|Year : 2018 | Volume
| Issue : 3 | Page : 297-306
Intrathecal nalbuphine as an adjuvant to bupivacaine in spinal anesthesia for lower-limb surgeries: intraoperative and postoperative effects
Saad I Saad1, Ehab E Afifi1, El-Sayed M Abd El-Azim1, Walid H.I Moftah2
1 Department of Anesthesiology and Intensive Care, Faculty of Medicine, Benha University, Benha, Egypt
2 Department of Anesthesiology and Intensive Care, Faculty of Medicine, Benha University, Benha; Department of Anesthesia, Ministry of Health, Benha City, Egypt
|Date of Submission||29-Apr-2017|
|Date of Acceptance||12-Jun-2017|
|Date of Web Publication||07-Jan-2019|
Dr. Walid H.I Moftah
Department of Anesthesia, Faculty of Medicine, Benha University, Benha, 44511
Source of Support: None, Conflict of Interest: None
Background Many opioids are added to intrathecal local anesthetics to provide longer duration of analgesia; however, we have to choose an additive with the longest analgesic time and least intraoperative and postoperative side effects. In this study, nalbuphine was compared with fentanyl and pethidine as additives to hyperbaric bupivacaine used in spinal anesthesia for lower-limb surgeries.
Patients and methods A total of 100 patients of both sexes, American Society of Anesthesiologists I and American Society of Anesthesiologists II, scheduled for lower-limb surgeries under spinal anesthesia were assigned randomly into four groups: group B received intrathecal injection of 0.5% hyperbaric bupivacaine (3+1 ml sterile water; n=25); group N received intrathecal injection of 0.5% hyperbaric bupivacaine (3+1 ml nalbuphine 500 μg; n=25); group F received intrathecal injection of 0.5% hyperbaric bupivacaine (3+1 ml fentanyl 25 μg; n=25); and group P received intrathecal injection of 0.5% hyperbaric bupivacaine (3+1 ml pethidine 10 mg; n=25). We recorded the onset of sensory and motor blocks, peak sensory and motor block times, sensory block levels and two-segment regression time using the pin-prick method, motor block level using the modified Bromage scale, and any intraoperative or postoperative complications.
Results The mean onset of sensory block significantly decreased in groups N, F, and P compared with group B, whereas the peak sensory time did not significantly change in all the four groups. In contrast, the mean onset of the motor block in all four groups was nonsignificantly different, whereas the mean time for peak motor block was significantly short in both the N group (nalbuphine and bupivacaine) and the P (pethidine and bupivacaine) group compared with the B (bupivacaine alone) and F (fentanyl and bupivacaine) groups. There was significant prolongation in both two-segment regression time and the first analgesic request time in groups N, F, and P (all narcotics and bupivacaine) compared with group B (bupivacaine alone).
Conclusion Nalbuphine, fentanyl, and pethidine as adjuvants to spinal anesthesia prolong the duration for first-rescue analgesia with minimal hemodynamic and respiratory complications; however, nalbuphine at a dose of 0.5 mg has the best quality of spinal block when added to intrathecal 0.5% heavy bupivacaine in patients undergoing lower-limb surgeries.
Keywords: fentanyl, intrathecal nalbuphine, lower-limb surgeries, pethidine, spinal anesthesia
|How to cite this article:|
Saad SI, Afifi EE, Abd El-Azim ESM, Moftah WH. Intrathecal nalbuphine as an adjuvant to bupivacaine in spinal anesthesia for lower-limb surgeries: intraoperative and postoperative effects. Benha Med J 2018;35:297-306
|How to cite this URL:|
Saad SI, Afifi EE, Abd El-Azim ESM, Moftah WH. Intrathecal nalbuphine as an adjuvant to bupivacaine in spinal anesthesia for lower-limb surgeries: intraoperative and postoperative effects. Benha Med J [serial online] 2018 [cited 2020 May 28];35:297-306. Available from: http://www.bmfj.eg.net/text.asp?2018/35/3/297/249430
| Introduction|| |
Spinal anesthesia was introduced about 100 years ago, and it is still the most popular regional anesthesia technique. However, the local anesthetic drugs used for spinal anesthesia do not have the advantage of prolonged postoperative analgesia. It is a continuous challenge for the anesthesiologists as perioperative pain management is their domain.
