Anesth Analg 2003;96:136-141
© 2003 International Anesthesia Research Society
ANESTHETIC PHARMACOLOGY
The Effects of Clonidine Premedication on the Blood Pressure and Tachycardiac Responses to Ephedrine in Elderly and Young Patients During Propofol Anesthesia
Tadahiko Ishiyama, MD, PhD,
Satoshi Kashimoto, MD, PhD,
Takeshi Oguchi, MD, PhD,
Takashi Matsukawa, MD, PhD, and
Teruo Kumazawa, MD, PhD
Department of Anesthesiology, Yamanashi Medical University, Japan
Address correspondence and reprint requests to Tadahiko Ishiyama, MD, PhD, Department of Anesthesiology, Yamanashi Medical University, 1110 Shimokato, Tamaho, Nakakoma, Yamanashi 409–3898, Japan. Address e-mail to ishiyama{at}res.yamanashi-med.ac.jp
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Abstract
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We studied the pressor and tachycardiac responses to ephedrine in elderly and young patients given either clonidine or midazolam during propofol anesthesia. In the first experiment, elderly (>60 yr) and young (20–45 yr) patients were randomly allocated to one of four groups according to age and premedicated regimens (n = 16 each; elderly-clonidine [EC], elderly-midazolam [EM], young-clonidine [YC], and young-midazolam [YM]). Under propofol anesthesia, ephedrine was injected, and hemodynamic measurements were made. In the second experiment, with clonidine premedication, elderly patients (n = 16) were given a reduced dose of propofol (EC-LP) and young patients (n = 16) were given an increased dose of propofol (YC-HP). Ephedrine was injected, and he- modynamic measurements were performed. The in-creases in mean blood pressure and heart rate were larger in the EC group than in the EM, YM, and EC-LP groups (P < 0.05). In the YC-HP group, the pressor response to ephedrine tended to be augmented as compared with the YC group but was not statistically significant. These results suggest that clonidine premedication augmented the pressor and tachycardiac responses to ephedrine, especially in elderly patients during a standard dose of propofol anesthesia, and that clonidine, age, and propofol could be involved in the augmentation of the blood pressure and tachycardiac responses to ephedrine.
IMPLICATIONS: Clonidine premedication augments the pressor and tachycardiac responses to ephedrine in elderly patients during standard or large doses of propofol anesthesia but does not augment during small doses of propofol anesthesia. Clonidine, age, and propofol could be involved in the augmentation of the pressor and tachycardiac responses to ephedrine.
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Introduction
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Propofol is widely used for the induction and maintenance of anesthesia; however, it produces hypotension (1), especially in elderly patients (2). Because ephedrine is a mixed  - and ß-adrenergic drug, it is helpful in treating hypotension but may cause tachycardia. The pressor response to ephedrine is enhanced by preoperative oral clonidine (3). It has been reported that the number of 2-adrenoceptors decreased (4,5) or did not significantly change (6,7) with aging. Age-related evaluation of pressor and tachycardiac responses to ephedrine in patients given clonidine under propofol anesthesia is required; however, little information is available on this issue. In addition, propofol has the presynaptic effect of inhibiting norepinephrine release from perivascular nerves (8). Therefore, propofol may also modulate the pressor response to ephedrine.
The purpose of the current study was to compare the pressor and tachycardiac responses of ephedrine in elderly and young patients given either clonidine or midazolam during propofol anesthesia. We also investigated the effects of propofol on blood pressure and tachycardiac responses to ephedrine.
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Materials and Methods
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The study was approved by the Yamanashi Medical University Ethics Committee, and written informed consent was obtained from each patient. Forty-eight elderly (more than 60 yr) and 48 young (20–45 yr) patients classified as ASA physical status I or II and scheduled to undergo elective surgery were enrolled in the study. Patients with respiratory or cardiovascular diseases, hypertension, diabetes mellitus, or autonomic disorders, as well as patients receiving medication that affects cardiovascular function, were excluded.
