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 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
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via Web of Science (1)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Orme, R.
Right arrow Articles by Ugoni, A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Orme, R.
Right arrow Articles by Ugoni, A.
Related Collections
Right arrow Cardiovascular
Right arrow Pharmacology
Anesth Analg 2002;94:112-116
© 2002 International Anesthesia Research Society

ANESTHETIC PHARMACOLOGY

Esmolol and Anesthetic Requirement for Loss of Responsiveness During Propofol Anesthesia

Ruari Orme, MBBS*{dagger}, Kate Leslie, MD FANZCA{dagger}, Abhay Umranikar, MBBS FANZCA*, and Antony Ugoni, BSc(Hons), MSciStat{ddagger}

*Department of Anaesthesia, Ballarat Base Hospital, Ballarat, Victoria, Australia; {dagger}Outcomes ResearchTM Group, Department of Anaesthesia and Pain Management, Royal Melbourne Hospital, Parkville, Victoria, Australia; and {ddagger}University of Melbourne, Victoria, Australia

Address correspondence and reprint requests to Kate Leslie, MD, FANZCA, Department of Anaesthesia and Pain Management, Royal Melbourne Hospital, Parkville, VIC, 3050, Australia. Address e-mail to kate.leslie{at}mh.org.au


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
The administration of esmolol decreases the propofol blood concentration, preventing movement after skin incision during propofol/morphine/nitrous oxide anesthesia. However, interaction with esmolol has not been tested when propofol is infused alone. Accordingly, we tested the hypothesis that esmolol decreases the propofol blood concentration, preventing response to command (CP50-awake) when propofol is infused alone in healthy patients presenting for minor surgery. With approval and consent, we studied 30 healthy patients, who were randomized to esmolol bolus (1 mg/kg) and then infusion (250 µg · kg-1 · min-1) or placebo. Five minutes later, a target-controlled infusion of propofol was commenced. Ten minutes later, responsiveness was assessed by a blinded observer. Oxygen saturation, heart rate, and noninvasive arterial blood pressure were recorded every 2 min. Arterial blood samples were taken at 5 and 10 min of propofol infusion for propofol assay. Results were analyzed with a generalized linear regression model: P <0.05 was considered statistically significant. The probability of response to command decreased with increasing propofol blood concentration (CP50-awake = 3.42 µg/mL). Esmolol did not alter the relative risk of response to command. We conclude that the previously observed effect of esmolol on propofol CP50 was not caused by an interaction between these two drugs.

IMPLICATIONS: There is no evidence to suggest that esmolol, an ultra-short-acting cardioselective ß-blocker, affects anesthetic requirement for loss of responsiveness during propofol anesthesia.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Esmolol is used in anesthesia to attenuate stress responses to tracheal intubation, control postoperative hypertension, and manage unstable coronary syndromes and tachyarrhythmias (1). Because of its potential for drug interactions via central nervous system depression (2,3) and for acute hemodynamic effects (4), esmolol has been investigated for possible interactions with anesthetics (5–8).

Johansen et al. (6) initially reported that esmolol decreased propofol blood concentrations, preventing movement after skin incision (CP50) during propofol/morphine/nitrous oxide anesthesia. Subsequently, they reported that esmolol increased the anesthetic-sparing effect of alfentanil during isoflurane anesthesia but had no effect on isoflurane requirements for skin incision on its own (7). However, interaction with esmolol has not been tested for propofol infused alone. Accordingly, we tested the hypothesis that esmolol decreases the propofol blood concentration, preventing response to command (CP50-awake) when propofol is infused alone in healthy patients presenting for minor surgery.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
With approval from the Institutional Ethics Committees and informed consent, 30 patients, aged 18–60 yr and of ASA physical status I or II, scheduled for minor orthopedic and general surgical procedures, were studied. Exclusion criteria included: 1) >150% of ideal body weight; 2) significant coexisting illness, including asthma or hypertension; 3) coincidental prescribed or nonprescribed drugs affecting anesthetic requirement; and 4) risk of gastroesophageal reflux during sedation.

