|Year : 2015 | Volume
| Issue : 4 | Page : 560-566
The effect of esmolol infusion as an adjunct to total intravenous anesthesia on the total anesthetic and analgesic requirements in arthroscopic shoulder surgery
Sherif A Elokda MD , Ibrahim A Nasr
Anesthesia Department, Ain Shams University, Cairo, Egypt
|Date of Submission||17-Jun-2014|
|Date of Acceptance||19-Aug-2014|
|Date of Web Publication||29-Dec-2015|
Sherif A Elokda
Anesthesia Department,, Ain Shams University, Abbasia, Cairo 11455
Source of Support: None, Conflict of Interest: None
Esmolol is the first intravenous, short-acting, titratable b-blocker for use in critical care and surgical settings. It influences core components of an anesthetic regimen, such as analgesia, hypnosis, and memory function.
To investigate whether perioperative esmolol infusion as an adjuvant to total intravenous anesthesia could affect the total anesthetic and analgesic requirements in adult patients undergoing arthroscopic shoulder surgery.
Settings and design
A randomized, double-blinded, prospective study.
Materials and methods
Eighty adult ASA I and II patients scheduled for elective arthroscopic rotator cuff repair were randomized into the esmolol group (n = 40) and the control group (n = 40). In the esmolol group, 1 mg/kg esmolol was given as a bolus over 30 s, followed by 15 mg/kg/min as an intravenous infusion, and in the control group, the same volume of normal saline was given during the same time period. The heart rate, the mean arterial blood pressure, the depth of anesthesia, the duration of anesthesia, the recovery time, total anesthetic requirements, the postoperative pain score (VAS), and the total postoperative analgesic requirements were monitored and calculated during the perioperative period.
There was no significant difference between both groups regarding the demographic data using the unpaired t-test. There was a significant difference between both groups (P < 0.05) regarding different parameters, except the duration of anesthesia, using the unpaired t-test. Preoperative mean values of heart rate (beats/min) and the mean arterial blood pressure (mmHg) were comparable between the two groups (P > 0.05). However, after induction of anesthesia and thereafter, there was a significant reduction in heart rate and mean arterial blood pressure mean values in the esmolol group when compared with the control group (P < 0.05). A significant change in bispectral index was noticed within each group in comparison with the baseline using the paired t-test. However, there was no significant difference between both groups. Postoperative pain assessments by VAS (0-100 mm) showed significantly lower pain scores in the esmolol group compared with the control group by the paired t-test (P < 0.05). There was a highly significant reduction (P < 0.001) in the total cumulative doses of morphine consumption by PCA during the first 24 h in the esmolol group compared with the control group.
Perioperative esmolol infusion reduces the total anesthetic and analgesic requirements and postoperative pain. Hence, esmolol can be considered as safe and suitable adjuvant to total intravenous anesthesia.
Keywords: analgesic, anesthetic, arthroscopic, bispectral index, esmolol, shoulder surgery, total intravenous anesthesia
|How to cite this article:|
Elokda SA, Nasr IA. The effect of esmolol infusion as an adjunct to total intravenous anesthesia on the total anesthetic and analgesic requirements in arthroscopic shoulder surgery. Ain-Shams J Anaesthesiol 2015;8:560-6
|How to cite this URL:|
Elokda SA, Nasr IA. The effect of esmolol infusion as an adjunct to total intravenous anesthesia on the total anesthetic and analgesic requirements in arthroscopic shoulder surgery. Ain-Shams J Anaesthesiol [serial online] 2015 [cited 2020 May 29];8:560-6. Available from: http://www.asja.eg.net/text.asp?2015/8/4/560/172741
| Introduction|| |
Shoulder surgery represents an important category of orthopedic surgeries. It varies from a fit patient with a sports injury who requires stabilization to elderly patients who need joint arthroplasty  . Currently, most of the shoulder surgeries are performed with arthroscopy. Reduced blood loss, better visualization of anatomic structures, a decreased surgery time, and the ability to perform therapeutic procedures are the major advantages of arthroscopic surgeries  . Because of limited access to the patient's airway during surgery and patient discomfort in long-duration surgeries, either general anesthesia alone or in combination with regional anesthesia is frequently selected. The management of postoperative pain after shoulder surgery is a challenge for many anesthetists  .
