JOURNAL HOME CME HOME THIS MONTH PAST ISSUES ETOC COLLECTIONS
AUTHORS REVIEWERS EDITORIAL BOARD FEEDBACK RSS HELP
A&A International Anesthesia Research Society
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (4)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Hayakawa-Fujii, Y.
Right arrow Articles by Dohi, S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hayakawa-Fujii, Y.
Right arrow Articles by Dohi, S.
Anesth Analg 1999;89:37
© 1999 International Anesthesia Research Society

CARDIOVASCULAR ANESTHESIA

Propofol Anesthesia Enhances Pressor Response to Ephedrine in Patients Given Clonidine

Yoko Hayakawa-Fujii, MD, Hiroki Iida, MD, and Shuji Dohi, MD

Department of Anesthesiology and Critical Care Medicine, Gifu University School of Medicine, Gifu City, Japan

Address correspondence and reprint requests to Shuji Dohi, MD, Department of Anesthesiology and Critical Care Medicine, Gifu University School of Medicine, 40 Tsukasamachi, Gifu 500-8705, Japan. Address e-mail to shu-dohi{at}cc.gifu-u.ac.jp


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
We studied the hemodynamic effects of ephedrine in patients with or without clonidine premedication during either isoflurane or propofol anesthesia. Forty adult patients were randomly assigned to one of two groups: 20 patients received famotidine 20 mg orally (control group) and 20 received clonidine 3 µg/kg and famotidine 20 mg orally (clonidine group). Within each group, 10 patients were then anesthetized with isoflurane and 10 with propofol. Hemodynamic measurements were taken at 1-min intervals for 10 min after a bolus injection of ephedrine 0.1 mg/kg. The magnitude of the maximal pressor response to ephedrine was no different whether patients without clonidine were anesthetized with isoflurane (increase 5 ± 7 mm Hg) or propofol (3 ± 9 mm Hg); however, this response was greater (P < 0.05) with propofol (17 ± 6 mm Hg) versus isoflurane (6 ± 5 mm Hg) in patients given clonidine. The arterial blood pressure increase in clonidine-premedicated patients with propofol anesthesia was the largest among the four subgroups. The heart rate response to ephedrine was not significant in patients anesthetized with isoflurane and was small but significant in those anesthetized with propofol. The present results, together with previous studies on the effect of ephedrine in patients medicated with clonidine, suggest that the interaction between clonidine and ephedrine is modulated by the anesthetic used.

Implications: We evaluated the pressor response to ephedrine during isoflurane or propofol anesthesia with or without clonidine premedication. Our study suggests that, in anesthetized patients premedicated with clonidine, decreases in blood pressure may be easier to reverse with ephedrine with some types of anesthesia (e.g., propofol) than with others (e.g., isoflurane).


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Ephedrine is a vasopressor commonly used during anesthesia (1). The responses to ephedrine may depend on clinical conditions (e.g., whether the patient is awake or anesthetized, the anesthetic technique, and/or anesthetics used). Indeed, the pressor response to ephedrine is greater in anesthetized than in awake patients (2). The pressor response to ephedrine in anesthetized patients is definitely important in the clinical setting. However, little information is available on the influence of the type of basal anesthesia on the hemodynamic response to ephedrine.

Whereas propofol can cause hypotension and bradycardia, especially in elderly patients (3), ephedrine is effective in reversing the hypotensive response to propofol with minimal overshoot (4). However, Jensen et al. (5) reported that IV techniques using propofol require greater pharmacological intervention (the need for ephedrine and glycopyrrolate) before surgery than the regular isoflurane-based technique if a stable blood pressure (BP) and heart rate (HR) are to be maintained.

Clonidine is used as a preanesthetic to improve hemodynamic stability and to reduce intraoperative anesthetic requirements (6). However, clonidine produces a hypotensive effect, partly due to a reduction in sympathetic activity (7). In animal models, clonidine inhibits central sympathetic outflow, reduces the release of norepinephrine from peripheral presynaptic terminals, and may have a vagomimetic action (8). Clonidine premedication augments the pressor response to IV ephedrine in awake and anesthetized patients (2,9,10). Clonidine's interaction with ephedrine has not been determined under the influence of different types of anesthesia, other than with enflurane (2).

