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AMBULATORY ANESTHESIA

The Effect of Intraoperative Use of Esmolol and Nicardipine on Recovery After Ambulatory Surgery

Paul F. White, PhD MD, FANZCA^*, Baoguo Wang, MD^*,, Jun Tang, MD^*,, Ronald H. Wender, MD, Robert Naruse, MD, and Alexander Sloninsky, MD

*Department of Anesthesiology and Pain Management, University of Texas Southwestern Medical Center, Dallas, Texas; and Department of Anesthesiology, Cedars-Sinai Medical Center, Los Angeles, California

Address correspondence and reprint requests to Dr. Paul F. White, Department of Anesthesiology and Pain Management, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390–9068. Address e-mail to paul.white{at}utsouthwestern.edu

	Abstract

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There is controversy regarding the optimal technique for maintaining hemodynamic stability during anesthesia. We designed this prospective, randomized, double-blinded study to test the hypothesis that the technique used for maintaining hemodynamic stability during general anesthesia can influence recovery after ambulatory surgery. Forty-five healthy consenting women undergoing gynecologic laparoscopy procedures were randomly assigned to 1 of 3 treatment groups: Group 1 (control, n = 15) received normal saline 5 mL and 1 mL, followed by a saline infusion at a rate of 0.005 mL · kg^-1 · min^-1; Group 2 (n = 15) received esmolol 50 mg and saline 1 mL, followed by an esmolol infusion 5 µg · kg^-1 · min^-1; and Group 3 (n = 15) received esmolol 50 mg and nicardipine 1 mg, followed by an esmolol infusion 5 µg · kg^-1 · min^-1. The study drugs were administered after the induction of anesthesia with fentanyl 1.5 µg/kg, and propofol 2 mg/kg IV. Tracheal intubation was facilitated with vecuronium 0.12 mg/kg IV. Anesthesia was initially maintained with desflurane 2% end-tidal and N₂O 67% in oxygen in all 3 groups. During surgery, the mean arterial blood pressure (MAP) was maintained within ±15% of the baseline value by varying the study drug infusion rate and the inspired concentration of desflurane. In addition to MAP and heart rate values, electroencephalogram bispectral index values were recorded throughout the perioperative period. Recovery times and postoperative side effects were assessed. Compared with the control group, adjunctive use of esmolol and nicardipine attenuated the increase in heart rate (in Group 2) and MAP (in Group 3) after tracheal intubation. Furthermore, the use of an esmolol infusion as an adjunct to desflurane to control the acute autonomic responses during the maintenance period significantly decreased emergence times (4 ± 2 versus 7 ± 4 min), decreased the need for postoperative opioid analgesics (43% versus 80%), and reduced the time to discharge (209 ± 89 versus 269 ± 100 min). We conclude that the adjunctive use of esmolol alone or in combination with nicardipine during the induction of anesthesia reduced the hemodynamic response to tracheal intubation. Furthermore, use of an esmolol infusion as an adjuvant to desflurane-N₂O anesthesia for controlling the acute hemodynamic responses during the maintenance period improved the recovery profile after outpatient laparoscopic surgery.

IMPLICATIONS: The adjunctive use of the ß-adrenergic blocker esmolol to control the acute sympathetic responses during desflurane-based anesthesia provided a more rapid awakening from anesthesia, reduced the postoperative opioid analgesic requirement, and decreased the time to discharge home after ambulatory laparoscopic surgery.

	Introduction

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Many different anesthetic drugs and techniques have been used for the prevention and treatment of acute hemodynamic responses during surgery (1,2). Acute hyperdynamic responses during general anesthesia are usually treated by increasing the inspired concentration of the volatile anesthetic and/or administering opioid analgesics. However, several studies have suggested that sympatholytic drugs may be effective alternatives to opioid analgesics (1–4). Zaugg et al. (5) reported that, in elderly inpatients undergoing noncardiac surgery, perioperative ß-blockade with atenolol improved hemodynamic stability, reduced the opioid analgesic requirement, and contributed to a faster early recovery. Theoretically, an anesthetic drug or technique capable of effectively controlling tachycardia and hypertension during surgery while providing a faster recovery with fewer side effects would be particularly beneficial for patients undergoing ambulatory surgery.