By using random number tables, patients were randomized to receive an esmolol bolus (1 mg/kg) and then infusion (250 µg · kg-1 · min-1) or a placebo (normal saline) bolus and infusion. In addition, patients were randomized to receive target propofol blood concentrations (1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, and 5.0 µg/mL; 2.5, 3.0, and 3.5, n = 4 patients; other targets, n = 3 patients), administered by a target-controlled infusion (TCI) device (9). The esmolol dose was chosen on the basis of the large dose in the study of Johansen et al. (6). Target propofol blood concentrations were chosen on the basis of the published CP50-awake of propofol (10). Randomization results were concealed in sealed opaque envelopes.

No premedication was given. Oxygen was administered via a Hudson mask at 6 L/min, and routine monitoring was commenced. A 22-gauge IV cannula was inserted into an antecubital vein, and intradermal local anesthetic was injected over the radial artery, in preparation for blood sampling for propofol assay.

A bolus of esmolol or normal saline then was administered, and the esmolol or normal saline infusion was commenced. Five minutes later, the TCI of propofol was commenced. Fifteen minutes after the esmolol infusion was started, the patient was tapped on the shoulder and asked to open his or her eyes by an observer who was blinded to the randomization and monitored vital signs. A positive response was recorded if the patient opened his or her eyes after any of three requests to do so. At the completion of the study, anesthesia was continued according to the needs of the patient and the surgery.

Arterial blood pressure was measured noninvasively every 2 min. Hemoglobin oxygen saturation and the electrocardiograph were monitored continuously.

To confirm steady-state propofol blood concentrations, blood was taken from the radial artery at 5 and 10 min of propofol infusion. Blood samples for propofol assay were collected in heparinized tubes, placed on ice, and subsequently stored at 4°C for up to 10 wk. Propofol blood concentrations decreased at <0.2%/wk at 4°C. They were subsequently analyzed with a high-performance liquid chromatography assay, modified from the method of Plummer (11). This assay is linear to at least 20 µg/mL and has a detection limit of 0.025 µg/mL and a coefficient of variation of 4.1% at 2 µg/mL.

Distributions of age and weight in the two groups were compared by using the two-sample Kolmogorov-Smirnov test, because a similar spread of age and weight is more important than similar average values when comparing groups at baseline.

Measured propofol concentration at 10 min of propofol infusion and patient age were included as independent variables in the analyses. Because of the design of the trial (cohort), results are expressed as relative risks. This was achieved by using a generalized linear model with a log link and a binomial error distribution. Where convergence of such a model was not attained, the method of Skov et al. (12) was used. For comparison, results also are presented as odds ratios, which were obtained with logistic regression.

Mean arterial blood pressure and heart rate values were compared with awake control values. Plots of changes in mean arterial blood pressure and heart rate were inspected before analysis (Figs. 1 and 2). Mean arterial blood pressures decreased over time from the start of the study in both groups. Percentage changes in mean arterial blood pressure from awake control values in each group therefore were analyzed with a generalized linear model with various links and Gaussian error distribution. Heart rates decreased initially, then returned to baseline after propofol infusion was commenced. Percentage change in heart rate at 2 min of infusion therefore was compared between the two groups by using an unpaired two-tailed Student’s t-test. The aim of this analysis was to determine whether a significant pharmacologic effect of esmolol (i.e., decreased heart rate) was present in the treatment group in the absence of propofol.



View larger version (16K):
[in this window]
[in a new window]
  		Figure 1. Mean arterial blood pressure (MABP) (mm Hg; percentage of awake control) versus time. Esmolol infusion commenced at 0 min; propofol infusion commenced at 5 min. Results presented as mean ± SD. MABP decreased significantly over time in both groups, but esmolol did not affect the change in MABP over time. Absolute values for change in MABP were used in the model Ln|MABP| = 1.2 + 0.11(time).

 


View larger version (15K):
[in this window]
[in a new window]
  		Figure 2. Heart rate (bpm; percentage of awake control) versus time. Esmolol infusion commenced at 0 min; propofol infusion commenced at 5 min. Results presented as mean ± SD. Heart rate was significantly slower in the Esmolol group compared with the Control group 2 min after commencement of propofol infusion (P = 0.02).

 
Median performance error (MDPE; bias) and median absolute performance error (MDAPE; inaccuracy) for each group were compared by using unpaired two-tailed Student’s t-tests, because they were normally distributed (13). The relationship between targeted and measured propofol concentrations for each group was determined with a generalized linear model with various links and Gaussian error distribution. Equality of agreement between the groups also was assessed by bootstrapping the difference in intercepts and slopes between the groups. All statistical analyses were performed with Stata 6.0 (Stata Corporation, College Station, TX). Results are presented as mean ± SD; P <0.05 was considered statistically significant.

