The Sparing Effect of Low-dose Esmolol on Sevoflurane during Laparoscopic Gynaecological Surgery

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1 The Journal of International Medical Research 2011; 39: [first published online as 39(5) 4] The Sparing Effect of Low-dose Esmolol on Sevoflurane during Laparoscopic Gynaecological Surgery YE MOON, WJ HWANG, HJ KOH, JY MIN AND J LEE Department of Anaesthesiology and Pain Medicine, Seoul St Mary s Hospital, Catholic Medical College, Seoul, Republic of Korea This double-blind, randomized, placebocontrolled study evaluated the sparing effect of esmolol on sevoflurane during laparoscopic gynaecological surgery in 54 patients between December 2009 and May The concentration of sevoflurane required to maintain adequate anaesthesia was determined. Patients received either a 0.5 mg/kg esmolol intravenous loading dose followed by infusion of 30 µg/kg per min or an identical volume of normal saline (placebo). During surgery the input concentration of sevoflurane was adjusted every 5 min to maintain systolic blood pressure within 15% of baseline and bispectral index at Infusion of esmolol resulted in an 18.2% decrease in mean sevoflurane input concentration. Patients receiving esmolol had an earlier discharge from the postanaesthetic care unit and a lower mean fentanyl dose. In conclusion, intraoperative esmolol infusion decreased both the requirement for sevoflurane and postoperative administration of fentanyl. KEY WORDS: ESMOLOL; SEVOFLURANE; POSTOPERATIVE RECOVERY Introduction A fundamental concept of anaesthetic management is to minimize the side-effects of anaesthetic drugs by administering the lowest dose necessary to maintain an adequate depth of anaesthesia while ensuring a rapid recovery. An increase in the concentration of volatile anaesthetic raises the risk of complications including intraoperative cardiovascular depression 1, slow recovery 2 and postoperative respiratory depression. 3 In order to prevent these sideeffects, anaesthetists monitor the depth of the hypnotic component of anaesthesia via the bispectral index (BIS), administer adjuvants such as short-acting opioids, local anaesthetics, or α 2 -agonists (balanced anaesthesia), and minimize the inhaled concentration of volatile anaesthetics. The use of β-receptor blockers reduces the requirement for intravenous (i.v.) anaesthetics such as opioids or propofol, 4 6 and decreases BIS during surgery. 7 9 Continuous infusion of β-blockers may affect the requirement for inhalation anaesthetics, but few studies have examined this and there is a lack of applicable clinical information. The requirement for inhalation anaesthetics can be estimated based on haemodynamic response and BIS, rather 1861

2 than on withdrawal response to skin incision stimulus, 5 or tail stimulus in animal experiments. 10,11 The present study examined whether a continuous infusion of low-dose esmolol reduced the requirement for sevoflurane during laparoscopic gynaecological surgery. Patients and methods PATIENTS Women aged years with American Society of Anaesthesiologists (ASA) status I or II, 12 scheduled for elective laparoscopic gynaecological surgery of < 2 h duration at Seoul St Mary s Hospital, Catholic Medical College, Seoul, Republic of Korea, between December 2009 and May 2010 were enrolled in this double-blind, randomized, placebocontrolled study. Patients were enrolled at the time of preoperative anaesthetic evaluation, which was carried out by the investigators. Exclusion criteria included cardiovascular disease (hypertension, arrhythmia or myocardial ischaemia), haemodynamic instability (active bleeding, hypovolaemia or loss of body fluid), asthma or chronic obstructive pulmonary disease, allergy to the study drug and body mass index < 16 or > 30 kg/m 2. The study was approved by the Ethics Committee of Seoul St Mary s Hospital prior to initiation and all patients provided written informed consent prior to participation. STUDY RANDOMIZATION An anaesthetist not involved in patient anaesthetic management prepared the covered syringe pump for esmolol and placebo solutions and held the randomization codes until the end of the study. Another anaesthetist, who was not involved with postoperative patient evaluation and was blinded to group allocation, conducted the course of anaesthesia. Patients and the anaesthetists in charge were blinded to group allocation for the duration of the study. ANAESTHETIC PROCEDURE Intraoperative monitoring included a threelead electrocardiogram, non-invasive blood pressure measurement, pulse oximetry, expired carbon dioxide measurement, pharyngeal temperature and urine output. After obtaining baseline values, anaesthesia was induced with 2.0 mg/kg propofol and 0.5 mg/kg atracurium. Following loss of consciousness, sevoflurane (2 5 vol.% with 100% oxygen) was inhaled for 90 s, according to the cardiovascular response of the patients, and endotracheal intubation was performed. Ventilation was mechanically controlled and adjusted to maintain end-tidal carbon dioxide of mmhg. Fresh gas flow throughout the surgery was 3 l/min medical air and 1 l/min oxygen using a semi-closed circuit system. Anaesthesia was maintained with sevoflurane and 1 ng/ml remifentanil via an effect-site concentration target-controlled infusion (TCI) using a computer-assisted continuous infusion system (Orchestra Base Primea; Fresenius Vial, Grenoble, France). Muscle relaxation was achieved by 5 µg/kg per min atracurium infusion. During surgery, 6 ml/kg per h Ringer s lactate was infused and, in the event of bleeding, 6% hydroxyethyl starch of the same volume as blood lost was infused. The concentration of sevoflurane required to maintain sufficient anaesthetic depth was determined 30 min after establishing pneumoperitoneum and the start of the surgical manipulation. Based on clinical experience, initial skin incision and establishing pneumoperitoneum had an important effect on blood pressure and

