|Ahead of print publication
Efficacy of epidural dexamethasone combined with intrathecal nalbuphine in lower abdominal oncology operations
Mohamed Ghanem1, Mona Gad1, Ahmed Abdallah2, Mosab Shetiwy2, Mohamed Shetiwy3
1 Department of Anesthesia and Surgical Intensive Care, Faculty of Medicine, Mansoura University, Mansoura, Egypt
2 Department of Surgical Oncology, Mansoura Oncology Center, Mansoura University, Mansoura, Egypt
3 Department of General Surgery, Mansoura University Hospital, Mansoura University, Mansoura, Egypt
Department of Anesthesia and Surgical Intensive Care, Faculty of Medicine, Mansoura University, Mansoura
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: Dragging pain during lower abdominal surgeries under intrathecal anesthesia is a common problem. Epidural steroid seemed to be effective in reducing intra and postoperative pain. Kappa receptor agonist like nalbuphine helps in reduction of visceral pain. Hence, this study was designed to detect the efficacy of epidural steroid dexamethasone with intrathecal Kappa opioid as a sole anesthetic technique in patients subjected to lower abdominal oncology operations. Patients and Methods: Patients were randomly allocated into two groups; epidural placebo group–control group (Group P) – Intrathecal injection of 20 μg fentanyl followed by intrathecal injection of (15 mg) of hyperbaric bupivacaine 0.5%, then (epidural injection placebo 15 mL volume of sterile saline 0.9%). Epidural dexamethasone group–study group (Group D) – Intrathecal injection of 0.6 mg nalbuphine followed by intrathecal injection of (15 mg) of hyperbaric bupivacaine 0.5% then (epidural injection of 8 mg dexamethasone in 15 mL total volume using sterile saline 0.9%). Results: Group D recorded significantly longer times to 1st analgesic request, sensory regression to S1 and modified bromage Score 0 with significant lower number of patients that had abdominal dragging pain in comparison with Group P. Visual analog score in the first four postoperative hours, total postoperative nalbuphine dose in 1st 24 h and incidence of nausea and vomiting were significantly lower in Group D. Heart rate and mean arterial pressure were comparable in both groups. Postoperative headache incidence was comparable in both groups. Both patient and surgeon satisfaction were significantly higher in Group D compared to Group P. Conclusion: Combined epidural dexamethasone with intrathecal nalbuphine as a sole anesthetic technique during lower abdominal oncology operations could be an efficient anesthetic technique that offered better block characteristics, with more analgesia and as a result it gained better patient and surgeon satisfaction.
Keywords: Combined spinal epidural, dexamethasone, fentanyl, intrathecal, nalbuphine, oncology
|How to cite this URL:|
Ghanem M, Gad M, Abdallah A, Shetiwy M, Shetiwy M. Efficacy of epidural dexamethasone combined with intrathecal nalbuphine in lower abdominal oncology operations. Anesth Essays Res [Epub ahead of print] [cited 2019 Aug 20]. Available from: http://www.aeronline.org/preprintarticle.asp?id=259931
| Introduction|| |
Higher sensory levels of spinal anesthesia (T6–T4) are required for lower abdominal surgeries such as hysterectomy. However, patients may perceive an unpleasant discomfort associated with the surgical traction on the peritoneum or abdominal viscera. Perioperative pain control depends mainly on multimodal therapy to minimize the need for opioids. The overprescribing of opioids has reached a critical level worldwide, and surgery may be the trigger for long-term opioid use in many patients.,
Combined spinal-epidural anesthesia (CSEA) offers excellent analgesia, with low incidence of postoperative nausea and vomiting. During spinal anesthesia, manipulation of the viscera and peritoneum produces dragging abdominal pain that sometimes necessitates induction of general anesthesia. Pain management for oncology patient is important for early mobilization, tuning the immune system, and attenuation of the serious immune suppression mediated by the surgically stimulated network of neuro-immune-endocrine interactions.
Postoperative opioid analgesia was associated with increased risk of biochemical cancer recurrence after open radical prostatectomy when compared with epidural nonopioid analgesia. Furthermore, opioid dose reduction may improve pain control, others advised avoiding opioid use for postoperative cancer pain.
