|Year : 2019 | Volume
| Issue : 3 | Page : 446-451
Comparative study of effectiveness of tramadol and butorphanol as adjuvants to levobupivacaine for supraclavicular brachial plexus block
Anita Kumari1, Himani Chhabra2, Ruchi Gupta1, Harmandeep Kaur1
1 Department of Anaesthesia, Sri Guru Ram Das Institute of Medical Sciences and Research, Sri Amritsar, Punjab, India
2 Department of Anaesthesia, Sir Ganga Ram Hospital, Delhi, India
|Date of Web Publication||20-Sep-2019|
632-A, E Block, Ranjit Avenue, Amritsar, Punjab
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: Butorphanol and tramadol, the synthetic opioid analgesics, have been used alone or in combination with a local anesthetic in supraclavicular brachial plexus block. Aim: The aim of this study was to evaluate the sensory and motor block characteristics with the addition of tramadol (100 mg) and butorphanol (2 mg) to levobupivacaine for supraclavicular brachial plexus anesthesia. Settings and Design: This study was a prospective, randomized, double–blind, and comparative study. Materials and Methods: Patients were randomly allocated to three groups of 30 each. Group A received 0.5% levobupivacaine (25 mL) and saline in 5 mL, Group B received 0.5% levobupivacaine in 30 mL with 100 mg tramadol, and Group C received 0.5% levobupivacaine in 30 mL with 2 mg butorphanol. The duration of sensory block was evaluated as a primary outcome and other parameters as secondary outcomes. Statistical Tests: Statistical analyses were performed using Chi-square test for nonparametric data and analysis of variance for parametric data. Results: Onset time of sensory block was fast and comparable in both Group B and C as compared to Group A (P = 0.000). Group C had the longest duration of sensory block and duration of analgesia followed by Group B and Group A. Group C and Group B showed statistically longer duration of motor block as compared to Group A (P = 0.000). Hemodynamic derangements and adverse effects were comparable. Conclusion: Butorphanol (2 mg) as an adjuvant to levobupivacaine in supraclavicular block hastens the onset and prolongs the duration of the block as well as postoperative analgesia to a greater extent as compared to the addition of 100 mg tramadol.
Keywords: Butorphanol, levobupivacaine, supraclavicular brachial plexus block, tramadol
|How to cite this article:|
Kumari A, Chhabra H, Gupta R, Kaur H. Comparative study of effectiveness of tramadol and butorphanol as adjuvants to levobupivacaine for supraclavicular brachial plexus block. Anesth Essays Res 2019;13:446-51
|How to cite this URL:|
Kumari A, Chhabra H, Gupta R, Kaur H. Comparative study of effectiveness of tramadol and butorphanol as adjuvants to levobupivacaine for supraclavicular brachial plexus block. Anesth Essays Res [serial online] 2019 [cited 2020 Jul 12];13:446-51. Available from: http://www.aeronline.org/text.asp?2019/13/3/446/267333
| Introduction|| |
Brachial plexus block has evolved as an important tool in anesthesiologist's armamentarium as a safe alternative to general anesthesia for upper limb because of its increased effectiveness, the margin of safety, reduced total cost, reduced hospital stay, avoidance of undesirable side effects of general anesthesia, and good postoperative analgesia. Supraclavicular brachial plexus block is a popular and widely used technique for perioperative anesthesia and analgesia for surgery of the upper extremity except shoulder surgery. A variety of local anesthetics (LAs) have been studied for brachial plexus blockade. Levobupivacaine is S-enantiomer of bupivacaine belonging to an amino-amide group, having favorable clinical profile and margin of safety with respect to both cardiovascular system (CVS) and central nervous system effects compared with racemic bupivacaine.
A variety of adjuvants have been added to improve the quality of block, reduce the total dose of local anesthetics used, and to reduce the need for supplementary postoperative analgesia. Several combinations of LAs and various adjuvants such as morphine, tramadol, buprenorphine, clonidine, dexamethasone, fentanyl, and butorphanol have been used in various studies, but there was a scarcity of literature comparing tramadol with butorphanol as adjuvants to LAs. Tramadol, a synthetic codeine analog, is an analgesic with mixed μ-opioid and nonopioid activities. It inhibits the reuptake of norepinephrine and serotonin from the nerve endings and potentiates the effect of LA when mixed together in peripheral nerve block. Butorphanol is a synthetic opioid antagonist of the phenanthrene series acting as an analgesic. It exhibits partial agonist and antagonist activities at the μ-opioid receptor and agonistic activity at κ-receptors.