3 min was sufficient to reach a stable vital sign. The inspired sevoflurane concentration (as shown by the scale marked on the vapourizer; vol.%) required to maintain systolic blood pressure within 15% of baseline and BIS at was defined as the before-concentration. Patients in the esmolol group received a 0.5 mg/kg esmolol i.v. loading dose followed by 30 µg/kg per min esmolol. Patients in the saline group were infused with the same volume of normal saline. Blood pressure and BIS were monitored every 5 min and the inspired concentration of sevoflurane was increased or decreased by 0.5 vol.% if a BIS < 50 or > 60 was recorded for > 30 s, if systolic blood pressure increased or decreased by > 15% of baseline or was > 150 or < 90 mmhg. In the case of bradycardia (heart rate < 50/min) or hypotension (systolic blood pressure < 80 mmhg), 0.5 mg atropine or 5 mg ephedrine, respectively, was injected i.v. and the patient was excluded from the study. Atracurium infusion was discontinued on the initiation of intraperitoneal irrigation. Sevoflurane, remifentanil and esmolol administration were terminated when the trocar was removed from the abdominal wall. The mean inspired concentration of sevoflurane during esmolol/placebo infusion was calculated and defined as the afterconcentration (vol.%). All patients received 4 mg ondansetron i.v. 30 min before the end of surgery. Neuromuscular block was antagonized with 0.4 mg glycopyrrolate i.v. and 10 mg pyridostigmine i.v. The train-offour ratio was measured and the patient was extubated. ASSESSMENT OF POSTSURGERY RECOVERY A nurse anaesthetist blinded to group allocation assessed the following: intraoperative awareness (by simply asking the patient); postoperative nausea and vomiting (PONV); pain numerical rating scale (NRS; 0 10, where 0 means the absence of pain and 10 represents the worst pain imaginable); requirement for antiemetic or analgesic rescue treatment; total dose of rescue analgesic; and time to discharge from the postanaesthetic care unit (PACU). Assessment of PONV and NRS were performed every 5 min and the time to discharge from the PACU was recorded. Analgesic rescue treatment was fentanyl 25 µg i.v., when requested by the patient or when NRS > 7. Persistent nausea (lasting > 5 min) or vomiting was treated with ondansetron 4 mg i.v. Patients were discharged from the PACU when their White Song 13 score was > 12 and NRS < 4. A patient-controlled analgesia device was applied after discharge from the PACU, if required. STATISTICAL ANALYSES Based on a pilot study by our research group (unpublished), the expected between-group difference in mean sevoflurane concentration was 0.24 ± 0.29 vol.%. A sample size of 24 in each group was required to achieve a power of 80% with an α error of To compensate for potential dropouts the study enrolled 27 patients in each group. Data are presented as mean ± SD, median (interquartile range) or absolute value (%). According to analysis of distribution, the Student s t-test or Mann Whitney U-test were used to compare between-group differences in NRS, demographic data, duration of anaesthesia and surgery, time to discharge from the PACU and total dose of rescue analgesic. Fisher s exact test was used to compare ASA physical status, incidence of PONV, and frequency of rescue analgesics and antiemetics. Student s t-test was used to 1863