The cardiovascular drugs esmolol and nicardipine both possess rapid onsets of action and short durations of clinical effects (6–10). Esmolol is more effective in decreasing heart rate (HR) than mean arterial blood pressure (MAP), whereas nicardipine decreases MAP as a result of its dose-dependent vasodilatory properties. With nicardipine, the blood pressure reduction is often accompanied by an increase in HR (8). Therefore, the combination of the two cardiovascular drugs might be expected to more effectively control acute hemodynamic responses than the ß-adrenergic blocker alone. In addition, the alleged anesthetic-sparing effect of esmolol (11) might facilitate the recovery process after outpatient anesthesia.

This prospective, randomized, double-blinded study was designed to test the hypothesis that the adjunctive use of esmolol, alone or in combination with nicardipine, would be as effective in controlling acute autonomic responses during desflurane-based anesthesia as varying the inspired concentration of the volatile anesthetic, and might facilitate the recovery process after outpatient laparoscopic surgery.

	Methods

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After obtaining written, informed consent, 45 healthy (ASA physical status I and II) outpatients scheduled to undergo gynecologic laparoscopic procedures under general anesthesia were randomly assigned to 1 of 3 treatment groups according to a double-blinded, placebo-controlled protocol approved by the IRB at Cedars Sinai Medical Center in Los Angeles. Women with clinically significant cardiovascular, pulmonary, renal, hepatic, and neurologic diseases, a body weight >100% above the ideal, or a history of alcohol or drug abuse were excluded from participating in this study.

All patients received midazolam 2 mg IV for preoperative medication in the holding area immediately before entering the operating room. Routine monitoring devices (including a blood pressure cuff, electrocardiogram, pulse oximeter) and electroencephalographic bispectral index (BIS) monitor (Aspect Medical Systems, Natick, MA) were applied. Zip-prep^TM electrodes were used to obtain the electroencephalographic signal and the displayed BIS values were recorded by one of the investigators (BW). However, the BIS values were not made available to the anesthesiologist for titrating the desflurane administration during the operation. Baseline MAP, HR, and BIS values were recorded 1–2 min before the induction of general anesthesia.

Anesthesia was induced with fentanyl 1.5 µg/kg and propofol 2 mg/kg IV. The 2 study drugs were prepared separately in 5- and 1-mL syringes, and were administered IV at 30- and 60-s intervals, respectively, after loss of consciousness. In Group 1 (control), the patients received normal saline 5 mL and 1 mL. In Group 2, patients received esmolol 50 mg and saline 1 mL IV, and Group 3 received esmolol 50 mg and nicardipine 1 mg IV. Tracheal intubation was performed 2–3 min after vecuronium 0.12 mg/kg IV. Anesthesia was initially maintained with desflurane 2% (inspired) and nitrous oxide (N₂O) 67% in oxygen (O₂). The total fresh gas flow rate was 1.5 L/min (N₂O/O₂ = 2:1). An IV infusion containing either saline (Group 1) or esmolol 1 mg/mL (Groups 2 and 3) was started at a rate of 0.005 mL · kg^-1 · min^-1 approximately 1–2 min before the skin incision (4). Ventilation was controlled to maintain PETCO₂ levels between 30 and 35 mm Hg. Supplemental neuromuscular blockade was provided with vecuronium 1–2 mg IV. A pneumoperitoneum was achieved and maintained at 15–20 mm Hg, and Trendelenburg position was used during the surgical procedure.