As there was scarcity of literature comparing tramadol with butorphanol as adjuvants to levobupivacaine, the objective of this study was to compare their effectiveness in terms of onset and duration of sensory and motor block, duration of postoperative analgesia, patient and surgeon satisfaction scoring, visual analog score (VAS) scoring, requirements of rescue analgesia, hemodynamics, procedure, and drug-related adverse effects in supraclavicular brachial plexus block.
| Materials and Methods|| |
This prospective, randomized, placebo-controlled, and double-blind study was conducted in the study period of 2 years (2014–2016) after obtaining institutional ethics committee approval on 90 patients in the age group of 18–65 years, American Statistical Association (ASA) physical status classes I and II, posted for upper limb surgeries. All patients provided written informed consent. Patients with ASA physical status classes III and IV coagulopathy, history of allergy to LA, glucose intolerance and diabetic patients, severe liver or renal disorder, unwilling or uncooperative patients, chronic analgesic therapy, previous nerve damage or brachial plexus injury, shoulder joint surgery, and morbidly obese (body mass index >40 kg/m2) were excluded from the study.
Patients were randomly divided into three Groups: A, B, and C of 30 each based on a computer-generated random sequence to produce a series of envelopes containing allocation instructions. One envelope was selected for each patient after consent was obtained and was immediately delivered to the anesthesiologists responsible for preparing the study drugs. This anesthesiologist was not involved in any subsequent study procedures, and the observer was blinded to the drug solution used. Group A received 0.5% levobupivacaine (isobaric) 25 mL + 5 mL normal saline (NS) making a total of 30 mL (placebo group), Group B received 0.5% levobupivacaine 25 mL + tramadol 100 mg (2 mL) +3 mL of NS making a total of 30 mL, and Group C received 0.5% levobupivacaine 25 mL + butorphanol 2 mg (1 mL) +4 mL of NS making a total of 30 mL [Figure 1].
A detailed preanesthetic checkup was performed a day before the surgery. Details pertaining to the patient's clinical history, general physical and systemic examinations, and basic routine investigations were observed. All patients were kept fasting overnight. Patients were explained in their own vernacular language about the brachial plexus block and linear visual analog score using a 10 cm line, where 0 denoted “no pain” while 10 “worst pain imaginable.” All patients were given tablet alprazolam (0.5 mg) orally on night before surgery. No patient received sedation and narcotic premedication before the surgery. All the patients were reassessed in the preanesthetic room and vitals were noted. In the operating room, intravenous line using 20-G cannula was secured and started with an infusion of ringer lactate. After attaching all the monitors (noninvasive blood pressure, electrocardiography, and SpO2), the baseline readings were recorded.
For the supraclavicular approach, the patient was placed in the supine position with the head turned away from the side to be blocked. The arm to be anesthetized was adducted, and the head was extended. The medial and lateral borders of the clavicle were identified as the first rib generally lies beneath the midpoint of the clavicle. The landmark was confirmed by sliding down the fingers in the interscalene groove till the arterial pulsation of the subclavian artery was felt. A skin wheal was then raised 0.5–1 cm posterior to the midpoint of the clavicle, and a 22-gauge, short beveled nerve stimulating needle was inserted in a caudal, slightly medial, and posterior direction. The needle was connected to the negative lead of the nerve locator, preset in the motor testing mode with a current setting of 2–3 mA, and the patient's arm was observed. When the patient got a distal contraction of the upper limb, the current was reduced to 0.4 mA. After observing the contractions at this reading, the drug solution was injected.
The primary outcome of this study was the duration of sensory blockade, whereas the onset of sensory and motor block, duration of motor block, duration of analgesia, VAS scoring, number of rescue analgesia, hemodynamic parameters, sedation scoring, patient as well as surgeon's satisfaction scoring, and adverse effects were recorded as secondary outcomes.
