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 ISI Web of Science (6)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Kanaya, N.
Right arrow Articles by Namiki, A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kanaya, N.
Right arrow Articles by Namiki, A.
Anesth Analg 2002;94:1207-1211
© 2002 International Anesthesia Research Society

ANESTHETIC PHARMACOLOGY

Propofol Anesthesia Enhances the Pressor Response to Intravenous Ephedrine

Noriaki Kanaya, MD, Hitoshi Satoh, MD, Sumihiko Seki, MD, Masayasu Nakayama, MD, and Akiyoshi Namiki, MD

Department of Anesthesiology, Sapporo Medical University School of Medicine, Sapporo, Japan

Address correspondence and reprint requests to Noriaki Kanaya, MD, Department of Anesthesiology, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-ku, Sapporo 060-8543, Japan. Address e-mail to kanaya{at}sapmed.ac.jp


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
The induction of anesthesia with propofol is often associated with a decrease in arterial blood pressure (BP). Although vasopressors are sometimes required to reverse the propofol-induced hypotension, little is known about the effect of propofol on these drugs. We studied the effects of propofol and sevoflurane on pressor response to IV ephedrine. Thirty adult patients were randomly assigned to one of two groups. In the Propofol group (n = 15), patients received pro-pofol 2.5 mg/kg IV for induction followed by 100 µg · kg-1 · min-1 IV for maintenance. In the Sevoflurane group (n = 15), anesthesia was induced with sevoflurane 3%–4% in oxygen and maintained with sevoflurane 2% in oxygen. All patients in both groups received ephedrine 0.1 mg/kg IV before and after the anesthetic induction. Ephedrine increased the heart rate significantly (P < 0.05) in awake patients in both study groups. In contrast, there was no increase in heart rate after the ephedrine administration under propofol or sevoflurane anesthesia. In awake patients, transient increases in mean BP were observed after IV ephedrine in both groups. In the Propofol group, 2 min after the administration of ephedrine, mean BP increased 16% ± 10% under anesthesia but increased only 4% ± 6% when the same patients were awake. The magnitudes of the pressor responses to ephedrine during propofol anesthesia were significantly greater (P < 0.05) than during the awake state. However, ephedrine 0.1 mg/kg IV showed no significant increases in BP during sevoflurane anesthesia. We conclude that propofol, not sevoflurane, anesthesia augments the pressor responses to IV ephedrine.

IMPLICATIONS: The effect of anesthetics on vasopressor-mediated cardiovascular effects is poorly understood. We evaluated the pressor response to ephedrine during propofol or sevoflurane anesthesia. Our study suggests that anesthesia-induced hypotension may be easier to reverse with ephedrine during propofol anesthesia than during sevoflurane anesthesia.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Propofol is now widely used in clinical practice because of its favorable recovery profile and infrequent incidence of side effects (1). However, the induction of anesthesia with propofol is often associated with a significant decrease in arterial blood pressure (BP) and heart rate (HR) (2). The hypotensive effect of propofol has been attributed to a decrease in systemic vascular resistance (1,3) or in cardiac output (4) caused by a combination of venous and arterial vasodilation (3,5), impaired baroreflex mechanisms (6), and depression of myocardial contractility (7). Although an inhibition of the sympathetic nervous system may explain all the propofol-induced hemodynamic changes (6), the direct vasodilation (8) and negative inotropic effect (7,9) may contribute to a lesser degree. Because of the multiplicity of mechanisms that can explain anesthetic-induced hypotension, the vasopressor response could be altered during anesthesia. In fact, the vasoconstrictor response to {alpha}-adrenoreceptor activation was potentiated during propofol anesthesia, whereas the vasodilator response to ß-adrenoreceptor activation was not altered in dogs (10). If this is the case in humans, the effects of pressor drugs might be altered during propofol anesthesia. Despite of the importance of this information, little is known about the effect of anesthetics on vasopressor pharmacology.