During anesthesia, the MAP was maintained within 15% of the preinduction baseline value by increasing or decreasing the infusion rate of the study medication by 50%–100%. If the patient failed to respond within 2 min to increases or decreases in the study drug infusion, the inspired concentration of desflurane was increased or decreased in increments of 1%–2%. The expired (end-tidal) desflurane and N₂O concentrations were measured using an infrared detection system (POET IQ Model 602; Criticare Systems Inc., Milwaukee, WI) and recorded at 5-min intervals throughout the maintenance period. The total amount of esmolol infused during the maintenance period was also recorded. All patients were administered prophylactic antiemetic therapy consisting of droperidol 0.625 mg IV and ondansetron 4 mg IV. Upon completion of the operation, desflurane and N₂O were discontinued, and residual neuromuscular block was antagonized with neostigmine 0.05 mg/kg and glycopyrrolate 0.01 mg/kg.

The emergence times from the end of anesthesia (e.g., opening eyes, extubation, following simple commands, orientation to person and place) were assessed at 1- to 2-min intervals, and the time to discharge home, as well as the incidences of postoperative side effects were assessed at 15-min intervals in the recovery room. Opioid analgesic (e.g., fentanyl 50 µg IV) and antiemetic (e.g., ondansetron 4 mg IV) medications were administered when patients complained of pain or emetic symptoms, respectively. The need for these "rescue" medications were recorded during the recovery period before discharge home. There was no "minimal" length of hospital stay and patients were discharged home when they satisfied standardized discharge criteria (4). At the time of discharge, all patients were asked two structured questions to determine whether they recalled any intraoperative events during the operation. The first question was "what was the last thing you remembered after entering the operating room?" The second question was "did you recall anything during your operation?"

Before initiating the study, a power analysis suggested that a sample size of 15 patients in each group should be adequate to detect a 30% reduction in the times to awakening and discharge home with a power of 0.8 and of 0.05. Data were presented as mean values ± SD unless otherwise noted. The patient’s age, weight and height, durations of anesthesia and surgery, the changes in MAP and HR from the baseline values during and after surgery, recovery variables, and times to discharge home were analyzed using analysis of variance with Bonferroni’s correction for multiple comparisons. The changes in MAP, HR, expired desflurane concentration, and BIS values over time were analyzed using repeated measures of analysis of variance with multiple comparisons to the baseline values. Fisher’s exact test was used to compare the noncontinuous demographic data and the numbers of patients receiving postoperative antiemetic and analgesic "rescue" treatments in Group 1 versus Groups 2 and 3 combined. A P value < 0.05 was considered statistically significant.

	Results

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The three treatment groups were comparable with respect to age, weight, height, and durations of anesthesia and surgery (Table 1). After the induction of anesthesia, the MAP decreased in all three groups (Fig. 1). However, the decrease in MAP was significantly larger in Group 3 than in the other two groups (P < 0.05). After tracheal intubation, MAP increased significantly above baseline value in Group 1, returned to baseline in Group 2, and remained below baseline in Group 3. In all 3 groups, MAP decreased to 10–15 mm Hg less than the preinduction baseline values 1–2 min before skin incision, and then increased with the onset of the pneumoperitoneum (Fig. 1). During the operation, MAP values were comparable in all three groups. To maintain comparable hemodynamic stability during the operation in the control group, a significantly larger end-tidal concentration of desflurane (4.3% ± 1%) was required compared with Groups 2 (1.8% ± 0.3%) and 3 (1.9% ± 0.2%) (Table 1). The maintenance dosages of esmolol were not significantly different between Groups 2 (92 ± 97 mg) and 3 (76 ± 21 mg).

View larger version (29K): [in this window] [in a new window]   Figure 1. Changes in mean arterial blood pressure (MAP) and heart rate (HR) from baseline (mean ± SEM): = control group, = esmolol group, = esmolol + nicardipine group. *P < 0.05 compared with the control group.