Modeling of effect-site concentrations was performed with TIVA Trainer (Version 4, Frank Engbers©, Leiden, Netherlands), with ke0 values of 0.26 per minute (used by the TCI device to predict effect-site concentrations) (14) and 1.21 per minute [calculated by the method of Struys et al. (15) on the basis of the pharmacokinetic model used by the TCI device (16) and a time to peak effect of 1.6 min (17)].


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Ten women and 20 men were studied. The distributions of age (range, 20–57 vs 19–54 yr; P = 0.999) and weight (range, 48–89 vs 62–110 kg; P = 0.116) were similar in the Control and Esmolol groups. Mean ages were 37 ± 12 vs 35 ± 12 yr and mean weights were 70 ± 14 vs 78 ± 12 kg in the Control and Esmolol groups, respectively. Many patients were sedated during propofol infusion, but no episode of airway obstruction or apnea occurred.

Measured propofol concentration was a significant predictor of response to command (relative risk = 1.58 [95% confidence limits, 1.05–2.36]; P = 0.03). Age and the addition of esmolol were not significant predictors of response in the model (Table 1). Esmolol did not change the effect of propofol concentration, or propofol concentration adjusted for age, on the likelihood of response to command (Table 2). The CP50-awake of propofol in this study was 3.42 µg/mL (Fig. 3).


View this table:
[in this window]
[in a new window]
  		Table 1. Relative Risks and Odds Ratios for Effect of Esmolol on Propofol CP50-Awake
 

View this table:
[in this window]
[in a new window]
  		Table 2. Relative Risks and Odds Ratios for Interactions Between Propofol and Esmolol
 


View larger version (21K):
[in this window]
[in a new window]
  		Figure 3. Probability of patients not responding to command versus measured propofol concentration. Raw data for nonresponders are displayed above and for responders are displayed below. For all patients, the relationship was defined by the equation log[p/(1 - p)] = -4.812134 + 1.40627 x propofol. The equations for the Control and Esmolol groups were, respectively, log[p/(1 - p)] = -4.036012 + 1.28231x propofol and log[p/(1 - p)] = -7.642414 + 2.048689 x propofol. Esmolol did not have a significant effect on the relationship between measured propofol concentration and response to command.

 
The mean arterial blood pressure decreased significantly over time in both groups (P <0.001), but when esmolol was added to the model, there was no evidence to suggest that the effect of time on mean arterial blood pressure differed between the Control and Esmolol groups (P = 0.36) (Fig. 1). After 2 min of esmolol infusion, the percentage change in heart rate was significantly larger in the Esmolol group compared with the Control group (-12% ± 8% vs -4% ± 10%; P = 0.02) (Fig. 2).

Measured propofol concentrations varied by -1% ± 7% (range, -14% to +9%) between 5 and 10 min of propofol infusion. The MDPE of the TCI device was +22% (95% confidence limits, 7%–38%); the MDAPE was 25% (95% confidence limits, 14%–42%). The addition of esmolol significantly altered the performance of the TCI device, because both the MDPE (42% [16%–73%] vs 7% [-8% to 28%]; P = 0.002) and MDAPE (42% [16%–73%] vs 15% [7%–34%]; P = 0.00001) were significantly greater in the Esmolol group compared with the Control group.

Targeted propofol concentration was a significant predictor of measured concentration in the model in both the Esmolol and Control groups (P <0.0001). However, esmolol was not a significant predictor of measured propofol concentration in the generalized linear model (P = 0.91) (Fig. 4) (Table 3). After bootstrapping, the 95% confidence limits for the difference in intercepts were -2.05072 to 1.68030, and for the difference in slopes they were -1.00125 to 0.26529, indicating a lack of evidence to reject the hypothesis that the regressions are the same.



View larger version (11K):
[in this window]
[in a new window]
  		Figure 4. Measured (arterial) propofol concentration (µg/mL) versus targeted propofol concentration (µg/mL) at 10 min of propofol infusion. Esmolol was not a significant predictor of the relationship between measured and targeted propofol concentrations.