After completion of the procedure, sensory and motor blockade was evaluated every 5 min for 30 min. Sensory block assessment was done using the Hollmen scale: 1 – normal sensation of pinprick, 2 – pinprick felt as sharp pointed but weaker compared with the same area in another limb, 3 – pinprick recognized as touch with a blunt object, and 4 – no perception of pinprick. The sensory block of Grade 3 within 30 min was considered successful block and the endpoint for the start of surgery.
Motor block assessment was done using the Bromage scale: 0 – normal motor function, 1 – decreased motor strength with ability to move fingers only, and 2 – complete motor block with inability to move fingers. The motor block of Grade 1 within 30 min was considered successful block and the endpoint for the start of surgery.
Sedation score was assesed using 4 point sedation score graded as: 0 – alert, 1 – awake but sedated, 2 – asleep but easily aroused, 3 – asleep and not arousable by verbal contact.
Onset time of sensory and motor block was defined as the time elapsed between injection of drug and complete loss of pinprick sensation and complete motor block, respectively. Duration of sensory and motor block was defined as time elapsed between injection of drug and return of pinprick sensation and complete return of motor power, respectively.If appropriate sensory and motor blockade was not achieved within 30 min, the patient was excluded from the study and categorized as a block failure. The duration of analgesia was defined as the time when the block was performed to VAS scoring of ≥4. Postoperative pain was evaluated using VAS score (0–10) which was recorded at 2 h, 4 h, 6 h, 8 h, 12 h, and 24 h after the surgery. Whenever VAS score was ≥4, rescue analgesia was given in the form of injection diclofenac 75 mg intravenous. Time to the first analgesia and total doses required for postoperative analgesia during 24 h were noted.
Each surgeon was interviewed by an assessor blinded to the allocation of the patient at the end of surgery to assess his/her satisfaction using a 7-point Likert scale: “on a scale of 1–7 with 1 being not at all, 4 being neutral, and 7 being completely satisfied, with the surgical conditions provided”. Patient satisfaction was assessed with a 7-point Likert scale: “on a scale of 1–7 with 1 being not at all, 4 is neutral, and 7 is completely satisfied, about the effectiveness of supraclavicular block”.
Hemodynamic changes, side effects, and complications such as procedure-related pneumothorax, hematoma, postoperative paresthesias, and drug related-hypotension, bradycardia, respiratory depression, excessive sedation, nausea, and vomiting were also noted.
After completion of the study, the results were compiled and were statistically analyzed using Chi-square test for nonparametric data and analysis of variance for parametric data. Post hoc Student's paired t-test was applied wherever indicated using SSPS 17.0 software (SPSS Inc., 233 South Wacker Drive, Chicago, IL, USA). The power of this study was kept at 0.95 and alpha error of probability is set at 0.05, and the total sample size was calculated to be 66 in three groups (22 patients in each group). Considering the dropout rate, 30 patients were taken in each group. We have shown the precision of our estimates of outcome statistics as 95% confidence limits. P ≤ 0.05 was considered significant and ≤0.001 as highly significant.
| Results|| |
One hundred patients were assessed for eligibility and offered enrollment in this study. Two patients refused and eight patients were excluded from the study, leaving 90 patients who were enrolled and were given intervention. One patient in Group A was excluded because of failed block from the result analysis.
Demographic data including patient's age, sex, and ASA physical status distribution were comparable in all the three groups [Table 1] with P > 0.05 (NS).
Onset times of sensorimotor block was prolonged in group A (placebo) compared to group B and C (P < 0.001) [Table 2]. The time of onset of sensory as well as motor block was shortened with addition of both tramadol and butorphanol when compared to placebo (P < 0.001). However, no significant difference was observed between group B and C (P > 0.05).
Group C had the longest duration of sensory block followed by Group B with P < 0.013 and placebo group [Table 2]. Group B and Group C showed statistically comparable (P = 0.922) and longer duration of motor block as compared to placebo group P < 0.001 [Table 2].
One patient in placebo group showed sparing of all nerves, i.e. axillary, musculocutaneous, radial, median, and ulnar nerves and was excluded from the study, whereas two patients showed only ulnar nerve sparing. One patient each in Group B and Group C showed ulnar nerve sparing. However, the intergroup comparison was insignificant [Table 3] with P > 0.05.
Postoperatively, the duration of analgesia was significantly longer in Group C (P = 0.049) followed by Group B and least with the placebo group [Table 2].