4 compare between-group differences in sevoflurane before-concentration, and repeated measures analysis of variance was used to compare between-group differences in after-concentration. Multivariable regression analysis was performed to assess the adjusted association between baseline variables and NRS. Modelling was performed by the stepwise method. All statistical analyses were performed using the SPSS statistical package, version 15.0 (SPSS Inc., Chicago, IL, USA) for Windows. A P-value < 0.05 was considered to be statistically significant. Results The study recruited 54 patients aged years with ASA status I or II. There were no significant between-group differences in patient characteristics, duration of anaesthesia and type of surgery (Tables 1 and 2). No patient was excluded from the study due to bradycardia or hypotension during surgery and there were no reports of intraoperative awareness. The before concentration of sevoflurane was similar between the two groups (2.1 vol.% vs 2.2 vol.%; Fig. 1). There was a statistically significant decrease in sevoflurane input concentration following esmolol infusion (18.2% decrease from 2.2 to 1.8 vol.%; P < 0.01; Fig. 1). There was no significant change in sevoflurane input concentration in the placebo group (Fig. 1). Patients in the esmolol group had a significantly shorter duration of stay in the PACU than the control group (P < 0.05). The degree of pain (NRS; P < 0.05), requirement for rescue analgesics (P < 0.05) and total fentanyl dose (P < 0.005) were also significantly lower in the esmolol group compared with placebo (Table 3). Results of multivariate regression analysis of the association between NRS and patient age, esmolol infusion or duration of surgery are given in Table 4. Esmolol infusion and duration of surgery showed negative association with NRS (P = and P = 0.01, respectively) Discussion The present study investigated whether a continuous infusion of low-dose esmolol reduces sevoflurane requirement during laparoscopic gynaecological surgery. Esmolol infusion maintained adequate anaesthesia depth, reduced sevoflurane use by 18.2% and had a positive effect on the speed and quality of recovery in the PACU. Previous studies have reported the opioid TABLE 1: Demographic data of the laparoscopic gynaecological surgery patients who were randomly assigned to receive either placebo (saline) or esmolol (0.5 mg/kg intravenous loading dose followed by infusion of 30 µg/kg per min) Placebo Esmolol Demographic n = 27 n = 27 Age, years 40.9 ± ± 11.7 Height, cm ± ± 5.40 Weight, kg 54.3 ± ± 7.50 ASA physical status, I/II 27/0 26/1 Preoperative systolic blood pressure, mmhg ± ± 11.7 Data expressed as number or mean ± SD. No statistically significant between-group differences (P > 0.05); Student s t-test or Fisher s exact test. ASA, American Society of Anaesthesiologists. 1864

5 TABLE 2: Surgical and anaesthetic characteristics of the laparoscopic gynaecological surgery patients who were randomly assigned to receive either placebo (saline) or esmolol (0.5 mg/kg intravenous loading dose followed by infusion of 30 µg/kg per min) Placebo Esmolol Characteristics n = 27 n = 27 Duration of surgery, min 82.5 ± ± 36.2 Duration of anaesthesia, min ± ± 34.3 Atracurium dose, mg 48.7 ± ± 10.4 Remifentanil dose, µg ± ± 38.3 Esmolol dose, mg Not applicable ± 49.8 Type of surgery Laparoscopic cystectomy Laparoscopic myomectomy 3 3 Laparoscopic total hysterectomy 7 6 Data expressed as number of patients or mean ± SD. No statistically significant between-group differences (P > 0.05); Student s t-test or Fisher s exact test. and i.v. anaesthetic sparing effect of β- 4 6,14 16 blockers; however, very few have investigated their effect on inhalation anaesthetic requirement. Chia et al. 17 found that perioperative infusion of 50 µg/kg per min esmolol during open total hysterectomy reduced the requirement for intraoperative isoflurane and postoperative fentanyl. In their study, intraoperative anaesthetic depth was estimated solely by haemodynamic Sevoflurane concentrarion (vol.%) Placebo (n = 27) Esmolol (n = 27) Before infusion After infusion FIGURE 1: Sevoflurane concentrations required for adequate anaesthesia in 54 laparoscopic gynaecological surgery patients randomly assigned to receive either placebo (saline) or esmolol (0.5 mg/kg intravenous loading dose followed by infusion of 30 µg/kg per min) before and after infusion of esmolol or placebo (saline) (mean ± SD; **P < 0.01 versus before infusion and versus placebo [repeated measures analysis of variance]) ** 1865