 

View this table:
[in this window]
[in a new window]
  		Table 3. Regression Results for Measured Propofol Concentration
 
On the basis of a ke0 of 0.26 per minute, effect-site propofol concentrations reached 93% ± 1% of the target propofol concentration at the end of a 10-min infusion. On the basis of a ke0 of 1.21 per minute, effect-site propofol concentrations equilibrated completely with target propofol concentrations in < 5 min.


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Esmolol had no significant effect on propofol CP50-awake in this study, and this is consistent with the previous work of Johansen et al. (6,7). They suggested that esmolol interacted with opioids to produce an anesthetic-sparing effect, probably via a pharmacokinetic mechanism. Esmolol is capable of pharmacokinetic interactions with digoxin (18) and rocuronium (8). In contrast, however, esmolol did not alter the pharmacokinetics of remifentanil in an animal study (19). The nature of the interaction between esmolol and the opioids therefore remains unclear.

Esmolol may have altered the pharmacokinetics of propofol in our study, as the bias and inaccuracy of the TCI device increased. This result does not affect our pharmacodynamic analysis, however, because only measured propofol concentrations were used. Esmolol may alter drug metabolism and distribution via effects on hepatic blood flow and subsequent drug clearance (20). In addition, redistribution of propofol from the central compartment may be limited. However, we did not measure cardiac output or hepatic blood flow or undertake pharmacokinetic modeling, and therefore we cannot confirm these hypotheses.

Our result contrasts with that of Johansen et al. (6), who reported no change in the performance of their TCI device with esmolol administration. In addition, they reported no significant differences in heart rate and mean arterial blood pressure between control and esmolol patients, whereas heart rate was significantly different at two minutes in patients receiving esmolol in our study. Endotracheal intubation, surgical incision, and the use of adjuvant drugs in the study of Johansen et al. complicate comparison with our results.

The lack of an anesthetic-sparing effect of esmolol in this study and those of Johansen et al. (6,7) could be caused by a lack of esmolol effect per se. However, esmolol infusion, at rates similar to those used in this and previous studies, produces ß-adrenergic blockade rapidly, with an onset time of two minutes and near steady-state effect within five minutes (4). We believe that an esmolol effect was present in our study, as evidenced by a greater decrease in heart rate in the Esmolol group compared with Control two minutes after the infusion of esmolol was started.

The CP50-awake of propofol in this study was 3.42 µg/mL, which is consistent with published values (10,21–23). Variation in reported CP50-awake values probably results from differences in the degree of stimulation when loss of responsiveness is assessed (23). Age also affects the propofol requirement for loss of responsiveness (17,21,24). However, age was not a significant predictor of the propofol concentrations preventing response to command in our model, perhaps because of the narrow age range of the patients we studied.

The duration of propofol infusion used in this study was relatively short but similar to previous studies (6). Propofol blood concentrations produced by the TCI device were stable when responsiveness was assessed. In addition, after our modeling of the effect-site concentrations by using various values for ke0, we are satisfied that effect-site concentrations would have been relatively stable at 10 minutes as they asymptotically approached the targeted blood concentration.

In conclusion, esmolol had no significant effect on propofol CP50-awake in this study. Our result is consistent with previous work by Johansen et al. (6,7), whose results are probably explained by a pharmacokinetic interaction between esmolol and the opioids.


   Acknowledgments
 
Supported by the Victor Hurley Fund, Royal Melbourne Hospital Research Foundation.

We acknowledge the contribution of Shona Charlton, BSc (Hon).