Drugs given by total intravenous anesthesia (TIVA) are generally less toxic than inhalational agents, not polluting the environmental air, and with less risk of malignant hyperthermia. With TIVA, there is no need for gas delivery systems or scavenging systems and no need for time-consuming procedures such as neuraxial or regional blocks  .
The bispectral index (BIS) was approved as the first electroencephalogram-based monitor for the depth of anesthesia in 1996. BIS reduces the sophisticated electroencephalogram processing to a simple number ranging from 100 to 0. BIS decreases with increasing depth of anesthesia, and it should be kept in the range from 40 to 60 to achieve an adequate level of anesthesia  .
Esmolol is a well-known ultra-short-acting b-blocker; its onset of action occurs after 1-2 min, its peak effect is about 5-6 min after injection, and its washout time is almost 9 min after the discontinuation of infusion  . All these pharmacokinetic properties make it the drug of first choice in critical patients. It is effective in attenuating the sympathetic overdrive during laryngoscopy and intubation  , and also for sternotomy and recovery from anesthesia and during extubation  . Esmolol has been proven to have an antinociceptive effect in both intraoperative and early postoperative periods, together with its beneficial effect on postoperative nausea and vomiting  . In addition to its peripheral analgesic effect, Davidson et al.  thought that esmolol may also play an important role in pain modulation centrally.
The objective of the current study was to evaluate the effect of perioperative esmolol infusion on the total anesthetic and analgesic consumption using the clinical parameters together with the BIS and neuromuscular monitoring using train-of-four (TOF).
| Participants and methods|| |
After getting approval from the ethical committee of Dallah Hospital (Riyadh, Saudi Arabia), written informed consents were obtained from all patients before beginning the study. This study was conducted on 80 adult male and female American Society of Anaesthesiologists (ASA) physical status I-II patients scheduled for elective arthroscopic rotator cuff repair during the period from May 2012 to April 2013; these patients were enrolled into this prospective, randomized, controlled, double-blind study using sealed envelopes.
Patients with uncontrolled systemic diseases (e.g. diabetes mellitus, asthma, and chronic obstructive lung disease), significant organ dysfunctions (e.g. cardiac, respiratory, renal, or liver disorders), morbid obesity (BMI > 40), a history of allergy to the drugs used, use of b-blockers or calcium channel blockers, and chronic use of opioids or NSAIDs were excluded from the study.
Patients were randomly divided into two groups: the Esmolol group (group E, n = 40) the and Control group (group C, n = 40). All patients were premidicated orally with bromazepam (3 mg) and ranitidine (150 mg) 1-2 h preoperatively. Before the induction of anesthesia, group E patients received unknown solution (A), whereas group C patients received unknown solution (B) in a double-blind manner. These solutions were prepared in the pharmacy with the same volumes, and the anesthetist was blinded to the grouping design.
In group E, patients received esmolol hydrochloride (Brevibloc premixed, 10 mg/ml; Baxter Healthcare Corporation, Deerfield, Illinois, USA) 1 mg/kg as a bolus dose over 30 s, followed by a continuous esmolol infusion of 15 mg/kg/min till after extubation. Patients in group C received a normal saline bolus of the same volume followed by a continuous normal saline infusion of the same volume per hour as group E. Postoperative pain assessment and management was performed by the acute pain management team, which was also blinded to the group assignment. This assessment was performed using a visual analogue scale (VAS) on which the patient was instructed during the preoperative visit.
The anesthetic technique
On arrival of the patient to the operating theater, all standard monitors were applied, including heart rate (HR), ECG, oxygen saturation (SpO 2 ), end-tidal CO 2 , arterial blood pressure (systolic, diastolic and mean), and temperature. In addition to these monitors, both neuromuscular monitoring, TOF, and bipolar BIS electrodes (BIS QUATRO-BX13366; Aspect Medical Systems Inc., Chicago, USA) were applied to the patient. After the induction of anesthesia, an arterial catheter was inserted into the radial artery of the contralateral side of surgery for continuous blood pressure monitoring and frequent blood gas analysis. Initial or baseline readings of all these monitors were taken and recorded before starting any drug infusion (baseline) in the preanesthetic period, and then during the intraoperative period also.