Because of the technical difficulties in identifying the epidural space and the toxicity associated with large doses of local anesthetics needed for epidural anesthesia, spinal anesthesia was the dominant form of neuraxial anesthesia in the 20th century .
Excessive high regional blocks and local anesthetic toxicity are the most common causes of mortality associated with regional blocks; therefore, reduction in doses of local anesthetics, the use of new techniques to avoid higher blocks, and better management of local anesthetic toxicity are the new goals for decreasing mortality associated with regional anesthesia .
Many adjuvants such as fentanyl, morphine, buprenorphine, midazolam, and clonidine have been used in the past to reduce the dose of local anesthetics and to prolong postoperative analgesia, but all of them have certain side effects .
The opioid additives specifically have certain specific advantages such as rapid onset of action, sympathetic and motor nerve-sparing activities, technical ease of administration, and simplicity of postoperative management. In addition to their combination of intrathecal local anesthetic, they limit the regression of sensory block observed with local anesthetic alone .
The major disadvantages of adding opioids are their side effects, some of which, such as respiratory depression, can be serious. To overcome these side effects, opioids with partial agonist–antagonist action have been studied extensively.
One of the best ways to control the intrathecal opioid-related side effects is the use of mixed agonist–antagonist opioids. Nalbuphine is one of the most recently used additives to spinal bupivacaine, considering its µ antagonist and κ agonist mechanisms of action, which may avoid some of the opioid adverse effects.
| Patients and methods|| |
This study was carried out at the Anesthesia Department, Faculty of Medicine, Benha University Hospitals after obtaining approval from the Ethics Research Committee and the Anesthesia Department.
Written informed consent was obtained from 100 patients of both sexes, American Society of Anesthesiologists (ASAI) and ASAII, aged 20–60 years, scheduled for lower-limb surgeries, during August 2015 to August 2016. Patients were randomization into four equal groups by the lottery method.
Inclusion criteria for the present study were as follows: patients with ASAI and ASAII status, normal coagulation profile, age range between 20 and 60 years, weight range between 60 and 100 kg, and duration of surgery between 45 and 120 min.
Exclusion criteria were as follows: patient refusal for either spinal anesthesia or inclusion to the study, infection at the site of injection, presence of any coagulopathy disorder or patients on anticoagulants, pre-existing neurological disorders, patients receiving phenothiazine, other tranquilizers, hypnotics, or other central nervous system depressants (including alcohol), uncooperative patients, patients with signs suggesting cardiac or respiratory problems, patients with evidence for hepatic or renal disease, patients with known history of allergy to local anesthetic drugs, pregnant patients, and failed spinal cases.
Patients were planned to be admitted for less than 12 h to the hospital, and all patients fasted for at least 6 h before the procedure. All patients was clinically assessed, and routine preoperative investigations were carried out (complete blood count, prothrombin time, partial thromboplastin time, international normalized ratio, liver function tests, renal function tests, and ECG).
On arrival to the operating room, an intravenous line was secured, and 500 ml of lactated Ringer’s solution was infused as a preload. After standard monitoring procedures (ECG, noninvasive blood pressure, and oxygen saturation) and recording of baseline vital data, each patient was placed in the sitting position. After scrubbing the back with antiseptic solution, a Whitacre spinal needle was introduced in the lumbar three to four interspace (one level above or below if there was any difficulty).
Patients were randomized to one of four groups: group B included 25 patients who received intrathecal injection of 3-ml 0.5% hyperbaric bupivacaine plus 1-ml sterile water; group N included 25 patients who received intrathecal injection of 3-ml 0.5% hyperbaric bupivacaine plus 1 ml of sterile water containing nalbuphine (preservative free) 500 μg; group F included 25 patients who received intrathecal injection of 3-ml 0.5% hyperbaric bupivacaine plus 1 ml of sterile water containing preservative-free fentanyl 25 μg; and group P included 25 patients who received intrathecal injection of 3-ml 0.5% hyperbaric bupivacaine plus 1 ml of sterile water containing preservative-free pethidine 10 mg. All study mixtures were prepared by well-trained anesthesia residents blinded to patient follow-up and data collection.
After spinal injection, all patients were allowed to rest in the supine position. The block level was tested every minute aiming for sensory block of the 10th thoracic dermatome.