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Wiest D. Esmolol: a review of its therapeutic efficacy and pharmacokinetic characteristics. Clin Pharmacokinet 1995; 28: 190–202.[Web of Science][Medline]
  2. Waal HJ. Propranolol-induced depression. Br Med J 1967; 2: 50.
  3. Granville-Grossman K, Turner P. The effect of propranolol on anxiety. Lancet 1966; 1: 788–90.[Medline]
  4. Reilly C, Wood M, Koshakji R, et al. Ultra-short-acting beta-blockade: a comparison with conventional beta-blockade. Clin Pharmacol Ther 1985; 38: 579–85.[Web of Science][Medline]
  5. Coloma M, Chiu J, White P, Armbruster S. The use of esmolol as an alternative to remifentanil during desflurane anesthesia for fast-track outpatient gynecologic laparoscopic surgery. Anesth Analg 2001; 92: 352–7.[Abstract/Free Full Text]
  6. Johansen J, Flaishon R, Sebel P. Esmolol reduces anesthetic requirement for skin incision during propofol/nitrous oxide/morphine anesthesia. Anesthesiology 1997; 86: 364–71.[Web of Science][Medline]
  7. Johansen J, Schneider G, Windsor A, Sebel P. Esmolol potentiates reduction of minimum alveolar isoflurane concentration by alfentanil. Anesth Analg 1998; 87: 671–6.[Abstract/Free Full Text]
  8. Szmuk P, Ezri T, Chelly J, Katz J. The onset time of rocuronium is slowed by esmolol and accelerated by ephedrine. Anesth Analg 2000; 90: 1217–9.[Abstract/Free Full Text]
  9. Glen JB. The development of "Diprifusor": a TCI system for propofol. Anaesthesia 1998; 53 (Suppl 1): 13–21.
  10. Vuyk J, Engbers F, Lemmens HJ, et al. Pharmacodynamics of propofol in female patients. Anesthesiology 1992; 77: 3–9.[Web of Science][Medline]
  11. Plummer G. Improved method for the determination of propofol in blood by high performance liquid chromatography with fluorescence detection. J Chromatogr 1987; 421: 171–6.[Web of Science][Medline]
  12. Skov T, Deddens J, Petersen M, Endall L. Prevalence proportion ratios: estimation and hypothesis testing. Int J Epidemiol 1998; 27: 91–5.[Abstract/Free Full Text]
  13. Varvel J, Donoho D, Shafer S. Measuring the predictive performance of computer-controlled infusion pumps. J Pharmacokinet Biopharm 1992; 20: 63–94.[Web of Science][Medline]
  14. Gray JM, Kenny GNC. Development of the technology for "Diprifusor" TCI systems. Anaesthesia 1998; 53: 22–7.
  15. Struys M, De Smet T, Depoorter B, et al. Comparison of plasma compartment versus two methods for effect compartment-controlled target-controlled infusion for propofol. Anesthesiology 2000; 92: 399–406.[Web of Science][Medline]
  16. Marsh B, White M, Morton N, Kenny G. Pharmacokinetic model driven infusion of propofol in children. Br J Anaesth 1991; 67: 41–8.[Abstract/Free Full Text]
  17. Schnider T, Minto C, Shafer S, et al. The influence of age on propofol pharmacodynamics. Anesthesiology 1999; 90: 1502–16.[Web of Science][Medline]
  18. Lowenthal D, Porter S, Saris S, et al. Clinical pharmacology, pharmacokinetics and interactions with esmolol. Am J Cardiol 1985; 56: 14F–18F.[Medline]
  19. Haidar S, Moreton J, Liang Z, et al. The pharmacokinetics and electroencephalogram response of remifentanil alone and in combination with esmolol in the rat. Pharmacol Res 1997; 14: 1817–23.
  20. Deegan R, Wood A. Beta-receptor antagonism does not fully explain esmolol-induced hypotension. Clin Pharmacol Ther 1994; 56: 223–8.[Web of Science][Medline]
  21. Smith C, McEwan AI, Jhavieri R, et al. The interaction of fentanyl on the CP50 of propofol for loss of consciousness and skin incision. Anesthesiology 1994; 81: 820–8.[Web of Science][Medline]
  22. Chortkoff BS, Eger EI, Crankshaw DP, et al. Concentrations of desflurane and propofol that suppress response to command in humans. Anesth Analg 1995; 81: 737–43.[Abstract]
  23. Kazama T, Ikeda K, Morita K. Reduction by fentanyl of the CP50 values of propofol and hemodynamic responses to various noxious stimuli. Anesthesiology 1997; 87: 213–27.[Web of Science][Medline]
  24. Kazama T, Takeuchi K, Ikeda K, et al. Optimal propofol plasma concentration during upper gastrointestinal endoscopy in young, middle-aged, and elderly patients. Anesthesiology 2000; 93: 622–9.
Accepted for publication August 15, 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 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
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via Web of Science (1)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Orme, R.
Right arrow Articles by Ugoni, A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Orme, R.
Right arrow Articles by Ugoni, A.
Related Collections
Right arrow Cardiovascular
Right arrow Pharmacology

Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2002 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press