The purpose of the current study was to compare the pressor response to ephedrine during isoflurane and propofol anesthesia with and without clonidine premedication.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
We studied 40 patients, ASA physical status I or II, aged 20–65 yr, who were scheduled to undergo general anesthesia for various surgical procedures. The study protocol was approved by our institutional human investigation committee, and informed consent was obtained from each patient. None of the patients had a history of cardiovascular disorders, diabetes mellitus, or other disorders known to affect autonomic function, and none was taking medication that affects cardiovascular function.

The patients were randomly allocated to one of two groups by one investigator. Twenty patients received famotidine 20 mg (control group) orally 90 min before the induction of anesthesia, whereas the remaining 20 patients received clonidine 3 µg/kg and famotidine 20 mg (clonidine group). In the operating theater, an 18-gauge cannula was inserted into a vein in the forearm under local anesthesia, and acetated Ringer's solution was administered at a rate of 10 mL · kg-1 · h-1 throughout the study period. After measurements of the preinduction BP and HR, general anesthesia was induced with IV propofol 2 mg/kg, and tracheal intubation was facilitated with vecuronium 0.2 mg/kg. In 10 patients in each group, anesthesia was maintained with isoflurane 1% (end-tidal) in oxygen, and in the other 10 with IV propofol 100 µg · kg-1 · min-1 during ventilation with oxygen. Ventilation was controlled mechanically to obtain an ETCO2 of 30–35 mm Hg. A single injection of ephedrine 0.1 mg/kg was given as a bolus after a stable hemodynamic period of at least 15 min. Hemodynamic measurements were made at 1-min intervals for 10 min after the injection. All BP measurements were performed using an automated BP cuff. Lead II of the electrocardiogram (ECG) was continuously monitored throughout the study, and HR was calculated as an average over four cycles from the electrocardiogram monitor. Arterial blood was analyzed for pHa, PaCO2, PaO2, and base excess. All measurements were completed before the operation with the patients in the supine position.

Data are expressed as mean ± SD. Mean blood pressure was calculated as DBP + 1/3 x (SBP - DBP) where DBP = diastolic BP and SBP = systolic BP. Statistical comparisons among the subgroups were performed by using a two-way analysis of variance (ANOVA), followed by an unpaired t-test with Bonferroni's correction. BP and HR responses to ephedrine among the various subgroups were analyzed by using a repeated-measurements ANOVA (one-way ANOVA), followed by a paired t-test with Bonferroni's correction. P < 0.05 was considered the minimal level of statistical significance.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
There were no significant differences among the four subgroups of patients with regard to age, weight, or height, although most of patients who entered the study were female (29 of 40) (Table 1). There were no significant differences among the four subgroups with respect to arterial blood gas values (Table 2). Moreover, in the groups anesthetized with isoflurane, there were no differences in the end-tidal concentration of isoflurane given to maintain general anesthesia (Table 2).


View this table:
[in this window]
[in a new window]
  		Table 1. Patient Demographics and Clonidine Doses
 

View this table:
[in this window]
[in a new window]
  		Table 2. Arterial Blood Gas Values During General Anesthesia and End-Tidal Concentrations of Isoflurane
 
Preoperative BP and HR values taken before premedicants were given were similar among the various subgroups (Table 3). In the clonidine group, preinduction BP values tended to be lower than preoperative BP values. However, preinduction BP and HR values were not significantly different from the preoperative values in any subgroup (Table 3). Baseline hemodynamic values during general anesthesia (immediately before the injection of ephedrine) were not significantly different among the subgroups, although baseline BP in the clonidine groups tended to be lower than that in the control groups (Table 3). After the injection of ephedrine, BP was significantly increased from the baseline value in the clonidine groups. The magnitude of the increase in mean blood pressure (absolute change from the baseline value) was greater in the clonidine plus propofol subgroup (P < 0.05) than in the other three subgroups (Fig. 1). Although we observed significant increases in HR compared with baseline values after the injection of ephedrine in patients anesthetized with propofol, there were no significant differences among the subgroups in terms of the HR response over the entire observation period.