VAS scoring at 6th, 8th, and 12th h postoperatively was similar and statistically insignificant in Group B and C (P > 0.05) and was significantly lower compared to the placebo group (P < 0.001). At 24 h postoperatively, VAS score, were statistically lowest in Group C with P = 0.003 [Figure 2].
|Figure 2: Visual analog scores in three groups at various time intervals postoperatively|
Click here to view
The requirement of number of rescue analgesia was maximum in placebo group as compared to other two groups (P < 0.001), whereas Group C showed clinically decreased requirement of rescue analgesia as compared to Group B but was statistically insignificant with P > 0.05 [Table 2].
A maximum number of patients in Group C were fully satisfied due to prolonged duration of analgesia postoperatively followed by Group B and lowest in Group A. Surgeon's satisfaction was comparable in both Groups B and C, whereas lowest in Group A.
Hemodynamically, comparison among all the three groups showed no statistically significant differences. No significant adverse effects were noted among all the three groups [Table 4]. One patient in Group B and two patients in Group C had Grade 1 sedation [Table 4], which was statistically insignificant (P > 0.05).
| Discussion|| |
Brachial plexus block is relatively easy to learn and execute and does not require bulky equipment for administration in upper limb surgeries. Brachial plexus block provides complete relaxation of muscles of the upper extremity, thus making approximation of tendons and fracture fragments easier. It also lessens postoperative spasm, pain, and edema due to sympathetic blockade of blood vessels. It reduces surgical stress response and gives better postoperative analgesia and earlier discharge of patients.
Bupivacaine is the widely used LA in peripheral nerve blocks. Levobupivacaine, S-enantiomer of bupivacaine with similar efficacy but better CVS stability and low neurological toxicity, had been used in this study instead of bupivacaine. Combinations of LAs have also been used to enhance the onset of sensory and motor block. Certain drugs may be used as adjuvants to LAs to lower the dose of each agent, to enhance the quality and duration of block, to increase the analgesic effect, and to reduce the need for supplementary analgesics, thus decreasing the incidence of adverse reactions.Addition of butorphanol (2 mg) with bupivacaine prolongs the duration of blockade and postoperative analgesia in supraclavicular brachial plexus blockade without compromising the hemodynamic parameters or producing any significant adverse drug reactions. On the other hand, Wakhlo et al. concluded that tramadol (100 mg) was found to be a good agent for hastening the onset and prolonging of sensory and motor block.
The effect of brachial plexus block comes between 15 and 20 min which at times becomes problematic to wait. The onset time for levobupivacaine is 15–20 min, similar to our study. The results showed delayed onset of sensory and motor block in placebo group as compared to Group B and Group C in our study. However, both Groups B and C had comparable onset times in this study. Bhavsar et al. also concluded that sensory and motor bock onset times were significantly shorter when 2 mg butorphanol was added to LA mixture (30 mL 1.5% lignocaine with adrenaline + 10 mL 0.5% bupivacaine) in supracalvicular block, similar to our study. Similarly, a study by Vinod et al. comparing butorphanol 1 mg with buprenorphine 150 μg as an adjuvant to LA mixture (20 mL 0.5% bupivacaine + 10 mL 2% lignocaine) in supraclavicular block found that sensory and motor onset times were significantly shorter in butorphanol group than buprenorphine group. So far, a dose of 100 mg tramadol when added to local anesthetic mixture (20 mL bupivacaine 0.5% +10 mL lignocaine with adrenaline) leads to faster onset as compared to control group in a study by Khosa et al., similar to our study.
The usual duration of anesthesia of levobupivacaine is 6–12 h, similar to our study. The duration of sensory block, i.e. the mean time interval from performance of block to regression of sensory level to a Hollmen sensory scale of ≤2, was significantly more in Group C as compared to Group B and placebo group. On the other hand, both Groups B and C showed comparable but prolonged motor block as compared to Group A. Mir and Hamid also concluded that 2 mg of butorphanol when added to 1% lignocaine in axillary brachial plexus block prolongs the duration of sensory as well as motor block, similar to our results. Bhavsar et al. by comparing the effect of adding 2 mg butorphanol to LA mixture (30 mL 1.5% lignocaine with adrenaline + 10 mL 0.5% bupivacaine) in supracalvicular block concluded that the duration of sensory and motor bock was significantly prolonged in butorphanol group than in control group. Similarly, Alemanno et al. using 1.5 mg/kg tramadol as adjuvant to 0.5% levobupivacaine for interscalene block showed prolonged duration of anesthesia with addition of tramadol. Similarly, a study conducted by Madhusudhan et al. concluded that the addition of 50 mg tramadol to 0.75% ropivacaine in supraclavicular block prolongs the duration of sensory and motor block when compared with 0.75% ropivacaine alone and with 50 μg fentanyl.