6 TABLE 3: Recovery variables of the laparoscopic gynaecological surgery patients who were randomly assigned to receive either placebo (saline) or esmolol (0.5 mg/kg intravenous loading dose, followed by infusion of 30 µg/kg per min) Placebo Esmolol Recovery variables n = 27 n = 27 Post-operative nausea and vomiting 4 (15) 3 (11) Rescue antiemetic 4 (15) 3 (11) NRS for pain at first measurement a 6.1 ± ± 1.8* Rescue analgesic 24 (89) 15 (56)* Fentanyl dose, µg 50 (50 50) 25 (0 25)** Duration of stay in PACU, min 40.9 ± ± 9.6* Data expressed as mean ± SD, median (interquartile range) or number (%). a NRS, numerical pain rating scale: 0, no pain; 10, the worst pain imaginable. *P < 0.05 versus placebo; Student s t-test or Fisher s exact test; **P < versus placebo; Mann Whitney U-test. PACU, postanaesthetic care unit. TABLE 4: Multivariate regression analysis of the relationship between age, esmolol infusion or duration of surgery and numerical pain rating scale at first measurement in laparoscopic gynaecological surgery patients Variables Regression coefficient SE Statistical significance Age, years NS Esmolol infusion (1) or not (0) P = Duration of surgery, min P = 0.01 Stepwise multiple linear regression analysis was applied (cut-off to enter, P < 0.05). R 2 = 0.241; constant value = SE, standard error; NS, not statistically significant (P > 0.05). Variables removed: weight, height and type of surgery. responses, such as blood pressure and heart rate. Although these indices are widely used, they cannot be relied upon to reflect anaesthetic depth accurately since they may be affected by various factors, including intravascular volume, pharmacological action of anaesthetic agents, underlying autonomic activity and variation in the autonomic nervous system response. In order to overcome these limitations, the present study measured BIS in addition to the haemodynamic values, since BIS has been widely acknowledged as an objective and efficient means to estimate anaesthetic depth Johansen et al. 21 reported that high-dose (250 µg/kg per min) esmolol spared 25% of the minimal alveolar concentration (MAC) of isoflurane. The data in that study were based on MAC at the time of skin incision, rendering the information inapplicable to the clinical situation of actual surgery and anaesthesia. During actual surgery and anaesthesia it is difficult to adjust the amount of inhalational anaesthetic on the basis of MAC-skin incision. High-dose esmolol is known to induce severe hypotension and bradycardia 22 and is not appropriate for actual patient management. The anaesthetic protocol outlined in the 1866

7 present study can be applied to actual clinical situations. A continuous 30 µg/kg per min esmolol infusion caused neither hypotension nor bradycardia, and was considered an effective and safe dosage. Previous investigations of inhalation anaesthetic dose have titrated the anaesthetic according to patient end-tidal concentration. 17,21 This, however, causes difficulty in controlling the input amount required because it is not easy to reach the target end-tidal concentration by controlling input concentration. The amount of anaesthetic input in the present study was controlled based on the scale value marked on the vapourizer the input concentration. This enabled prompt control of the input amount and exact calculation of the mean input concentration of inhalation anaesthetic. The end-tidal concentration of inhalation anaesthetic is more accurately reflective of brain concentration. In a steadystate condition, however, there is a close relationship between brain, end-tidal and input concentrations. The maintenance of constant fresh gas flow and the use of the same type of anaesthesia circuit throughout the study period (semi-closed circuit) in the present study, minimized differences between brain concentration and input concentration of sevoflurane. In agreement with previous reports, the present study found that low-dose esmolol infusion during surgery reduced the duration of stay in the PACU. 14,23 25 This may be due to the esmolol-induced reduction in sevoflurane requirement, resulting in a lower degree of central nervous system depression and a shorter time to alveolar concentration of sevoflurane (MAC awakening). Esmolol infusion also led to reduction in postoperative fentanyl use, contributing to earlier discharge from the PACU. The difference in the length of stay in the PACU was not clinically significant and may be a consequence of the use of short-acting anaesthetics such as sevoflurane and remifentanil. Several factors may account for the esmolol-related reduction in postoperative pain and lower requirement for rescue analgesia. Functional magnetic resonance imaging studies have demonstrated that the hippocampus plays a role in nociception, via stress-related secretion of noradrenaline, 26 a process that would be blunted by esmololinduced blockade of β-adrenergic receptors. Since esmolol does not cross the blood brain barrier, it may act by blocking β- adrenoceptors within the brainstem, decreasing neuronal inflow traffic into the central nervous system, rather than acting directly within the brain. 27 An alternative mechanism of action could involve antinociception via β-adrenergic antagonist regulation of voltage-gated Ca 2+ channels that stimulate inhibitory G proteins in the cell membrane. 28 The regulation of these channels controls the release of neurotransmitters, causing an antinociceptive effect and reducing the requirement for anaesthetic. 29 β-blockers may affect the pharmacokinetics of sevoflurane and fentanyl via a decrease in cardiac output and changes in the distribution of organ blood flow. 30 The blood pressure and heart rate of patients in the present study were not affected by esmolol infusion, indicating no effect on cardiac output, so any changes in the pharmacokinetics of sevoflurane and fentanyl are unlikely to have been significant. This finding is supported by a previous study in which it was stated that esmolol infusion had no effect on the metabolism of drugs with a large hepatic extraction ratio. 31 The finding that BIS remained stable with esmolol infusion in the 1867