Prophylactic use of ephedrine, a vasopressor commonly used during anesthesia, attenuates the hemodynamic response to the bolus administration of propofol (11–14). However, the magnitude of the decreases in BP was almost identical in the presence or absence of prophylactic treatment with ephedrine (13). In contrast, other investigators reported that ephedrine did not cause a pressor response during propofol anesthesia (15). Because ephedrine acts indirectly, primarily by releasing endogenous catecholamines from the adrenergic nerve terminals and the adrenal medulla (16), the responses to ephedrine can differ depending upon particular clinical circumstances. In fact, the pressor responses to ephedrine are different between awake and anesthetized patients and also different in patients with or without oral clonidine premedication (15,17). Lack of information concerning the pressor response to ephedrine without the influence of anesthesia could be attributed to these differences. The first goal of the current study was to test the hypothesis that the pressor response to IV ephedrine would be altered during propofol anesthesia. Sevoflurane is also frequently used for induction and maintenance of anesthesia. Our second goal was to test the hypothesis that the effect of sevoflurane on the pressor response to IV ephedrine would be different from that of propofol. Therefore, we designed this study to determine whether propofol anesthesia could affect the pressor response to IV ephedrine when compared with the awake state and to compare the effects of propofol and sevoflurane on the ephedrine-induced pressor response.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
The Institutional Ethics Committee at Sapporo Medical University approved this study, and all patients granted their written informed consent. The authors studied 30 patients (ASA physical status I) scheduled for elective oral or otolaryngeal surgery. Patients were excluded if they suffered from severe ischemic heart disease, congestive heart failure, diabetes mellitus, or other disorders known to affect autonomic function. None of the patients were taking medications that affect cardiovascular function.

A summarized protocol is represented in Figure 1. All patients were premedicated with oral zopiclone 7.5 mg, a cyclopyrrolone hypnosedative. On arrival to the operating room, standard monitoring was used. The inspired oxygen and end-tidal concentrations of carbon dioxide and sevoflurane were measured continuously with a calibrated infrared gas analyzer. Before the induction of anesthesia, patients were randomized to one of two groups by use of sealed, shuffled envelopes. All patients received 100% oxygen via a face mask for 2–3 min before the induction of general anesthesia. In the Propofol group, patients received propofol 2.5 mg/kg IV for the induction followed by 100 µg · kg-1 · min-1 IV for maintenance. In the Sevoflurane group, anesthesia was induced with sevoflurane 3%–4% in oxygen and maintained with sevoflurane 2% (end-tidal) in oxygen. Tracheal intubation was facilitated with vecuronium 0.1 mg/kg IV. Ventilation was controlled mechanically to maintain end-tidal carbon dioxide in the 34–38 mm Hg range. All patients in both groups received ephedrine 0.1 mg/kg IV twice before and after the anesthetic induction. Before each ephedrine administration, a stable hemodynamic period of at least 10 min had been obtained. Hemodynamic measurements were made at 1-min intervals for 10 min after the injection of ephedrine.



View larger version (31K):
[in this window]
[in a new window]
  		Figure 1. The study protocol.

 
Data are expressed as mean ± SD. Mean blood pressure (MBP) was calculated as diastolic blood pressure plus 1/3 x systolic blood pressure. We decided that a 10% difference in percentage change of MBP relative to baseline between the groups would be clinically important. Therefore, n = 15 patients in each group would be necessary to detect such a difference if {alpha} = 0.05 and ß = 0.1. Similar sample sizes (n = 10–20 in each group) are used in published studies (15,17). Continuous variables were analyzed using analysis of variance, and the {chi}2 test was used for descriptive (categorical) variables. Bonferroni correction was used for multiple comparisons between groups and for repeated comparisons over time. P values <0.05 were considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
The two study groups were comparable with respect to age, weight, height, and sex (Table 1). Baseline values of BP and HR in awake patients were similar in both groups (Table 2). Although BP decreased after the induction of anesthesia in both groups, baseline BP and HR values under propofol or sevoflurane anesthesia were not significantly different as compared with the corresponding baseline values while awake.