The BIS decreased from preinduction baseline values of 96 ± 2, 95 ± 4, and 93 ± 7 to 38 ± 5, 34 ± 5, and 37 ± 8 after the induction of anesthesia, and then increased to 53 ± 17, 58 ± 10, and 58 ± 8 at 1–2 min after skin incision in Groups 1, 2, and 3, respectively (Fig. 2). During the maintenance period, the average BIS value (±SD) in Group 1 (33 ± 14) was significantly reduced compared with Groups 2 (58 ± 12) and 3 (63 ± 5). However, the BIS value returned to the preanesthetic baseline values in all 3 groups within 5 min of eye opening.

View larger version (23K): [in this window] [in a new window]   Figure 2. Changes in the electroencephalographic (EEG) bispectral index (BIS) values in the three treatment groups (mean ± SEM): = control group, = esmolol group, = esmolol + nicardipine group. *P < 0.05 compared with the baseline values for the 3 study groups; #P < 0.05 compared with the control group for the other 2 groups.

	Discussion

Top Abstract Introduction Methods Results Discussion Conclusion References

 
A wide variety of anesthetic, analgesic, and cardiovascular drugs have been used in an attempt to attenuate the acute hemodynamic responses that occur during surgery (1). Potent opioid analgesics and volatile anesthetics are usually used to maintain hemodynamic stability during surgery. However, this study suggests that there may be advantages to using cardiovascular drugs to control these transient autonomic responses during surgery in the ambulatory setting. Compared with esmolol alone, adjunctive use of nicardipine during the induction period increased hypotension and failed to improve any of the outcome measures. The adjunctive use of an esmolol (versus saline) infusion during the maintenance period resulted in a faster emergence from desflurane-N₂O anesthesia and reduced the length of the hospital stay (e.g., the time to discharge home). Analogous to the findings of Zaugg et al. (5), fewer esmolol-treated patients required opioid analgesics in the early postoperative period. Thus, the use of esmolol seems to be a viable alternative to varying the inspired concentration of the volatile anesthetic during ambulatory surgery.

Myles (12) reported that 47% of patients experienced arrhythmias during gynecologic laparoscopy, with 30% of these being bradyarrhythmias. Nearly all the episodes occurred during the performance of the pneumoperitoneum and/or after traction on pelvic structures. It has been suggested that the sudden stretching of the peritoneal surface after initiating the insufflation of CO₂ may contribute to the reflex bradyarrhythmias. In this study, 2 patients in Group 2 developed transient nodal rhythms during pneumoperitoneum which subsequently disappeared when the esmolol infusion rate was decreased. However, no arrhythmias were observed in Groups 1 and 3. None of the intraoperative arrhythmias required treatment or led to adverse cardiovascular outcomes. However, the use of this anesthetic technique may be relatively contraindicated in patients with sick sinus syndrome, bifascicular block (or intraventricular conduction delays), and permanent pacemakers.

One of the major concerns in using sympatholytic drugs to control the hemodynamic responses during surgery relates to the fact that it may be more difficult to determine whether the patient is adequately anesthetized because acute changes in MAP and HR values in response to surgical stimulation are often used as an indicator of "depth of anesthesia." The BIS has been previously demonstrated to be quantifiable which reflects the depth of sedation-hypnosis (13–16). When unpremedicated patients were "deeply" sedated with midazolam (i.e., failed to respond to prodding or shaking), the BIS decreased from 95 ± 2 (±SD) to 69 ± 14 (13). Similar changes in the BIS values have been reported with increasing doses of propofol (14). Flaishon et al. (16) found that the average (±SD) BIS values were 89 ± 9 and 90 ± 13 when unpremedicated patients lost consciousness after propofol or thiopental, respectively. However, when patients regained consciousness after anesthesia, the BIS values were 80 ± 7 and 81 ± 5, respectively. In an earlier study (15), no patient was conscious when the BIS value was <60.