Anesthesia was induced by intravenous fentanyl (2 mg/kg), followed by propofol (1.5-2 mg/kg). Intubation was performed using rocuronium bromide at a dose of 0.6 mg/kg. Maintenance of anesthesia was carried out by continuous infusion of propofol (5-8 mg/kg/h), and was titrated to keep the 'BIS' value within the range of 40-60, and fentanyl 1-2 mg/kg/h was given to maintain hemodynamic parameters within 20% of the baseline preoperative values. Muscle relaxation was monitored by 'TOF' every 10 min; rocuronium infusion from 0.3 to 0.6 mg/kg/h was given and adjusted to maintain one to two twitches of 'TOF' stimulation. Lungs were ventilated mechanically to maintain normocapnia (EtCO 2 35-40 mmHg). All surgical procedures were performed by the same surgeon who was blinded to the study.
All vital signs were recorded after induction, before intubation, and after intubation, and then every 15 min till the end of the surgery, before extubation and after extubation. All patients were anesthetized by one anesthetist who was not involved in the study and was instructed to follow the study design. Lactated Ringer's solution was set at a rate of 6 ml/kg/h as a baseline infusion in both groups. Additional solutions were infused if required. Neither anti-inflammatory drugs nor local anesthetic infiltration of the surgical wounds was used in both groups.
At the end of the surgery, all infusion solutions together with all anesthetic drugs were discontinued. The residual effect of rocuronium was reversed with neostigmine at a dose of 50 mg/kg and glycopyrrolate 10 mg/kg. Then, the patient was extubated and transferred to the postanesthesia care unit for routine follow-up. Every patient was observed continuously during and after the termination of anesthesia; any events were recorded. Pain was assessed by VAS (0-100 mm) from the immediate postoperative period till 24 h postoperatively. Postoperative pain management was achieved by intravenous morphine using patient-controlled analgesia 'PCA' (Baxter Healthcare Corporation). A dose of 50 mg of morphine was diluted in a volume of 50 ml normal saline (1 mg/ml), and then fixed to a PCA machine that was adjusted to deliver 1 mg boluses, and the lockout interval was 10 min.
Data for assessments
- Mean HR (beats/min).
- Mean arterial blood pressure (MAP).
- Depth of anesthesia (BIS).
- Duration of anesthesia (in min) from the time of induction to withdrawal of all anesthetics.
- Recovery time (in min) from withdrawal of all anesthetics to extubation.
- Postoperative pain score by 'VAS' (0-100 mm).
- Total anesthetic requirements during surgery (propofol, fentanyl, and rocuronium).
- Total postoperative analgesic requirements of morphine (mg) during the first 24 h.
Sample size calculation was guided by a power of 80%, a confidence level of 95%, and a Z score of 1.96, together with an accepted margin of error of 5%. Manual formula was used on the basis of the success rate of the drugs. The total sample calculated was 80 divided on equal bases 1 : 1 to be 40 per group. Analysis of data was performed by an IBM computer using statistical package for social science (version 16, Chicago, USA) as follows: description of quantitative variables as mean, SD, and range; description of qualitative variables as number and percentage. The c2 -test was used to compare qualitative variables between groups. The Fisher exact test was used instead of the c2 -test when one or more expected cells were less than 5. The unpaired two-tailed t-test was used to compare quantitative variables in parametric data (SD < 50% mean) between both groups. The two-tailed significant test was used in this study. Significant results were considered when the P value was less than 0.05.
| Results|| |
Demographic data of patients
Analysis of the results showed that there was no significant difference in the demographic data between the patients of the two groups [Table 1].
|Table 1 Demographic data of both the esmolol and the control groups (mean ± SD)|
Click here to view
The results of the current study showed that there was no significant difference between both groups regarding the duration of anesthesia (P > 0.05). However, the recovery time was significantly shorter in the esmolol group when compared with the control (P < 0.05) [Table 2].
|Table 2 Anesthetic data of both the esmolol and the control groups (mean ± SD)|
Click here to view
Anesthetic agents' consumption
The statistical analysis of the total amount of propofol consumed (mg) during the study showed that there was a significant reduction in the esmolol group when compared with the control group (320 ± 120.6 vs. 667.4 ± 134) (P < 0.001). Also, intraoperative fentanyl consumption (mcg) was less in the esmolol group compared with the control group (150.3 ± 65 vs. 240.7 ± 110) (P < 0.05). At the same time, the total amount of rocuronium consumed (mg) was less in the esmolol group in comparison with the control group (101 ± 30 vs. 126 ± 55) (P < 0.05) [Table 2].
