemodynamic measurements were performed at 1 min intervals for the first 10 min after the start of the infusion by the blinded anesthesiologist. If either HR or mean BP (MBP) increased by more than 40% of baseline values, the study was terminated. The scheduled operation began after all the previous measurements had been taken.
Values are presented as mean ± SD. The patients’ demographic and hemodynamic data were analyzed using a two-way analysis of variance, followed by an unpaired or paired t-test with Bonferroni’s correction. Hemodynamic changes from baseline at each time point were analyzed for each group by using repeated-measures analysis of variance, followed by a paired t-test with Bonferroni’s correction. P < 0.05 was considered the minimum level of statistical significance.
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Results
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There were no significant differences among the 10 subgroups of patients with regard to age (38 ± 12 yr; range 18–64 yr), weight (55 ± 11 kg; 40–85 kg), and height (160 ± 8 cm; 146–183 cm). Most patients were female (49 of 70). Pretreatment HR and BP (systolic, diastolic, and MBP) values did not differ significantly among groups (Tables 1 and 2). Baseline HR and BP values in the CLON group were significantly lower than the corresponding pretreatment values (Tables 1 and 2).
The effects on BP by DOA-5 in the CLON group were attenuated when compared with those in the CONT group. However, there was no significant difference between the CLON and CONT groups, with respect to the responses to DOA-3 (Fig. 1). On the other hand, the effects on BP by DOB-0.5, DOB-1, and DOB-3 were all augmented in the CLON group, compared with those in the respective CONT group (Fig. 2). The exclusion criterion set for MBP responses (see "Methods") was achieved in all patients receiving DOB-3 in the CLON group within 3 min after the start of the infusion of DOB. HR responses were not significantly different whether clonidine had or had not been given (Tables 1 and 2), although we could not measure HR after exceeding the exclusion criterion for MBP for DOB-3 in the CLON group. Transient arrhythmia were observed in three patients in the course of the study: two patients in the CLON group who received DOB-3 and one patient in the CONT group who received DOB-3 had monofocal premature ventricular contractions. Recovery from arrhythmia occurred within the study period without treatment.
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Figure 1. Change in mean blood pressure at various times after the start of a continuous infusion of 3 (n = 14) or 5 (n = 14) µg · kg-1 · min-1 of dopamine. Premedication of clonidine significantly attenuated the effect on change in mean blood pressure to 5 µg · kg-1 · min-1 of dopamine (P < 0.01). Data are expressed as mean ± SD. * P < 0.01 compared with the value for the control group at the same time.
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Figure 2. Change in mean blood pressure at various times after the start of a continuous infusion of 0.5 (n = 14), 1 (n = 14), or 3 (n = 14) µg · kg-1 · min-1 of dobutamine. Premedication of clonidine significantly attenuated the effect on change in mean blood pressure to 0.5 (P < 0.01), 1.0 (P < 0.01), and 3 (P < 0.05) µg · kg-1 · min-1 of dobutamine. Data are expressed as mean ± SD. * P < 0.05, ** P < 0.01 compared with the value for the control group at the same time.
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Discussion
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The results of the present study on patients under general anesthesia produced with nitrous oxide, oxygen, and a small dose of fentanyl indicate that the effects on BP induced by DOA are attenuated, whereas those induced by DOB are enhanced in patients premedicated with clonidine. HR changes, however, were not significantly different, regardless of whether or not the patients were premedicated with clonidine.
Previous reports in patients premedicated with clonidine at 4–5 µg/kg have demonstrated augmented hemodynamic responses to vasoactive drugs, such as phenylephrine [under enflurane and nitrous oxide anesthesia (6) or fentanyl and nitrous oxide anesthesia (7)], norepinephrine [under enflurane and nitrous oxide anesthesia (6)], ephedrine [in the awake state or under enflurane and nitrous oxide anesthesia (9)], and epinephrine [in awake patients (8)]. We observed an enhanced effect of the small dose of DOB on BP in patients premedicated with a similar dose of clonidine (5 µg/kg). Although the mechanisms underlying such augmented pressor responses to DOB are not clearly understood, it is possible that augmented effect on BP by DOB seen in clonidine-premedicated patients is attributable primarily to an enhanced sensitivity and/or upregulation of the tissue receptors to which DOB binds, and/or to a potentiation of -adrenoceptor-mediated vasoconstriction.
Although we usually use both a small dose of DOA and DOB for the purpose of increasing cardiac contractility and cardiac output, the different effects on BP by DOA and DOB that we demonstrated are presumably caused by differences in their pharmacological characteristics. DOA has both a direct ß1-receptor stimulation at an infusion rate of 3–10 µg · kg-1 · min-1 and an indirect-acting property by a release of endogenous norepinephrine at doses above 5 µg · kg-1 · min-1 (12). In vitro experiments demonstrate that DOA attenuates cardiac contractility in the failing heart, in which cardiac norepinephrine was depleted to a level of 76% lower than that in the nonfailing heart (13). Moreover, the effect of DOA has been reported to be reduced by reserpine pretreatment, which decreases vesicular storage of norepinephrine (14). On the other hand, in patients with cardiac sympathectomy induced by thoracic epidural anesthesia, a moderate dose of DOA (4 or 8 µg · kg-1 · min-1) was sufficient to maintain MBP and cardiac output at adequate levels (comparable with those seen before the epidural block) (15). Thus, a reduced effect of DOA on BP in patients premedicated with clonidine might be expected, and could be a consequence of suppression of the release of neuronal norepinephrine from peripheral nerve endings caused by clonidine pretreatment (1).