View this table:
[in this window]
[in a new window]
  		Table 1. Demographic Characteristics of the Two Anesthetic Groups
 

View this table:
[in this window]
[in a new window]
  		Table 2. Hemodynamic Responses to Ephedrine 0.1 mg/kg
 
In both groups, while the patients were awake, HR increased significantly (P < 0.05) after the administration of ephedrine (Table 2). The HR increases after ephedrine were sustained during the 10-min study period in both groups, and the magnitudes of positive chronotropic responses to ephedrine in the two groups were almost identical. In contrast, there was no increase in HR after the ephedrine administration under propofol or sevoflurane anesthesia.

In awake patients, transient increases in BP were observed after IV ephedrine in both groups (Table 2 and Fig. 2). During propofol anesthesia, the magnitudes of the pressor responses to ephedrine were significantly greater (P < 0.05) than during the awake state (Fig. 2). Two minutes after IV ephedrine, MBP increased by 16% ± 10% and 4% ± 6% during propofol anesthesia and the awake state, respectively. However, ephedrine 0.1 mg/kg IV showed no significant increase in BP during sevoflurane anesthesia (Table 2 and Fig. 3).



View larger version (22K):
[in this window]
[in a new window]
  		Figure 2. Percent changes in mean blood pressure (MBP) after ephedrine 0.1 mg/kg IV in patients during propofol anesthesia and when awake. Values are expressed as mean ± SD. *P < 0.05 versus baseline. {dagger}P < 0.05 versus awake.

 


View larger version (20K):
[in this window]
[in a new window]
  		Figure 3. Percent changes in mean blood pressure (MBP) after ephedrine 0.1 mg/kg IV in patients during sevoflurane anesthesia and when awake. Values are expressed as mean ± SD. *P < 0.05 versus baseline.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The major findings of this study were as follows: (a) propofol anesthesia was associated with significant enhancement of the pressor response to IV ephedrine during a quasi steady state of anesthesia when compared with the awake state, (b) in contrast to propofol, sevoflurane had no effect on the pressor response to ephedrine, and (c) both propofol and sevoflurane attenuated the positive chronotropic effect of ephedrine.

Because hypotension is an important problem during the induction of anesthesia with propofol (1,2), prophylactic use of vagolytic drugs (18), vasopressors (11–14), or intravascular fluid administration (11) have been used in an attempt to overcome it. Propofol probably causes hypotension mainly by decreasing sympathetic activity (6). Ephedrine is a partial, indirectly acting, sympathomimetic amine that exerts its effect primarily by the release of endogenous catecholamines from the adrenergic nerve terminals and the adrenal medulla (16). Therefore, ephedrine should be able to attenuate propofol-induced hypotension effectively by increasing sympathetic activity. Although prophylactic IV ephedrine is effective for propofol-induced hypotension (11–14), indiscriminate use of vasopressors can cause tachycardia, hypertension, and complications thereof. This study was conducted to examine the effect of propofol on the pressor response to ephedrine. We have shown that the pressor response to ephedrine is augmented during propofol anesthesia when compared with the awake state.

The mechanism underlying the greater pressor response to ephedrine under propofol anesthesia is unclear from this study. Similar observations have been made during enflurane anesthesia (17). Nishikawa et al. (17) compared the pressor response to IV ephedrine (0.1 mg/kg) in awake patients with patients under enflurane anesthesia. The magnitude of pressor response to ephedrine was greater in patients under enflurane anesthesia than in awake patients. They suggested that general anesthetics might augment the pressor effects of ephedrine primarily by potentiating {alpha}-adrenoreceptor-mediated vasoconstriction. Their findings are compatible with our results concerning an augmentation of pressor effects of ephedrine under propofol anesthesia; however, the augmentation was not seen during sevoflurane anesthesia.