In the control group, the BIS values (±SD) ranged from 33 (±14) to 47 (±13) at the desflurane concentrations required to maintain MAP within ±15% of baseline value during the maintenance period. However, the BIS values in Groups 2 (58 ± 12 to 61 ± 15) and 3 (62 ± 9 to 64 ± 6) were significantly larger during the maintenance period because of the use of smaller end-tidal desflurane concentrations in the patients receiving the esmolol infusion. Although the study was not adequately powered to assess awareness under anesthesia, no patient in any of the groups reported recall of intraoperative events. When using this anesthetic technique, our data suggest that BIS value <65 was not associated with intraoperative awareness. The combination of midazolam, propofol, desflurane, and N₂O provided effective intraoperative amnesia in these cases. End-tidal N₂O concentrations exceeding 60% provide effective amnesia in most patients, and N₂O has little, if any, effect on the BIS value (17).

Another interesting observation was that significantly more patients in the control group required postoperative opioid analgesics compared with the other two groups despite the fact that all three groups received similar dosages of fentanyl during the intraoperative period. This observation confirms the earlier findings of Zaugg et al. (5) in an elderly surgical population. In addition, Johansen et al. (11) previously reported that esmolol could potentiate the isoflurane minimum alveolar anesthetic concentration reduction produced by alfentanil, and significantly decrease anesthetic requirements at skin incision during balanced anesthesia. Using a rodent model to assess the effect of esmolol on pain modulation in the absence of anesthesia, Davidson et al. (18) reported that this ß-adrenergic blocking drug possessed analgesic-like properties, and was able to attenuate the cardiovascular responses to noxious stimuli. Yet, further studies are needed to clarify the mechanism responsible for esmolol’s anesthetic and analgesic-sparing action during and immediately after surgery.

Of particular importance in the ambulatory setting, the esmolol-treated patients in Groups 2 and 3 were discharged home earlier (209 ± 89 minutes) than those in the control group (269 ± 100 minutes). The faster emergence from anesthesia and smaller postoperative opioid analgesic requirement may have contributed to the shorter time to discharge home. Of interest, the reduced time to discharge home was achieved without the benefit of a formal fast-tracking program. If patients in the esmolol groups had achieved fast-tracking criteria (19) while still in the operating room as a result of their faster emergence from anesthesia (Table 2), they would have been eligible to bypass the postanesthesia care unit (4,20), thereby further reducing the recovery time in Groups 2 and 3 (versus control group). An earlier discharge after ambulatory surgery can produce economic benefits in a busy ambulatory facility, especially if the need for overtime nursing personnel could be reduced. Unfortunately, the number of patients enrolled in this study was inadequate to perform a detailed cost-benefit analysis. A further limitation in interpreting these data relates to the fact that the study population consisted exclusively of female outpatients undergoing gynecologic laparoscopic procedures. These findings may not apply to outpatient populations undergoing more invasive surgical procedures.

	Conclusion

Top Abstract Introduction Methods Results Discussion Conclusion References

 
Esmolol was effective in preventing the HR increase after tracheal intubation, whereas the esmolol-nicardi-pine combination decreased the increase in MAP. More importantly, the use of an esmolol infusion as an adjuvant to desflurane-N₂O for controlling acute hemodynamic responses during laparoscopic surgery facilitated a faster emergence from anesthesia, decreased postoperative opioid analgesic requirements, and reduced the time to discharge home without increasing side effects.

	Acknowledgments

 
This work was supported by departmental resources and endowment funds from the Margaret Milam McDermott Distinguished Chair in Anesthesiology.

	References

Top Abstract Introduction Methods Results Discussion Conclusion References

 

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (9) Citing Articles via Google Scholar Google Scholar Articles by White, P. F. Articles by Sloninsky, A. Search for Related Content PubMed PubMed Citation Articles by White, P. F. Articles by Sloninsky, A. Related Collections Cardiovascular Ambulatory Pharmacology

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