View this table:
[in this window]
[in a new window]
  		Table 3. Hemodynamic Responses to Ephedrine 0.1 mg/kg
 


View larger version (26K):
[in this window]
[in a new window]
  		Figure 1. Changes in mean blood pressure (mean ± SD) after the IV injection of ephedrine 0.1 mg/kg. Patients in the clonidine-isoflurane and clonidine-propofol subgroups received clonidine 3 µg/kg and famotidine 20 mg orally 90 min before the induction of anesthesia. Patients in the control-isoflurane and control-propofol subgroups received famotidine 20 mg alone. *P < 0.05 compared with control-isoflurane, control-propofol, and clonidine-isoflurane.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
In patients with clonidine premedication, the pressor response to ephedrine was greater during propofol than during isoflurane, although no difference in the pressor response was observed between the isoflurane and propofol groups without clonidine premedication. None of patients receiving clonidine showed an abnormally exaggerated pressor response to IV ephedrine under either isoflurane or propofol anesthesia.

Clonidine interacts with the catecholaminergic neuronal system, which mediates tonic and phasic (reflex) BP control and reduces the release of norepinephrine from nerve endings both centrally and peripherally (6). The net effect is a reduction in BP and HR that is most likely due to a reduced sympathetic outflow (7). Some authors have suggested that clonidine preanesthetic medication may cause a higher incidence of hypotension and a more frequent requirement for vasopressor drugs (6,8). However, it has been previously reported that clonidine premedication could enhance the pressor response to ephedrine in enflurane-anesthetized patients (2). The results of the present study demonstrate a similar effect of clonidine premedication in patients under propofol anesthesia. These findings could be explained by increased catecholamine storage secondary to inhibition of its release by clonidine, enhanced sensitivity of the tissue receptors to which ephedrine binds, potentiated {alpha}-adrenoceptor–mediated vasoconstriction (because this is induced by both ephedrine and clonidine), or all of these. In the current study, the pressor response induced by ephedrine did not differ significantly regardless of whether patients received clonidine before isoflurane anesthesia. This suggests that whether an enhanced cardiovascular response to ephedrine is seen in clonidine-premedicated patients depends on the specific anesthetic used.

Many years ago, Moore and Moran (11) demonstrated that the augmentation of myocardial contractile force produced by ephedrine was altered by reserpine or chronic sympathectomy. In fact, the pressor effect to ephedrine seems to depend primarily on the existing level of sympathetic nervous activity (12), the response being greater at lower basal levels of sympathetic activity. Thus, the anesthetic used, and probably its dose, may affect or modify the pressor response to ephedrine through its effects on sympathetic activity. Although the doses of propofol and isoflurane used in the current study produced similar hemodynamic effects, there might have been a difference in their effects on sympathetic activity. Investigators have demonstrated that propofol causes vasodilation by relaxing vascular smooth muscle (13) and by reducing the tonic sympathetic discharge (14–16). Thus, hypotension during propofol anesthesia may be caused primarily by its central actions, leading to a depression of sympathetic firing (16). However, isoflurane, which also produces hypotension and vasodilation, maintains cardiac output, possibly by an accompanying tachycardia. Because the direct vasodilator effects of isoflurane may reflexly induce a relative increase in sympathetic nerve activity, isoflurane may cause a relatively greater decrease in parasympathetic versus sympathetic activity (17,18). The depression of sympathetic activity induced by isoflurane may be less than that induced by enflurane or propofol (19). The profound suppression of sympathetic activity due to propofol anesthesia accompanied by clonidine premedication may have created the conditions necessary to enhance the pressor response to ephedrine, whereas the other conditions imposed in the current study did not.