We postulate two possible mechanisms for the augmented pressor response to ephedrine during propofol anesthesia. First, propofol, but not sevoflurane, could cause a depression in sympathetic activity. In humans, similar doses of propofol reduced muscle sympathetic nerve activity by 76% (6), whereas 3% sevoflurane showed only a minimum effect on the muscle sympathetic nerve activity (19). The different baseline levels of sympathetic nerve activity between the two anesthetic groups could be attributed to the differences in the pressor response to ephedrine. In addition, enflurane suppresses the sympathetic nerve activity more than sevoflurane or isoflurane in rabbits (20). This finding also supports our idea that differences in anesthetic-specific sympathetic tone could cause the differences in the response to ephedrine. Second, propofol could have a different effect on adrenergic receptors. Ephedrine causes {alpha}- and ß-adreno-receptor actions. Thus, stimulation of ß-adreno-receptors causes vasodilation, which counterbalances the {alpha}-adrenoreceptor-mediated vasoconstriction. If propofol selectively attenuates the ß-adrenergic response, the pressor effect of ephedrine would be augmented. In the present study, the fact that the positive chronotropic effect of ephedrine was attenuated during propofol anesthesia would support this idea. In fact, an attenuation of ß-adrenergic response by propofol has been reported in vitro (9). Moreover, propofol would potentiate a vasoconstrictor response to {alpha}-adrenoreceptor activation. This idea is supported by the fact that the vasoconstrictor response to {alpha}-adrenoreceptor activation was potentiated during propofol anesthesia, whereas the vasodilator response to ß-adrenoreceptor activation was not altered in chronically instrumented dogs (10). In vitro, propofol also potentiates {alpha}-adrenoreceptor-mediated pulmonary vasoconstriction by inhibiting the concomitant production of prostacyclin by cyclooxygenase (21). Although alterations in adrenergic receptor-mediated response by propofol are evident in animals (9,10,21), further study concerning responsiveness of {alpha}- or ß-adrenoreceptors during propofol anesthesia in humans is required to confirm this hypothesis.

In contrast to our results, ephedrine did not cause any significant pressor response under propofol anesthesia in a similar study by Hayakawa-Fujii et al (15). Ephedrine 0.1 mg/kg caused no significant changes in HR and BP in patients anesthetized with propofol in their study (15). In the present study, during propofol anesthesia, the magnitudes of the pressor responses to ephedrine were significantly greater than when patients were awake (Fig. 1). The precise reason for the different responses to ephedrine during propofol anesthesia between our present results and their study is not clear. The lack of information about the pressor response to ephedrine in awake subjects in their study might explain the differences. Because the pressor effect of ephedrine depends on the basal level of sympathetic activity, the pressor response could be underestimated when a control response was not estimated in the awake state. In addition, the relatively small number of patients (n = 10 in each group) may have reduced the detecting power in their study (15).

There are several limitations in our study. We did not study different doses of each anesthetic and therefore are unable to generate dose-response information. In addition, we chose to use the usual and often administered dose and concentration of propofol and sevoflurane, respectively (22). Because there is no MAC-equivalent for IV anesthetics such as propofol, and there is no reliable monitor for estimating depth of anesthesia, it was not possible for us to determine whether an equal depth of anesthesia was achieved with sevoflurane and propofol during the study period. However, we believe it is unlikely that the anesthetic depth was significantly different in the two groups because the baseline hemodynamics were almost identical.