The preoperative mean values of HR (beats/min) were comparable between the two groups (P > 0.05), whereas the preoperative mean blood pressure values (mmHg) were less in the esmolol group. However, after the induction of anesthesia and thereafter, there was a significant reduction in HR and MAP mean values in the esmolol group when compared with the control group (P < 0.05) [Figure 1] and [Figure 2].
Bispectral index values
There was no significant difference (P > 0.05) in the BIS mean values between both groups starting from the preoperative period and throughout the anesthesia, till after extubation and recovery. However, there was a statistically significant difference in both groups when we compared intraoperative BIS values with preoperative BIS values [Table 3].
|Table 3 BIS mean values in both the esmolol and the control groups (mean ± SD)|
Click here to view
Postoperative pain management
Postoperative pain assessments by VAS (0-100 mm) showed lower pain scores in the esmolol group compared with the control group (P < 0.05) [Figure 3].
Regarding the postoperative pain relief, comparison between the two groups showed that there was a significant reduction (P < 0.001) in the total cumulative doses of morphine consumption by PCA during the first 24 h in the esmolol group compared with the control group [Table 4].
|Table 4 Postoperative morphine consumption by patient-controlled analgesia (mg) in both the esmolol and the control groups (mean ± SD)|
Click here to view
| Discussion|| |
Laryngoscopy, tracheal intubation, and extubation are usually associated with an increase in both the HR and the blood pressure. These changes may result in serious outcomes such as heart failure, cerebrovascular hemorrhage, and pulmonary edema  . The main reason for these cardiovascular changes during laryngoscopy and tracheal intubation is the increased catecholamine release due to sympathetic overactivity  .
The current study demonstrates that esmolol hydrochloride reduced both the mean HR and the MAP from the start of anesthesia till the recovery time. This was in agreement with other studies. In a comparative study between esmolol and lignocaine regarding their effect on the hemodynamics during laryngoscopy and tracheal intubation, Begum et al.  reported that esmolol 1.5 mg/kg is superior to lignocaine 1.5 mg/kg.
Our results are in accordance with the results of Coloma et al.  , who studied the use of esmolol as an alternative to remifentanil for hemodynamic stability in patients undergoing outpatient gynecological laparoscopic procedures, and they found that esmolol is a good alternative to remifentanil to maintain hemodynamic stability. This study is also supported by Singh et al.  , who established the benefit of the prophylactic use of esmolol at a dose of 2 mg/kg, in attenuating the hemodynamic responses to laryngoscopy and intubation in a normotensive black population without any complications such as hypotension and bradycardia.
The increases in HR and blood pressure during anesthesia are interpreted as light anesthesia and onset of pain provided the other factors are constant  . The present study showed a significant reduction in the total amount of both propofol and fentanyl used in the esmolol group compared with the control group. This means that the coadministration of esmolol with propofol may potentiate the anesthetic effect and the NMDA antagonism of propofol. Davidson et al.  reported that esmolol had antinociceptive and cardiovascular properties after formalin injection in rats.
Johansen et al.  found that esmolol administration during surgery potentiates the alfentanil-induced reduction of minimum alveolar concentration of isoflurane. Our results are in agreement with the results of another study, which showed that continuous esmolol infusion reduces the plasma concentration of propofol during propofol/nitrous oxide/morphine anesthesia  .
Another mechanism that can explain the antinociceptive effect of esmolol was explained by Sun et al.  , who mentioned that because esmolol cannot cross the blood-brain barrier, it may prevent the increase in the BIS index and decrease inhalational anesthetic MAC by blocking B-receptors within the brain stem and decreasing neuronal inflow traffic into the central nervous system rather than acting directly within the brain.
Also, the present study demonstrates that there is a significant reduction in the total amount of rocuronium used intraoperatively in the esmolol group than in the control group. This can be due to the prolongation of action of rocuronium by esmolol infusion. These results are supported by the results of another study conducted by Ohriak et al.  , who investigated whether the duration of nondepolarizing muscle relaxant pancuroium was affected by perioperative esmolol infusion by monitoring the clinical signs of the patients, and they discovered that there was a significant prolongation of the duration of action of pancuroium in the esmolol group compared with the control group.