Duration of analgesia of brachial plexus which affects postoperative analgesia was taken as the time interval between the administration of block till the first dose of diclofenac (75 mg) administered intravenously when VAS scoring ≥4. The addition of 2 mg butorphanol increases the duration to much longer than tramadol. Bhavsar et al. and Acharya et al. who concluded that the addition of 2 mg of butorphanol to LA mixture and 0.5% bupivacaine, respectively, in supraclavicular block prolongs the duration of analgesia., Similarly, Wajima et al. conducted a study comparing continuous intravenous infusion with brachial plexus infusion of butorphanol for postoperative analgesia after surgery on upper extremities and concluded that butorphanol via brachial plexus block produces significant prolonged duration of analgesia as compared to intravenous butorphanol., Madhusudhana et al. concluded that the addition of 50 mg tramadol to 0.75% ropivacaine in supraclavicular block prolongs the duration of analgesia when compared with 0.75% ropivacaine alone and with 50 μg fentanyl. Furthermore, Akhtar et al. and Khosa et al. found that the addition of 100 mg tramadol to ropivacaine and LA mixture, respectively, led to significantly prolonged duration of analgesia as compared to control group.,
In our study, placebo group required a maximum number of rescue analgesia as compared to Group B and Group C. Similar results were observed by a study by Wajima et al. who concluded that butorphanol as an adjuvant in brachial plexus block required least number of supplementary analgesia doses as compared to intravenous butorphanol., Khosa et al. also reported that the addition of 100 mg tramadol to LA mixture decreased the number of rescue analgesia doses.
At 6, 8, and 12 h, VAS scoring in Group B and Group C was significantly lower compared to Group A (P < 0.001). At 24 h postoperatively, VAS score, were lowest in butorphanol and tramadol group, followed by the placebo group. Our study was in concordance with Wajima et al. who concluded that VAS scores at 3, 6, and 9 h postoperatively were significantly lower in butorphanol when given in brachial plexus block group as compared to intravenous butorphanol group., Furthermore, the study by Khosa et al. and Madhusudhana et al. reported that the addition of 100 mg tramadol to LA mixture and 0.75% ropivacaine, respectively, decreased the postoperative VAS scoring., Bhatia et al. reported that butorphanol is more potent and produces a longer duration of postoperative analgesia than tramadol, with an extra advantage of sedation and calmness. Bharathi et al. reported that higher dose of butorphanol in brachial plexus block hastens the onset and prolongs the duration of sensorimotor blockade and analgesia but is associated with a higher incidence of sedation which requires intense monitoring.
In our study, there were no significant changes in the hemodynamic parameters among all the three groups. Furthermore, only 1 patient in Group B and 2 patients in Group C developed sedation of Grade 1 which was not statistically significant. No significant differences regarding intraoperative adverse effects and complications were found among all the three groups.
In our study, adjuvants such as tramadol and butorphanol are less costly and easily available drugs, improved the quality of supraclavicular block as well as prolonged the duration of analgesia without producing any significant adverse effects.
The major limitation of our study was unavailability of ultrasound in our department.
| Conclusion|| |
Butorphanol as an adjuvant in a dose of 2 mg when added to levobupivacaine in supraclavicular block shortens the onset times similar to the addition of tramadol but causes prolongation of sensory and motor block as well as duration of postoperative analgesia to a greater extent as compared to addition of 100 mg tramadol without any side effects.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Sahu D, Sahu A. Lateral approach for supraclavicular brachial plexus block. Indian J Anaesth 2010;54:215-8.
] [Full text]
Piangatelli C, De Angelis C, Pecora L, Recanatini F, Cerchiara P, Testasecca D. Levobupivacaine and ropivacaine in the infraclavicular brachial plexus block. Minerva Anestesiol 2006;72:217-21.