In conclusion, the pressor response to ephedrine 0.1 mg/kg IV was enhanced during propofol anesthesia as compared with awake patients. In contrast, sevoflurane anesthesia showed no significant effect on the pressor response to ephedrine. We expect that intraoperative hypotension can be treated more effectively by IV ephedrine during propofol anesthesia when compared with sevoflurane anesthesia.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Smith I, White PF, Nathanson M, Gouldson R. Propofol: an update on its clinical use. Anesthesiology 1994; 81: 1005–43.[ISI][Medline]
  2. Hug CCJ, McLeskey CH, Nahrwold ML, et al. Hemodynamic effects of propofol: data from over 25,000 patients. Anesth Analg 1993; 77: S21–9.
  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. Monk CR, Coates DP, Prys-Roberts C, et al. Haemodynamic effects of prolonged propofol infusions supplementing nitrous oxide anaesthesia for peripheral vascular surgery. Br J Anaesth 1987; 59: 954–60.[Abstract/Free Full Text]
  5. Robinson BJ, Ebert TJ, O’Brien TJ, et al. Mechanisms whereby propofol mediates peripheral vasodilation in humans: sympathoinhibition or direct vascular relaxation? Anesthesiology 1997; 86: 64–72.[ISI][Medline]
  6. Ebert TJ, 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]
  7. Kanaya N, Murray PA, Damron DS. Propofol and ketamine only inhibit intracellular Ca2+ transients and contraction in rat ventricular myocytes at supraclinical concentrations. Anesthesiology 1998; 88: 781–91.[ISI][Medline]
  8. Chang KSK, Davis RF. Propofol produces endothelium-independent vasodilation and may act as a Ca2+ channel blocker. Anesth Analg 1993; 76: 24–32.[Abstract/Free Full Text]
  9. Kanaya N, Namiki A, Murray PA, Damron DS. Propofol attenuates inotropic response to beta adrenoreceptor activation in rat cardiomyocytes. Anesthesiology 1999; 91: A665.
  10. Kondo U, Kim SO, Nakayama M, Murray PA. Pulmonary vascular effects of propofol at baseline, during elevated vasomotor tone, and in response to sympathetic {alpha}- and ß-adrenoreceptor activation. Anesthesiology 2001; 94: 815–23.[ISI][Medline]
  11. El-Beheiry H, Kim J, Milne B, Seegobin R. Prophylaxis against the systemic hypotension induced by propofol during rapid-sequence intubation. Can J Anaesth 1995; 42: 875–8.[Abstract/Free Full Text]
  12. Kasaba T, Yamaga M, Iwasaki T, et al. Ephedrine, dopamine, or dobutamine to treat hypotension with propofol during epidural anesthesia. Can J Anaesth 2000; 47: 237–41.[Abstract/Free Full Text]
  13. Michelsen I, Helbo-Hansen HS, Køhler F, et al. Prophylactic ephedrine attenuates the hemodynamic response to propofol in elderly female patients. Anesth Analg 1998; 86: 477–81.[Abstract]
  14. Gamlin F, Vucevic RM, Winslow L, Berridge J. The haemodynamic effects of propofol in combination with ephedrine. Anaesthesia 1996; 51: 488–91.[ISI][Medline]
  15. Hayakawa-Fujii Y, Iida H, Dohi S. Propofol anesthesia enhances pressor response to ephedrine in patients given clonidine. Anesth Analg 1999; 89: 37–41.[Abstract/Free Full Text]
  16. Zaimis E. Vasopressor drugs and catecholamines. Anesthesiology 1968; 29: 732–62.[ISI][Medline]
  17. 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]
  18. Sneyd JR, Mayall R. The effect of pre-induction glycopyrronium on the haemodynamic response of elderly patients to anesthesia with propofol. Anaesthesia 1992; 47: 620–1.[ISI][Medline]
  19. Ebert TJ, Muzi M, Lopatka CW. Neurocirculatory responses to sevoflurane in humans: a comparison to desflurane. Anesthesiology 1995; 83: 88–95.[ISI][Medline]
  20. 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]
  21. Ogawa K, Tanaka S, Murray PA. Propofol potentiates phenylephrine-induced contraction via cyclooxygenase inhibition in pulmonary artery smooth muscle. Anesthesiology 2001; 94: 833–9.[ISI][Medline]
  22. Fredman B, Nathanson MH, Smith I, et al. Sevoflurane for outpatient anesthesia: a comparison with propofol. Anesth Analg 1995; 81: 823–8.[Abstract]
Accepted for publication December 17, 2001.





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 ISI Web of Science (6)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Kanaya, N.
Right arrow Articles by Namiki, A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kanaya, N.
Right arrow Articles by Namiki, A.

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