Intraoperatively, patients were continuously monitored for blood pressure, heart rate, oxygen saturation, and respiratory rate. If the systolic blood pressure decreased to less than 20% of the baseline, 5 mg of intravenous ephedrine was injected incrementally.
Patients were excluded if intraoperative pain required the use of opioids or conversion to general anesthesia. The intraoperative recordings included conscious level, ephedrine doses, operation time, sensory block level using the pin-prick method, and motor block level using the modified Bromage scale ([Table 1]).
Any intraoperative complications were recorded and treated symptomatically.
Postoperatively, all patients of the four groups were assessed every 15 min in the first hour then every hour for the subsequent 4 h for consciousness levels, respiratory rate, heart rate, oxygen saturation, and noninvasive blood pressure.
In addition, we recorded the time for the first request of analgesia (effective analgesic time) according to the visual analog scale (it ranges from 0 indicating no pain till 10 indicating severe intolerable pain with variable degree of ascending pain in between; first request of analgesia was considered when the visual analog scale was above 4).
Any complication such as hypotension (systolic below 90 mmHg), bradycardia (heart rate below 60 beats/min), pruritus or rash, nausea, vomiting, shivering, breathlessness (respiratory rate below 10 breaths/min), and urine retention were noted.
Complications were treated symptomatically as follows.
Patients with vomiting were given 10 mg of metoclopramide, those with shivering were treated with pethidine 20 mg, and pruritus was managed with 10-mg chlorpheniramine maleate.
Ephedrine 10 mg and atropine 0.5 mg, intravenous, were injected in boluses for hypotension and bradycardia, respectively, whereas patients who developed urine retention were catheterized for evacuation.
All data were analyzed using SPSS 20.0 for Windows (SPSS Inc., Chicago, Illinois, USA). Continuous variables are expressed as mean±SD and medians (ranges), and categorical variables are expressed as numbers (percentages). Continuous variables were checked for normality using the Shapiro–Wilk test. One-way analysis of variance was used to compare normally distributed variables between the four groups, whereas the Kruskal–Wallis H test was used for non-normally distributed variables. Independent samples Student’s t-test was used to compare two groups of normally distributed data, whereas the Mann–Whitney U test was used for non-normally distributed data. Percentages of categorical variables were compared using the χ2-test. All tests were two tailed. A P-value less than 0.05 was considered statistically significant, a P-value less than 0.01 was considered highly statistically significant, and a P-value greater than 0.05 was considered statistically insignificant.
| Results|| |
Hundred patients were enrolled for this study. As shown in [Table 2], there were no significant differences between the four groups with regard to age, weight, sex, ASA classification, or duration of surgery.
|Table 2 Comparison between groups B, N, F, and P with regard to demographic data|
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The results regarding the sensory and motor block times are summarized in [Table 3]. The onset of sensory block significantly decreased in groups N, F, and P compared with group B with bupivacaine alone, whereas the peak sensory time nonsignificantly changed among all the four groups.
|Table 3 Comparison between groups B, N, F, and P with regard to sensory block, motor block, and analgesia|
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In contrast, regarding the motor parameters of the block, the onset of motor block in the four groups included was nonsignificantly different, whereas the means for peak motor block were significantly short in both N (nalbuphine and bupivacaine) and P (pethidine and bupivacaine) groups when compared with B (bupivacaine alone) and F (fentanyl and bupivacaine) groups.
Regarding the parameters describing sensory duration in Tables 3 and 4, there were significant prolongations of both two-segment regression time and the first analgesic request time in groups N, F, and P (all narcotics plus bupivacaine) compared with group B (bupivacaine alone).
As shown in [Table 5],[Table 6],[Table 7], the modified Bromage scale was analyzed by two methods: first the analysis of means of the total scale was carried out by the Kruskal–Wallis test, and the results indicated highly significant increases in the 5-min assessments of opioid groups N, F, P versus B group and nonsignificant differences in the 10-min scale.
|Table 5 Comparison between groups B, N, F, and P with regard to the modified Bromage scale|
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|Table 7 Comparison between groups B, N, F, and P with regard to the Bromage scale|
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The second analysis was performed using the categorical variables of the scale expressed as percentages using the χ2-test. It confirmed the same results, which were significantly different in the 5-min assessments of the modified Bromage scale within groups N, F, and P compared with the scale in group B, whereas there was no significant differences in the 10-min assessments in all four groups. As shown in Tables 6 and 8, comparing each group against the other, there was a highly significant difference in motor block assessment by the modified Bromage scale for the pethidine group compared with all other groups.