Because the hemodynamic responses could be the net results of central and direct vasorelaxing effects of anesthetics used and cardiovascular effects of vasopressor, the reactivity and the responses to ephedrine could differ in the depth of anesthesia and in the different state of autonomic activity, especially in the sympathetic tone. The minimum alveolar anesthetic concentration value for isoflurane is 1.15% in 100% oxygen, and the addition of 70% nitrous oxide decreases the isoflurane MAC by 0.7% (20). The minimum infusion rate for propofol has been reported to be 51.3 µg · kg-1 · min-1 for patients premedicated with morphine and breathing 67% nitrous oxide in oxygen (21). Thus, 0.45% isoflurane seems to be the anesthetic equivalent of 50 µg · kg-1 · min-1 propofol (plus morphine sulfate). Because we used 0.9% isoflurane or 100 µg · kg-1 · min-1 propofol, it is not likely that there are much different effects on neural activity between the two groups. The presence of clonidine could also influence anesthetic depth and hemodynamic reactivity. Although clonidine 5 µg/kg PO would cause a greater incidence of hypotension or bradycardia (22), no patient given 3 µg/kg clonidine experienced hypotension (systolic BP <80 mm Hg) and bradycardia (HR <50 bpm) before IV ephedrine. Although clonidine reduces sympathoexcitation, it does not seem to significantly alter the gain of the baroreceptor reflex regulating cardiac interval or peripheral sympathetic nerve activity (7,23). However, because propofol is a potent inhibitor of sympathetic neuronal activity that decreases the sensitivity of the baroreflex (24,25) and markedly attenuates reflex responses to hypotension (25), it is possible that propofol may cause hypotension and bradycardia in patients premedicated with clonidine in some situations. During surgery, the vasodilating effect of propofol overrides the neural vasoconstriction induced by surgery, and a further inhibition of the cardiac baroreflex may be observed (24). Although a smaller dose of clonidine did not cause any significant hypotension and bradycardia in patients given propofol in the present study, we cannot exclude the possibility that BP and HR responses to ephedrine could differ with different depths or doses of anesthetics, as well as with different dose of clonidine premedication.

In conclusion, the pressor response to ephedrine in patients premedicated with clonidine was augmented with propofol, but not with isoflurane. The interaction between the anesthetic and clonidine as a premedicant can apparently modify the hemodynamic response to ephedrine depending on the anesthetic used. Hypotension in anesthetized patients premedicated with clonidine may be more effectively reversed with ephedrine with some types of anesthesia (e.g., propofol) than with others (e.g., isoflurane).