Similar to the results of the current study, Jain et al.  studied the effect of a bolus dose of 200 mcg/kg esmolol on the duration of action of the nondepolarizing muscle relaxant vecuronium in 20 adult patients ASA I and II undergoing different surgeries under general anesthesia. They concluded that esmolol caused significant prolongation of the duration of action of vecuronium in comparison with the control group. They assumed that this effect could be a result of either the partial agonist activity of esmolol or the direct membrane depressant activity of esmolol.
The recovery time from anesthesia was significantly shorter among the patients in the esmolol group compared with the control group. This can be explained by the lower anesthetic consumption in the esmolol group. This rapid recovery was also reported by White et al.  , who studied the effect of intraoperative esmolol and nicardipine on the recovery time of 45 healthy women undergoing gynecologic laparoscopic procedures. The authors noticed that the adjunctive use of esmolol alone or in combination with nicardipine was associated with rapid awakening from anesthesia.
The results of the present study demonstrated that there is significant decrease in the total amount of morphine consumption by PCA used for postoperative pain relief together with decreased postoperative pain scores in the esmolol group during the first 24 h in comparison with the control group.
Although there are data indicating that esmolol cannot cross the blood-brain barrier, it is known that esmolol is a short-acting b-blocker with moderate lipophilicity and may be involved in the modulation of central adrenergic activity  . Booz et al.  mentioned that the hippocampus plays an important role in nociception through the action on N-methyl-d-aspartate receptors. They also reported that this role is mediated through the activation of b-adrenergic receptors, and thus, the blockade of these receptors resulted in the attenuation of the intensity of perceived pain. Another mechanism that can explain the antinociceptive effect of b-blockers is that they decrease the hepatic blood flow, and consequently, they decrease the metabolism of opioids. One study that investigated the effect of propranolol on fentanyl consumption noticed that there was a significant reduction in fentanyl consumption, and they explained this by the decrease in cardiac output and hepatic blood flow caused by propranolol  .
The results of this study are in accordance with the results of another study of Chia et al.  , who studied the role of b-blockade in anesthesia and postoperative pain management after hysterectomy and reported that continuous intraoperative esmolol infusion was associated with decreased postoperative analgesic consumption. In contrast, Koivusalo et al.  investigated the effects of esmolol on the hemodynamic response to CO 2 pneumoperitoneum for laparoscopic surgery and reported that the use of esmolol did not affect the postoperative analgesic consumption.
| Conclusion|| |
From the data mentioned previously, we conclude that esmolol is a safe and suitable supplement to the general anesthetic regimen with propofol, fentanyl, and rocuronium as it reduces the total anesthetic requirements, the postoperative pain score, and postoperative analgesic requirements.
| Acknowledgements|| |
Conflicts of interest
| References|| |
Beecroft LC, Coventry DM. Anesthesia for shoulder surgery. Continuing education in anesthesia, critical care & pain 2008; 8:193-195.
Gwak MS, Kim WH, Choi SJ, Lee JJ, Ko JS, Kim GS, Kim MH. Arthroscopic shoulder surgery under general anesthesia with brachial plexus block. Ansesthesist 2013; 62:113120.
McGoldrick KE. Day-case shoulder surgery: anesthetic challenges. Ambul Surg 2012; 17:47-49.
Gokce BM, Ozkose Z, Tuncer B, Pampal K, Arslan D. Hemodynamic effects, recovery profiles, and costs of remifentanil-based anesthesia with propofol or desflurane for septorhiniplasty. Saudi Med J 2007; 28:358-363.
Mansour EE. Bis-guided evaluation of dexmedetomidine vs midazolam as anaesthetic adjuncts in off-pump coronary artery bypass surgery (OPCAB). Saudi J Anaesth 2009; 3:7-14.
Zangrillo A, Turi S, Crescenzi G, Oriani A, Distaso F, Monaco F, et al
. Esmolol reduces perioperative ischemia in cardiac surgery: a meta-analysis of randomized controlled studies. J Cardiothorac Vasc Anesth 2009; 23:625-632.
Begum M, Akter P, Hossain MM, Alim SMA,Khatun UHS, Islam SMK, et al.