Complications encountered are summarized in [Table 8].
Heart rate and mean arterial blood pressure were stable with minimal variations, which were not statistically significant. Pruritus was significant in group F (fentanyl plus bupivacaine) when compared with the other groups. Nausea or vomiting, respiratory depression, and urine retention were not statistically significant among all study groups ([Table 8],[Table 9],[Table 10] and [Figure 1])
|Table 9 Comparison between groups B, N, F, and P regarding complications|
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| Discussion|| |
Spinal anesthesia is the most common type of anesthesia used for lower-limb surgeries; however, adding intrathecal opioids to local anesthetics decrease their dose, provide more hemodynamic stability, and increase the time required for postoperative analgesia.
Nalbuphine is a synthetic opioid with mu agonist and antagonist properties. The mechanism of analgesia relies on its agonistic action on this receptor. It also stimulates kappa receptors, which inhibit the release of neurotransmitters that mediate pain such as substance p; in addition it acts as a postsynaptic inhibitor on the interneuron and the output neuron of the spinothalamic tract, which transports nociceptive information .
Nalbuphine, administered intrathecally, binds to kappa receptors in the brain and spinal cord areas, which are involved in nociception, producing analgesia and sedation without μ side effects . It improves quality of block and offers prolonged and long-lasting postoperative analgesia. It has low incidence of adverse effects known for other opioids (e.g. respiratory depression, nausea, vomiting, pruritus). It is also a cost-effective drug .
Relying on the fact that nalbuphine administered systemically reduced the incidence of respiratory depression, and it also was used to reduce the side effects of spinal opiates , we hypothesized that spinal nalbuphine should demonstrate improved therapeutic effects consistent with that seen after systemic administration.
There have been a few studies of varying quality that support the utility of neuroaxially administered nalbuphine in managing postoperative pain .The general trend of these reports is that epidural or intrathecal delivery of nalbuphine produces significant analgesia accompanied by minimal pruritus and respiratory depression .
In this prospective, randomized, controlled study, we compared the use of intrathecal hyperbaric bupivacaine 0.5% without additives (control group) with the use of nalbuphine 0.5 mg, fentanyl 25 μg, and pethidine 10 mg as different adjuvants to intrathecal heavy bupivacaine 0.5 % for lower-limb surgeries in 100 patients.
Our choice of nalbuphine doses depended on a previous study by Mukherjee et al. , who studied 100 patients undergoing lower-limb orthopedic surgeries using subarachnoid block. They used different doses of nalbuphine intrathecally (200, 400, and 800 μg) added to 0.5% hyperbaric bupivacaine. They concluded that the duration of sensory block and the duration of effective analgesia were prolonged with the 400-μg and the 800-μg doses, but the side effects were higher with the 800-μg dose.
Therefore, we chose to add 500 μg of preservative-free nalbuphine, which is very close to the best-recognized dose earlier and is practically easier to calculate.
The same dose (0.5 mg) of intrathecal nalbuphine was used in the study of Dubey and Bisht , where they studied 40 ASA, ASAI, and ASAII, patients. Their patients were divided into two equal groups: a control group with hyperbaric bupivacaine and normal saline and the second group with hyperbaric bupivacaine and 0.5 mg of nalbuphine in normal saline.
Our results showed that the onset of sensory block was significantly short in opioid additive groups F, N, and P compared with bupivacaine alone in group B, whereas the time for peak sensory block was not significantly different among the four groups.
The mean onset of sensory block time in group N was 88.84±12.23 s, and the peak sensory time was 355.24±28.48 s. In group F, the mean onset of sensory block time was 86.84±13.19 s, and the peak sensory time was 349.40±30.90 s. In group P, the mean onset of sensory block time was 86.68±14.21 s, and the peak sensory time was 348.04±35.78 s compared with a mean sensory block time of 119.52±16.87 s and peak sensory time of 369.84±31.37 s in group B.