In the first experiment, we investigated the effects of clonidine and age on pressor and tachycardiac responses to ephedrine. Thirty-two elderly and 32 young patients were assigned randomly from a previously generated chart to receive either oral clonidine 4 µg/kg 90 min before or IM midazolam 0.04 mg/kg 30 min before the induction of anesthesia. They were allocated to one of four groups according to age and premedicated regimens (n = 16 per group) as follows: elderly-clonidine (EC), elderly-midazolam (EM), young-clonidine (YC), and young-midazolam (YM) (Table 1). Investigators were blinded to whether patients received clonidine or midazolam. Before anesthesia, electrocardiogram electrodes, automated blood pressure cuff, and pulse oxymetry were placed. A venous catheter was inserted, and acetated Ringer’s solution was infused at a rate of 10 mL · kg-1 · h-1. After measurements of blood pressure, heart rate (HR), and oxygen saturation, all patients were anesthetized with bolus propofol 1.5 mg/kg (induction of anesthesia) followed by a continuous IV infusion of 10 mg · kg-1 · h-1 (maintenance of anesthesia). Vecuronium 0.15 mg/kg was given, and tracheal intubation was performed. Controlled ventilation was instituted to maintain an end-tidal carbon dioxide value of 30–35 mm Hg. Ephedrine 0.1 mg/kg was injected as a bolus 10 min after the tracheal intubation. Hemodynamic measurements were made at 1-min intervals for 10 min.
In the second experiment, we investigated the effects of propofol on pressor and tachycardiac responses to ephedrine. Sixteen elderly and 16 young patients received clonidine (4 µg/kg) 90 min before the induction of anesthesia. Elderly patients were given bolus propofol 1 mg/kg (induction of anesthesia) followed by 6 mg · kg-1 · h-1 (maintenance of anesthesia) (EC-LP group). Young patients were given bolus propofol 2.5 mg/kg (induction of anesthesia) followed by 15 mg · kg-1 · h-1 (maintenance of anesthesia) (YC-HP group) (Table 1). Hemodynamic measurements were performed in the aforementioned manner by investigators who did not know the study protocols.
Results are expressed as mean ± SD. The comparisons of patients’ age, height, weight, oxygen saturation, end-tidal carbon dioxide pressure, and rectal temperature were performed by means of factorial analysis of variance (ANOVA) and, if appropriate, followed by the Scheffé F test for multiple comparisons. Blood pressure and HR after the ephedrine injection among the intragroups were compared using repeated-measurements ANOVA followed by the Dunnett post hoc test. Intergroup differences in changes of mean blood pressure and HR were analyzed using factorial ANOVA followed by the Scheffé F test for multiple comparisons. A P value <0.05 was considered statistically significant.
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Results
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Demographic data are shown in Table 2. There was an approximate 35-yr age difference among the elderly and young groups (P < 0.0001). Preoperative oxygen saturation was lower in the elderly groups than in the young groups (P < 0.05). However, there were no differences in oxygen saturation, end-tidal carbon dioxide tension, and rectal temperature during the study period.
Preinduction blood pressure was higher in the EM group than in the other groups, and preinduction HR was higher in the YM group (P < 0.05) (Table 3). However, preephedrine blood pressure and HR were comparable among the groups. After the ephedrine injection, blood pressure and HR were significantly increased from the preephedrine values in all groups (P < 0.05) (Table 3). The increase in systolic blood pressure was sustained for 8 min in the EC group, for 3 min in the EM group, for 5 min in the YC group, and for 3 min in the YM group (Table 3). In addition, 2 patients in the EM group reached hypotension (66/33 and 79/53 mm Hg, respectively) within 10 min after the ephedrine injection, whereas no patients in the other three groups experienced hypotension. Change of mean blood pressure (mean blood pressure of each time after ephedrine injection - mean blood pressure of preephedrine;  MBP) in the EC group was significantly increased from 5 to 7 min than in the EM group and was significantly increased at 6 min than in the YM group (P < 0.05) (Fig. 1). Absolute values of HR after ephedrine injection were comparable among the groups (Table 3). However, change of HR (HR of each time after ephedrine injection - HR of preephedrine; HR) in the EC group was significantly faster from 6 to 9 min compared with the EM group and was significantly faster at 2 and 7 min compared with the YM group (P < 0.05) (Fig. 2). Tachycardia (111 bpm) in response to ephedrine developed in one patient in the EC group.