Shrestha BR, Maharjan SK, Shrestha S, Gautam B, Thapa C, Thapa PB, et al.
Comparative study between tramadol and dexamethasone as an admixture to bupivacaine in supraclavicular brachial plexus block. JNMA J Nepal Med Assoc 2007;46:158-64.
Acharya R, Jena M, Mishra S, Rath SK. Effect of butorphanol versus placebo as adjuvant to bupivacaine for supraclavicular brachial plexus blockade. Int J Appl Pharm 2014;6:8-10.
Bonica JJ, Moore DC, Orlov M. Brachial plexus block anesthesia. Am J Surg 1949;78:65-79.
Chang DH, Ladd LA, Wilson KA, Gelgor L, Mather LE. Tolerability of large-dose intravenous levobupivacaine in sheep. Anesth Analg 2000;91:671-9.
Sharan R, Singh M, Attri JP, Singh D. Additive effect of butorphanol in supraclavicular brachial plexus block. Int J Med Res Rev 2016;4:910-7.
Wakhlo R, Gupta V, Raina A, Gupta SD, Lahori VU. Supraclavicular plexus block: Effect of adding tramadol or butorphanol as an adjuncts to local anaesthetic on motor and sensory Block and duration of post-operative analgesia. J Anaesth Clin Pharmacol 2009;25:17-20.
Stoelting RK, Hiller SC, editors. Local anesthetics. In: Pharmacology and Physiology in Anesthetic Practice. Vol. 4. Philadelphia: Lippincott Williams and Wilkins; 2006. p. 158-81.
Bhavsar GM, Shah RB, Chavda HK, Shah VD, Bateriwala KM. Use of butorphanol as an adjuvant to local anaesthetics in brachial plexus block for upper limb surgery. PIJR 2016;5:169-72.
Vinod CN, Talikoti DG. Comparison of butorphanol and buprenorphine as an adjuvant to local anaesthesia in supraclavicular brachial plexus block for post-operative analgesia. JEMDS 2014;3:4287-93.
Khosa AH, Asad N, Durrani H. Does the addition of tramadol to local anaesthetic mixture improve the quality of axillary brachial plexus block: A comparative study. PJMHS 2015;9:1120-3.
Mir IH, Hamid A. Addition of butorphanol to lidocaine prolongs duration of the axillary brachial plexus block. Internet J Anaesthesiol 2007;16:1-5.
Alemanno F, Ghisi D, Fanelli A, Faliva A, Pergolotti B, Bizzarri F. Tramadol and 0.5% levobupivacaine for single-shot interscalene block: Effects on postoperative analgesia in patients undergoing shoulder arthroplasty. Minerva Anestesiol 2012;78:291-6.
Madhusudhana R, Kumar K, Kumar R, Potli S, Karthik D, Kapil M. Supraclavicular brachial plexus block with 0.75% ropivaciane and with additives tramadol, fentanyl – A comparative pilot study. Int J Biol Med Res 2011;2:1061-3.
Wajima Z, Nakajima Y, Kim C, Kobayashi N, Kadotani H, Adachi H. IV compared with brachial plexus infusion of butorphanol for postoperative analgesia. Br J Anaesth 1995;74:392-5.
Wajima Z, Shitara T, Nakajima Y, Kim C, Kobayashi N, Kadotani H, et al.
Continuous brachial plexus infusion of butorphanol-mepivacaine mixtures for analgesia after upper extremity surgery. Br J Anaesth 1997;78:83-5.
Akhtar N, Butt TA, Nazeer T, Shah A. Comparison of efficacy of ropivacine alone with tramadol – Ropivacaine combination in supraclavicular brachial plexus block for upper limb surgery. Biomedica 2015;31:281-5.
Bhatia U, Panjabi G, Patel A. Comparison of butorphanol and tramadol as an adjuvant to local anesthetic drug in axillary brachial plexus block. Ain-Shams J Anaesthesiol 2017;10:242-6. [Full text]
Bharathi B, Praveena BL, Krishnaveni KN. Supraclavicular brachial plexus block: Comparison of varying doses of butorphanol combined with levobupivacaine – A double-blind prospective randomized trial. Anesth Essays Res 2019;13:174-8.
] [Full text]
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]