8 present study, in spite of a reduction in sevoflurane dose, infers that esmolol had a hypnotic or antinociceptive effect. Despite the reduction in fentanyl dose in the esmolol group, there were no significant between-group differences in the incidence of PONV or requirement for antiemetic treatment in the present study. These unexpected results may be due to the prophylactic injection of ondansetron 30 min before the end of surgery in both patient groups. This drug was administered because of the high risk of PONV in laparoscopic gynaecological surgery. 32,33 A relatively low dose of remifentanil, the adjuvant coadministered with sevoflurane for maintenance of anaesthesia, was used in the present study. This was a deliberate choice in order to examine more clearly the sparing effect of esmolol on sevoflurane, the main anaesthetic agent in this study. In conclusion, intraoperative administration of low-dose esmolol produced a sparing effect on sevoflurane and induced earlier discharge from the PACU in patients undergoing laparoscopic gynaecological surgery with sevoflurane and remifentanil anaesthesia. We recommend esmolol as a useful adjuvant for anaesthesia when using sevoflurane and remifentanil. Conflicts of interest The authors had no conflicts of interest to declare in relation to this article. Received for publication 4 March 2011 Accepted subject to revision 28 March 2011 Revised accepted 13 June 2011 Copyright 2011 Field House Publishing LLP References 1 Pagel PS, Nijhawan N, Warltier DC: Quantitation of volatile anesthetic-induced depression of myocardial contractility using a single beat index derived from maximal ventricular power. J Cardiothorac Vasc Anesth 1993; 7: Nicholau D: The postanesthesia care unit. In: Miller s Anesthesia (Miller RD, ed). Philadelphia: Churchill Livingstone, 2007; pp Berthoud MC, Reilly CS: Adverse effects of general anaesthetics. Drug Saf 1992; 7: Coloma M, Chiu JW, White PF, et al: The use of esmolol as an alternative to remifentanil during desflurane anesthesia for fast-track outpatient gynecologic laparoscopic surgery. Anesth Analg 2001; 92: Johansen JW, Flaishon R, Sebel PS: Esmolol reduces anaesthetic requirement for skin incision during propofol/nitrous oxide/ morphine anesthesia. Anesthesiology 1997; 86: Ozturk T, Kaya H, Aran G, et al: Postoperative beneficial effects of esmolol in treated hypertensive patients undergoing laparoscopic cholecystectomy. Br J Anaesth 2008; 100: Menigaux C, Guignard B, Adam F, et al: Esmolol prevents movement and attenuates the BIS response to orotracheal intubation. Br J Anaesth 2002; 89: Oda Y, Nishikawa K, Hase I, et al: The shortacting beta1-adrenoceptor antagonists esmolol and landiolol suppress the bispectral index response to tracheal intubation during sevoflurane anesthesia. Anesth Analg 2005; 100: Choi SH, Kim CS, Kim JH, et al: A single dose of esmolol blunts the increase in bispectral index to tracheal intubation during sevoflurane but not desflurane anesthesia. J Neurosurg Anesthesiol 2009; 21: Davidson EM, Doursout MF, Szmuk P, et al: Antinociceptive and cardiovascular properties of esmolol following formalin injection in rats. Can J Anaesth 2001; 48: Zhao H, Sugawara T, Miura S, et al: Intrathecal landiolol inhibits nociception and spinal c-fos expression in the mouse formalin test. Can J Anaesth 2007; 54: American Society of Anesthesiologists: ASA Physical Status Classification System (available at: status.htm). 13 White PF, Song D: New criteria for fast-tracking after outpatient anesthesia: a comparison with the modified Aldrete s scoring system. Anesth Analg 1999; 88: Collard V, Mistraletti G, Taqi A, et al: Intraoperative esmolol infusion in the absence of opioids spares postoperative fentanyl in patients undergoing ambulatory laparoscopic cholecystectomy. Anesth Analg 2007; 105:

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