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Zaimis E. Vasopressor drugs and catecholamines. Anesthesiology 1968;29:732–62.[ISI][Medline]
  2. Nishikawa T, Kimura T, Taguchi N, Dohi S. Oral clonidine preanesthetic medication augments the pressor responses to intravenous ephedrine in awake or anesthetized patients. Anesthesiology 1991;74:705–10.[ISI][Medline]
  3. Claeys MA, Gepts E, Camu F. Haemodynamic changes during anaesthesia induced and maintained with propofol. Br J Anaesth 1988;60:3–9.[Abstract/Free Full Text]
  4. Gamlin F, Vucevic M, Winslow L, et al. The haemodynamic effects of propofol in combination with ephedrine. Anesthesia 1996;51:488–91.[ISI][Medline]
  5. Jensen AG, Granfeldt H, Kalman SH, et al. A comparison of propofol and isoflurane anesthesia : the need for ephedrine and glycopyrrolate. Eur J Anaesthesiol 1995;12:291–9.[ISI][Medline]
  6. Maze M, Tranquilli W. Alpha-2 adrenoceptor agonists : defining the role in clinical anesthesia. Anesthesiology 1991;74:581–605.[ISI][Medline]
  7. Muzi M, Goff D, Kampine J, et al. Clonidine reduces sympathetic activity but maintains baroreflex responses in normotensive humans. Anesthesiology 1992;77:864–71.[ISI][Medline]
  8. Ghignone M, Clvillo O, Quintin L. Anesthesia and hypertension : the effect of clonidine on perioperative hemodynamics and isoflurane requirements. Anesthesiology 1987;67:3–10.[ISI][Medline]
  9. Inomata S, Nishikawa T, Kihara S, Akiyoshi Y. Enhancement of pressor response to intravenous phenylephrine following oral clonidine medication in awake and anaesthetized patients. Can J Anaesth 1995;42:119–25.[Abstract/Free Full Text]
  10. Tanaka M, Nishikawa T. Enhancement of pressor response to ephedrine following clonidine medication. Anesthesia 1996;51:123–7.[ISI][Medline]
  11. Moore J, Moran N. Cardiac contractile force responses to ephedrine and other sympathomimetic amines in dogs after pretreatment with reserpine. Ther 1962;136:89–96.
  12. Philip T, Distler A, Cordes U. Sympathetic nervous system and blood pressure control in essential hypertension. Lancet 1978;4:959–63.
  13. Bentley GN, Gent JP, Goodchild CS. Vascular effects of propofol : smooth muscle relaxation in isolated veins and arteries. J Clin Pharmacol 1989;41:797–8.
  14. Sellgren J, Ponten J, Wallin G. Percutaneous recording of muscle nerve sympathetic activity during propofol, nitrous oxide, and isoflurane anesthesia in humans. Anesthesiology 1990;73:20–7.[ISI][Medline]
  15. Ebert T, Muzi M, Berens R, et al. Sympathetic responses to induction of anesthesia in humans with propofol or etomidate. Anesthesiology 1992;76:725–33.[ISI][Medline]
  16. Krassioukov A, Gelb A, Weaver L. Action of propofol on central sympathetic mechanisms controlling blood pressure. Can J Anaesth 1993;40:761–9.[Abstract/Free Full Text]
  17. Seagard J, Hopp F, Bosnjak Z, et al. Sympathetic efferent nerve activity in conscious and isoflurane-anesthetized dogs. Anesthesiology 1984;61:266–70.[ISI][Medline]
  18. Seagard J, Elegbe E, Hopp F, et al. Effects of isoflurane on the baroreceptor reflex. Anesthesiology 1983;59:511–20.[ISI][Medline]
  19. Saeki Y, Hasegawa Y, Shibamoto T, et al. The effects of sevoflurane, enflurane, and isoflurane on baroreceptor-sympathetic reflex in rabbits. Anesth Analg 1996;82:342–8.[Abstract]
  20. Eger EI II. Isoflurane : a review. Anesthesiology 1981;55:559–76.[ISI][Medline]
  21. Spelina K, Coates D, Monk C, et al. Dose requirements of propofol by infusion during nitrous oxide anaesthesia in man. Anaesth 1986;58:1080–4.
  22. Nishikawa T, Dohi S. Oral clonidine blunts the heart rate response to intravenous atropine in humans. Anesthesiology 1991;75:217–22.[ISI][Medline]
  23. Watanabe Y, Iida H, Dohi S, et al. Clonidine premedication modifies responses to adrenoceptor agonists and baroreflex sensitivity. Can J Anaesth 1998;45:1084–90.[Abstract/Free Full Text]
  24. Sellgren J, Ejnell H, Elam M. Sympathetic muscle nerve activity, peripheral blood flows, and baroreceptor reflexes in humans during propofol anesthesia and surgery. Anesthesiology 1994;80:534–44.[ISI][Medline]
  25. Ebert TJ, Muzi M. Propofol and autonomic reflex function in humans. Anesth Analg 1994;78:369–75.[Abstract]
Accepted for publication March 18, 1999.




This article has been cited by other articles:


Home page
 Anesth. Analg.Home page
T. Ishiyama, S. Kashimoto, T. Oguchi, T. Matsukawa, and T. Kumazawa
The Effects of Clonidine Premedication on the Blood Pressure and Tachycardiac Responses to Ephedrine in Elderly and Young Patients During Propofol Anesthesia
Anesth. Analg., January 1, 2003; 96(1): 136 - 141.
[Abstract] [Full Text] [PDF]

Home page
 Anesth. Analg.Home page
N. Kanaya, H. Satoh, S. Seki, M. Nakayama, and A. Namiki
Propofol Anesthesia Enhances the Pressor Response to Intravenous Ephedrine
Anesth. Analg., May 1, 2002; 94(5): 1207 - 1211.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (4)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Hayakawa-Fujii, Y.
Right arrow Articles by Dohi, S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hayakawa-Fujii, Y.
Right arrow Articles by Dohi, S.

Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press