Higher doses of DOA (10–20 µg · kg-1 · min-1) can stimulate both - and ß1-adrenoceptors, and produce predominantly the -vasoconstrictive effects. Thus, we speculate that large doses of DOA and DOB would produce different effects on hemodynamic responses in clonidine-premedicated patients. Considering these pharmacologic actions, we thought that the different circulatory effects of the adrenergic agonists observed in this study contraindicated evaluation of larger doses of DOA and DOB.
We are uncertain of the explanation for the effect of clonidine on the hemodynamic response to a small dose of DOA, which is the opposite of its reported effect on the response to ephedrine, since both are direct- and indirect-acting drugs. The indirect action of ephedrine is explained as an inhibitory action on active uptake by the nerve terminal and a displacement of norepinephrine from storage vesicles, thus providing more norepinephrine to interact with its receptors (12). The mechanisms by which norepinephrine is released from nerve terminals are two-fold. One is Ca2+-dependent and involves so-called exocytosis after activation of the Ca2+ current conducted via N-type Ca2+ channels (16,17). The other involves carrier-mediated release of norepinephrine after activation of the Na+-H+ antiporter (18). Imamura et al. (18) demonstrated that presynaptic 2-adrenoceptor blockade inhibits carrier-mediated norepinephrine release, but enhances norepinephrine exocytosis. The cardiovascular stimulating effects of ephedrine were not suppressed after acute or chronic reserpine treatment (19), whereas those of DOA were suppressed (14). Thus, there is a possibility that the indirect action of DOA is due to an effect on the release of norepinephrine by exocytosis, whereas that of ephedrine is due to an effect on the carrier-mediated release of norepinephrine. Another possible explanation for the opposite actions of clonidine on the effects induced by DOA and ephedrine might be related to differences in the mechanism or quantity of norepinephrine release, and/or to differences in the proportion of the effect of each drug that is accounted for by direct and indirect actions. However, at present, the previous explanations remain speculative.
Recent reports have demonstrated that presynaptic ß-adrenergic receptors facilitate the local release of norepinephrine in humans in vivo (20), and that the cardiovascular actions of DOB may be mediated in part through an indirect action via adrenoceptors (21). The hemodynamic responses induced by DOB have been reported neither to be depressed by reserpine pretreatment (22) nor by ephedrine (19). Possibly, the clonidine-induced enhancement of the responses to DOB seen in the present study could be due, at least in part, to an effect on an indirect action of DOB that is similar to that of ephedrine, although DOB is usually thought to have only a direct action on cardiac function (12). In our previous studies, the administration either of 0.02 µg/kg isoproterenol in patients anesthetized with fentanyl and nitrous oxide (7) or of 7.5 µg/kg epinephrine in awake patients (8) produced greater HR changes in patients with clonidine pretreatment than in those without clonidine premedication. The explanation for the absence of a significant modulation by clonidine of the effects on HR seen in the present study during infusion of DOA or DOB remains unknown. However, it may be that a baroreflex response to the enhanced effects of these drugs on BP tended to counteract the effect on HR of an enhancement of the stimulation of ß1-adrenoceptors induced by DOA or DOB. Possibly, the effects on HR of DOA and DOB may differ, depending on the general anesthetic state; and differences in the level of basal anesthesia could have modified the interaction between clonidine and DOA or DOB and so have further confounded the results.
Our study is limited by the relatively small number of subjects in each subgroup as a result of the wide range of doses used. Although it may be less powerful to find more positive results in statistical analysis in the present study, our sample size did permit identification of actual differences between study groups. Since the present results were obtained in healthy, hemodynamically stable adults, our data should not be extrapolated to aged patients and/or to patients with hypovolemic or cardiogenic shock. However, 2-adrenergic agonists are often used in elderly patients (23) and in patients with cardiovascular disorders (24) for improving cardiovascular stability during anesthesia and surgery (1,5,24). Moreover, DOA and DOB are used to increase cardiac output for patients with shock during perioperative periods. Thus, further study will be required to understand the interaction of clonidine and DOA or DOB in patients who are elderly and/or have various cardiovascular disorders.
In conclusion, clonidine preanesthetic medication enhanced the effects on BP of low doses of DOB (0.5, 1.0, and 3.0 µg · kg-1 · min-1). A small dose of DOA (3–5 µg · kg-1 · min-1) had attenuated effects on BP in healthy adult patients premedicated with oral clonidine.
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Acknowledgments
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This work was supported by Grant-in-Aid for Scientific Research No. 09671555 from the Ministry of Education, Science and Culture, Japan.
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Footnotes
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Presented in part at the annual meeting of the American Society of Anesthesiologists, San Diego, October 18–22, 1997, and at the annual meeting of the Japan Society of Anesthesiology, Kagoshima, April 16–18, 1998.
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Accepted for publication May 28, 1999.
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Abstract
Introduction