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Table 3. Blood Pressure and Heart Rate Responses to Ephedrine 0.1 mg/kg in Elderly and Young Patients Premedicated with Either Clonidine or Midazolam Under Propofol (10 mg · kg-1 · h-1) Anesthesia
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In the EC-LP group, diastolic blood pressure did not increase after ephedrine injection (Table 3). Two patients reached hypotension (72/35 and 77/40 mm Hg, respectively) within 10 min after the ephedrine injection. MBP was significantly smaller in EC-LP at 2, 4, 5, 6, and 9 min than in the EC group (P < 0.05) (Fig. 1). HR increased from 2 to 10 min after the ephedrine injection in the EC-LP group. However, HR was significantly smaller in EC-LP from 2 to 4 min and from 7 to 9 min than in the EC group (P < 0.05) (Fig. 2). The increase in systolic blood pres- sure was sustained for 8 min in the YC-HP group, whereas it was sustained for 5 min in the YC group (Table 2 and 3). However, absolute values of systolic and diastolic blood pressure after ephedrine injection in YC-HP were comparable to the YC group (Table 3 and 4). MBP tended to be greater as compared with the YC group but was not statistically significant. HR at each time did not show statistically significant differences among the YC, YM, and YC-HP groups (Fig. 1, 2).
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Table 4. Blood Pressure and Heart Rate Responses to Ephedrine 0.1 mg/kg in Elderly and Young Patients Premedicated with Clonidine Under Propofol (6 mg · kg-1 · h-1 for Elderly and 15 mg · kg-1 · h-1 for Young Patients) Anesthesia
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Discussion
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Our major finding is that clonidine premedication augmented the pressor and tachycardiac responses to ephedrine in elderly but not in young patients given the same dose of propofol anesthesia. A reduced dose of propofol in elderly patients lessened the pressor and tachycardiac responses to ephedrine, and an increased dose in young patients tended to potentiate those effects but did not enhance absolute values of systolic and diastolic blood pressure.
Propofol produced a plasma concentration-dependent decrease in arterial blood pressure (2), and reducing doses of propofol improved hemodynamic stability (9,10). In addition, those effects were more prominent in elderly patients as compared with young patients (2). Therefore, hypotension sometimes occurs during standard or large doses of propofol anesthesia, especially in elderly patients. The present study demonstrated that although ephedrine increased blood pressure in elderly patients with midazolam premedication, the magnitude of the increase in blood pressure was small, and two patients reached unacceptable hypotension (systolic blood pressure <80 mm Hg). On the contrary, ephedrine effectively increased blood pressure in elderly patients with clonidine premedication. The hemodynamic changes were quite narrow between the EC and EM groups; however, no patients in the EC group experienced hypotension after the ephedrine injection. Thus, clonidine premedication for the elderly may be reasonable. However, we also detected that a reduced dose of propofol did not augment ephedrine responses. Therefore, hypotension during standard or large doses of propofol anesthesia may be more effectively rescued with ephedrine in elderly patients with clonidine premedication, although it is required to note that ephedrine would not be effective for hypotension during small doses of propofol anesthesia despite clonidine premedication.
Regarding the HR response to ephedrine, we detected that absolute values of HR after the ephedrine injection were comparable in patients given either clonidine or midazolam. However, an increase in HR was larger in elderly patients with clonidine premedication. Elderly patients have more frequent rates of cardiovascular complications, and tachycardia can cause serious cardiovascular compromise. Actually, we observed tachycardia in response to ephedrine in one elderly patient with clonidine premedication. Augmentation of a tachycardiac response to ephedrine would be potentially unfavorable.
Aging is accompanied by a variety of autonomic nervous system changes. The distributions of - and ß-adrenoceptors in cardiac tissue and vasculature may change with aging. Arterial 1-adrenoceptor density increases with aging (11). Thus, 1-adrenoceptor-mediated vasoconstriction seems to increase with aging. In addition, -adrenoceptor-mediated vasoconstriction is augmented in clonidine-premedicated patients (12), and propofol potentiates -adrenoceptor-mediated pulmonary vasoconstriction (13). Therefore, 1-adrenoceptor- mediated vasoconstriction may be potentiated in elderly patients with clonidine premedication under propofol anesthesia. Age-related changes in density of 1-adrenoceptor could be one possible cause for augmented pressor response to ephedrine in the elderly.