Similar results were documented by Shakooh and Bhoole  in their study on 60 ASAI and ASAII patients aged 18–65 years, scheduled for lower-limb and lower-abdominal surgeries. One group of patients was given 3 ml of hyperbaric bupivacaine 0.5% plus 800 µg of nalbuphine intrathecally, and the other group was given 3 ml of hyperbaric bupivacaine 0.5% plus normal saline. They found that intrathecal nalbuphine provided significantly faster onset of sensory block and shorter peak sensory time compared with bupivacaine alone.
In contrast to this study, Sapate et al.  in their study have shown that onset of sensory block and peak time for sensory block was not affected by adding nalbuphine intrathecally in 40 patients aged between 40 and 70 years scheduled for below-umbilicus surgeries.
Similar results were obtained by Tiwari et al.  in their study on 75 patients who underwent lower-abdominal surgeries.
Onset of motor block was nonsignificant in all four groups, whereas the time for peak motor block was significantly short in the opioid groups.
The peak motor time in group N was 326.76±22.65 s, in group F it was 342.24±21.76 s, and in group P it was 309.76±34.93 s; these values are highly significant when compared with group B (352.72±19.29 s).
Consequently, the 5-min modified Bromage scale , when analyzed as mean±SD and as a percentage of each scale from 0 to 3, there were highly significant differences between all opioid additive groups N, F, and P and bupivacaine group B.
Similar results were obtained by Shakooh and Bhoole .
On the other hand, Ahmed et al.  studied 100 patients scheduled for abdominal hysterectomy. Patients were divided into four groups: one plain bupivacaine group and three groups of three different doses of nalbuphine (0.8, 1.6, and 2.4 mg). They concluded that there was no difference in the time to peak motor blockade among the four groups. Although this conclusion is recently published, we could not find many studies supporting it.
When comparing the peak motor time among the opioid groups only, we found that pethidine as an additive has a significantly shorter peak time for motor block compared with nalbuphine and fentanyl. This result was supported by Patel et al.  who used pethidine alone as an intrathecal local anesthetic for endoscopic urological procedures and concluded that low-dose pethidine 0.5 mg/kg is effective as a spinal anesthetic agent and has a few complications.
The same findings were observed by Anaraki and Mirzaei  when they were studying the effects of different intrathecal doses of pethidine on shivering during delivery under spinal anesthesia.
Another important efficacy measure of intrathecal additives is the two-segment regression time, which is the time required for regression of the sensory level by two segments. In our study, when comparing the two-segment regression times of the three opioid groups (N, F, and P) with that of the bupivacaine group, it was highly significant for a longer time in the opioid groups: 120.08±19.36 min in the N group, 122.48±18.26 min in the F group, and 133.24±27.65 min in the P group compared with 104.28±23.67 min in the B group.
The same results were supported by Tiwari et al. . They found that 200 and 400 μg of intrathecal nalbuphine prolonged the two-segment regression time of sensory blockade of 12.5 mg of hyperbaric bupivacaine by about 16 and 24 min, respectively.
Shakooh and Bhoole  and Mukherjee et al.  agreed that addition of nalbuphine to bupivacaine intrathecally slows down the two-segment regression time of sensory block.
Even Ahmed et al.  who disagreed with most of them regarding the effect of intrathecal nalbuphine on peak motor time reached the same conclusion regarding prolongation of the two-segment regression time when nalbuphine was added to spinal anesthesia.
In the same direction, we observed that the first request for analgesics was after 234.48±38.56 min in group N, 206.28±40.44 min in group F, and 261±27.95 min in group P, in comparison with 173±27.42 min in the bupivacaine group. There was a highly significant difference between the narcotic additive groups N, F, and P from one side and the pure bupivacaine group on the other side; this confirms the apparent prolongation of analgesic time when opioids are used as additives to heavy bupivacaine in spinal anesthesia.
These results are in agreement with Culebras et al. , Tiwari et al. , Sapate et al. , Dubey and Bisht , Gomaa et al. , Shakooh and Bhoole , Jyothi et al. , and Ahmed et al. .
Regarding the side effects, in our study groups, there were neither cases of respiratory depression (respiratory rate below 10 or SpO2≤90%) nor cases with persistent serious hypotension. Nalbuphine exhibits a ceiling effect for respiratory depression; this has been proved in studies conducted by Romagnoli and Keats , as respiratory depression is predominantly μ-receptor mediated and nalbuphine is mainly a μ-receptor antagonist; respiratory depression effect is expected to be attenuated by nalbuphine even when increasing the dose from 0.8 to 2.4 mg .