A comparative study between efficacy of esmolol and lignocaine for attenuating haemodynamics response due to laryngoscopy and endotracheal intubation. Faridpur Med Coll J 2010; 5:25-28.
Wang YQ, Guo QL, Xie D. Effects of different doses of esmolol on cardiovascular responses to tracheal extubation. Hunan Yi Ke Da Xue Xue Bao 2003; 28:259-262.
Ozturk T, Kaya H, Aran G, Aksun M, Savaci S. postoperative beneficial effects of esmolol in treated hypertensive patients undergoing laparoscopic cholecystectomy. Br J Anaesth 2008; 100:211-214.
Davidson EM, Doursout MF, Szmuk P, Chelly JE. Antinociceptive and cardiovascular properties of esmolol following formalin injection in rats. Can J Anaesth 2001; 48:59-64.
Kayhan Z, Aldemir D, Mutlu H, Ogus E. Which is responsible for the haemodynamic response due to laryngoscopy and endotracheal intubation? Catecholamines, vasopressin or angiotensin?. Eur J Anaesthesiol 2005; 22:780-785.
Coloma M, Chiu JW, White PF, Armbruster SC. The use of esmolol as an alternative to remifentanil during desflurane anesthesia for fast-track outpatient gynecologic laparoscopic surgery. Anesth Analg 2001; 92:352-357.
Singh S, Laing EF, Owiredu WKBA, Singh A. Attenuation of cardiovascular response by B-blocker esmolol during laryngoscopy and intubation. J Med Biomed Sci 2012; 4:27-33.
Gan TJ, Glass PS, Windsor A, Payne F, Rosow C, Sebel P, Manberg P. Bispectral index monitoring allows faster emergence and improved recovery from propofol, alfentanil, and nitrous oxide anesthesia. BIS Utility Study Group. Anesthesiology 1997; 87:808-815.
Johansen JW, Schneider G, Windsor AM, Sebel PS. Esmolol potentiates reduction of minimum alveolar isoflurane concentration by alfentanil. Anesth Analg 1998; 87:671-676.
Johansen JW, Flaishon R, Sebel PS. Esmolol reduces anesthetic requirement for skin incision during propofol/nitrous oxide/morphine anesthesia. Anesthesiology 1997; 86:364-371.
Sum CY, Yacobi A, Kartzinel R, Stampfli H, Davis CS, Lai CM. Kinetics of esmolol, an ultra-short acting beta blocker, and its major metabolite. Clin Pharmacol Ther 1983; 34:427-434.
Ohri AK, Sharma DR, Thakur JR. Effect of esmolol infusion on the duration of action of nondepolarizing muscle relaxant. J Anaesth Clin Pharmacol 1999; 15:55-59.
Jain S, Jain S, Pareek A, Gupta HK. Interaction of esmolol with vecuronium regarding its neuromuscular blocking action. Akymographic study. Indian J Anaesth 2002; 46:53-57.
White PF, Wang B, Tang J, Wender RH, Naruse R, Sloninsky A. The effect of intraoperative use of esmolol and nicardipine on recovery after ambulatory surgery. Anesth Analg 2003; 97:1633-1638.
Avram MJ, Krejcie TC, Henthorn TK, Niemann CU. Beta-adrenergic blockade affects initial drug distribution dueto decreased cardiac output and altered blood flow distribution. J Pharmacol Exp Ther 2004; 311:617-624.
Booze RM, Crisostomo EA, Davis JN. Beta-adrenergic receptors in the hippocampal and retrohippocampal regions of rats and guinea pigs: autoradiographic and immunohistochemical studies. Synapse 1993; 13:206-214.
Krodel DJ, Bittner EA, Abdulnour RE, Brown RH, Eikermann M. Negative pressure pulmonary edema following bronchospasm. Chest 2011; 140:1351-1354.
Chia YY, Chan MH, Ko NH, Liu K. Role of beta-blockade in anaesthesia and postoperative pain management after hysterectomy. Br J Anaesth 2004; 93:799-805.
Koivusalo AM, Scheinin M, Tikkanen I, Yli-Suomu T, Ristkari S, Laakso J, Lindgren L. Effects of esmolol on haemodynamic response to CO 2
pneumoperitoneum for laparoscopic surgery. Acta Anaesthesiol Scand 1998; 42:510-517.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4]