With regard to the relation between density of 2-adrenoceptors and aging, they have been reported as no significant change (6,7) and decrease (4,5). In addition, an age-related increase in 2-adrenoceptor density has not been reported. Thus, the effects of clonidine would not increase in elderly patients, whereas density of ß-adrenoceptors in the heart declined with aging (14). In fact, elderly subjects have lower chronotropic responses to isoproterenol by the reduction in ß-adrenoceptors associated with aging (15). Therefore, age-related ß-adrenoceptor change also could not enhance the tachycardiac response to ephedrine. It is suggested that age-related 2- and ß-adrenoceptor changes would be less likely involved in the augmentation of pressor and tachycardiac responses to ephedrine in elderly patients with clonidine premedication.
We detected that clonidine and propofol doses influenced the ephedrine action in elderly but not in young patients. This result suggests that clonidine, age, and propofol could be involved in the augmentation of the pressor and tachycardiac responses to ephedrine. Clonidine acts presynaptically to decrease release of norepinephrine from nerve terminals via activation of 2-adrenoceptors. Propofol also has the presynaptic effect of inhibiting norepinephrine release from perivascular nerves (8). Inhibition of norepinephrine release from nerve terminals caused by clonidine and propofol could produce increased norepinephrine storage in nerve terminals. Ephedrine acts at - and ß-adrenoceptors in two mechanisms of action: directly at a receptor and indirectly by releasing endogenous norepinephrine. Indirect action may result in a large quantity of norepinephrine release from increased norepinephrine storage during increased doses of propofol anesthesia accompanied by clonidine premedication.
It is also possible that different depths of propofol anesthesia were associated with augmented pressor and tachycardiac responses to ephedrine in patients premedicated with clonidine. The same dose of propofol causes more profound anesthesia in elderly patients than in young patients. Propofol induces dose-dependent depressions of sympathetic nerve activity (16). Thus, profound propofol anesthesia should produce profound depression of sympathetic nerve activity. Hayakawa-Fujii et al. (3) suggested that profound suppression of sympathetic activity because of propofol anesthesia accompanied by clonidine enhanced the pressor response to ephedrine. Therefore, profound propofol anesthesia accompanied by clonidine premedication may cause augmentation of the pressor and tachycardiac responses to ephedrine.
The induction dose of propofol varies from 1 to 2.5 mg/kg (17). It has been demonstrated for years that a propofol dose should be reduced in the elderly (18) and that reducing the doses improved hemodynamic stability (9,10). A dose of 1 mg/kg to 1.75 mg/kg has been recommended for inducing anesthesia in patients older than 60 years of age (17). Anesthesia was induced successfully in young patients given propofol 1.46 mg/kg (10). Therefore, the induction dose of propofol 1.5 mg/kg could be acceptable for both elderly and young patients. After an induction dose, an infusion of 6 to 12 mg · kg-1 · h-1 is required to maintain anesthesia. A propofol dose of 1.5 mg/kg followed by 10 mg · kg-1 · h-1, as used in the present study, should be clinically relevant. We used a propofol dose of 1 mg/kg followed by 6 mg · kg-1 · h-1 for elderly patients as the clinically small range and 2.5 mg/kg followed by 15 mg · kg-1 · h-1 for young patients for deep anesthesia.
It has been detected that blood pressure decreased more in the elderly than in young patients after propofol injection, but it stabilized gradually (2). In addition, although a faster infusion of propofol produced a larger decrease in systolic and diastolic pressure between two and five minutes after the injection, they became comparable within 10 minutes (9). In the present study, tracheal intubation was performed approximately three minutes after the propofol injection, and 10 minutes of stabilization was instituted thereafter. Comparable preephedrine blood pressure might be produced with stabilization.
In summary, the pressor and tachycardiac responses to ephedrine were augmented, especially in elderly patients, with clonidine premedication during standard or large doses of propofol anesthesia. Hypotension during standard or large doses of propofol anesthesia may be more effectively rescued with ephedrine in elderly patients with clonidine premedication than in elderly patients without clonidine, although it is required to note that ephedrine would not be effective for hypotension during small doses of propofol anesthesia despite clonidine premedication. Clonidine, age, and propofol could be involved in the augmentation of the blood pressure and tachycardiac responses to ephedrine.
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Accepted for publication September 12, 2002.
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Abstract
Introduction
P < 0.05 compared with YM. 
P < 0.05 compared with EC-LP. Data are expressed as mean ± SD.