Urine retention was observed in one patient in the F group (fentanyl) and in two patients in the P group (pethidine), which was solved by bladder evacuation, but they were statistically nonsignificant.
Nausea and vomiting occurred in two patients in the B group, one patient in the N group, three patients in the F group, and six patients in the P group; however, they were nonsignificant statistically. Anaraki and Mirzaei  studied 56 parturient women scheduled for elective cesarean delivery who were divided into four groups receiving pethidine 0.2, 0.3, 0.4 mg/kg to heavy bupivacaine, and pure bupivacaine 0.5% (control group). They concluded that intrathecal pethidine cannot be recommended for the prevention of shivering during spinal anesthesia for cesarean delivery as its use is associated with increased incidence of nausea and vomiting.
The only complication that was significant in our study was pruritus, it did not occur in any of the groups except for the fentanyl group where three (12%) patients complained of pruritus. This result is in agreement with the study by Gomaa et al. , who studied 60 female patients, ASAI and ASAII, who presented for elective cesarean deliveries. Their patients were divided into two equal groups: group F received heavy bupivacaine plus fentanyl 25 μg and the other group received 0.8 mg nalbuphine added to heavy bupivacaine. They found that the incidence of pruritus was higher with addition of fentanyl compared with the nalbuphine group.
In 2011, Mukherjee et al.  formulated a case–control study to determine whether nalbuphine prolongs analgesia and to find out the optimum dose of intrathecal nalbuphine by comparing doses of 0.2, 0.4, and 0.8, which prolonged postoperative analgesia without increased side effects. It was observed that effective analgesia increased with increase in concentration but the ultimate observation of prolongation of analgesia without any side effects was the addition of 0.4 mg with 0.5% hyperbaric bupivacaine.
Thus, from our study, it was observed that nalbuphine as well as fentanyl and pethidine can be used as additives to intrathecal heavy bupivacaine.
They prolong the time for first request of analgesics and slow down the two-segment regression time with minimal side effects.
When comparing the narcotic additives of groups N, F, and P, we additionally made some observations that need confirmation by future studies. First, pethidine as an intrathecal additive has a significantly shorter time for motor block and significantly longer time for both two-segment regression time and the first request for analgesics, making it superior to fentanyl and nalbuphine in the duration of analgesia; however, the documented higher rate of nausea and vomiting may limit its use as the best choice. Second, nalbuphine is the next class regarding time of analgesia; however, its devoid side effects may raise it as the first choice as an opioid additive not only when compared with pethidine and fentanyl as in our study but also when compared with morphine as in Mohamed and Gad , where they concluded that intrathecal nalbuphine when compared with intrathecal morphine provides a significantly faster onset of pain relief probably because of its lipophilic properties. However it does not seem to be as effective as intrathecal morphine in prolonging postoperative analgesia because of the ceiling effect of nalbuphine analgesia.
Culebras et al.  concluded that intrathecal nalbuphine was safer when compared with morphine with regard to serious side effects that were recorded with the use of intrathecal morphine.
A large number of animal studies have been carried out to prove that intrathecal nalbuphine is not neurotoxic. Rawal et al.  studied the behavioral and histopathological effects following intrathecal administration of butorphanol, fentanyl, and nalbuphine in sheep. They found that nalbuphine was the least irritating to neural tissues even at large doses of 15–24 mg. It was not associated with any histopathological changes in the spinal cord .
There have been no reports on the neurotoxic effects of using intrathecal nalbuphine for over 10 years. Many studies have been conducted on pregnant patients, but they have not revealed any unwanted effects .
In conclusion, the present study showed that nalbuphine, fentanyl, and pethidine as adjuvants to spinal anesthesia shorten the onset of sensory and motor block, prolong the duration of sensory and motor blockade, provide effective postoperative analgesia, and prolong the duration for first-rescue analgesia with minimal hemodynamic and respiratory complications. However nalbuphine at a dose of 0.5 mg has a peculiar advantage over other opioids: it does not result in any major adverse effects, and it has the best quality of spinal block when added to intrathecal 0.5% heavy bupivacaine in patients undergoing lower-limb surgeries.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9], [Table 10]