Rawal et al. animal study documented the safety of intrathecal injection of nalbuphine was proved to be nontoxic nonharmful in a dose more than 1 mg despite that the use of intrathecal nalbuphine in anesthesia was restricted to a narrow sector of publications despite the strong analgesic kappa agonistic criteria of that drug and has been used in the concept of reducing the morphine-related adverse effects after epidural morphine. Peripheral kappa opioid receptors are important modulator of visceral pain, kappa receptor agonists reduced visceral pain and have less adverse effects on gastrointestinal motility than Mu agonists. Multiple neurotransmitters, channels, and receptors are responsible for abdominal pain, so analgesics combinations are anticipated to be better than single analgesic.
Dexamethasone is a high potency, long-acting glucocorticoid with little mineralocorticoid effect that has been used for prophylaxis of postoperative nausea. Single doses of dexamethasone and other glucocorticoids have also reported to improve analgesia after various operations, whether oral or intravenous (IV). Epidural dexamethasone had almost the same analgesic potency as fentanyl when added to local anesthetic (LA) bupivacaine avoiding opioid side effects in addition to its antiemetic effect. In addition, preoperative epidural dexamethasone with or without bupivacaine was reported to reduce postoperative pain and opioid consumption. Moreover, epidural dexamethasone in a dose 8 mg is probably more effective than lower doses to control moderate-to-severe postoperative pain without associated increase in glucose level or delayed wound healing.
Hence, goal-directed better perioperative analgesia that avoids Mu opioid analgesics use in cancer patients,,, the combined epidural steroid with intrathecal Kappa opioid analgesic utilizing CSEA technique would prevent intraoperative dragging pain due to surgical viscera manipulation (Kappa agonist effect), reduce the postoperative rescue analgesic use and as a result side effects in cancer patients and improve surgeon satisfaction with CSEA anesthesia as a sole technique in lower abdominal oncology surgery.,,, Hence, the present study was designed to evaluate the efficacy of epidural steroid combined with intrathecal nalbuphine in patients subjected to lower abdominal oncology operations.
| Patients And Methods|| |
The present study was carried out after approved by Institutional Research Board (R1704127). Thirty-four patients with physical status American Society of Anesthesiologists (ASA) Classes I and II of both genders, aged 18–65 years scheduled for lower abdominal (below the umbilicus) such as hysterectomy, open prostatectomy, oophorectomy, rectal mass excision, and pelvic exploration surgery were included in this study after obtaining informed written consents from all of them. Patients refused, with body mass index >35, hypersensitivity to amide LA, fentanyl, nalbuphine, or dexamethasone were excluded from the study. Moreover, failed cases who were shifted to general anesthesia, excluded from the study and reported. General contraindications to spinal anesthesia, surgeon total refusal (surgeon who totally refuse regional anesthesia as a sole anesthesia technique in lower abdominal operations), cardiac, hepatic, renal or respiratory failure or difficult communication with the patient (psychological or deafness) all were also excluded from the current study.
Randomization and blinding patients
Patients were randomly assigned to either Group P (epidural placebo saline control group) (n = 17) and = Group D (epidural dexamethasone study Group) (n = 17). A person not involved in the data collection or in patient care randomly assigned the patients using Research Randomizer Program into two blocks each of block size 17 patient was also randomized using two lists of random numbers. Block size and randomization codes were not revealed to the investigators until all measurements and calculations had been entered into the database for all patients. Each patient, the investigators, and all medical caregivers were blinded to group allocation. One hour before the CSE block procedure of an enrolled patient, a nurse, not otherwise participating in the study, opened a sealed opaque envelope containing group allocation. The nurse then filled size 20 mL syringe containing (15 mL sterile normal saline) labeled “control medicine” or size 20 mL syringe (15 mL sterile normal saline containing 8 mg dexamethasone) labeled “study medicine.” All data were entered into the database before entering the randomization codes.
Combined spinal epidural block technique
Preoperative patient and drug preparation
After patient clinical examination and consultation about any comorbidities and explanation of the anesthetic procedure, the consent was taken after clarification of the visual analog score (VAS). Then, 20 gauge IV catheter and preloading by 1000 mL ringers solution over 30 min before anesthesia. After attaching 5 L oxygen face mask, all standard monitors pulse oximeter probe, noninvasive blood pressure cuff, and electrocardiogram, and recording basal data.
Using needle-through-needle CSE technique, (18-gauge Tuohy needle, 25 mm × 120 mm gauge/length spinal needle), at level below L2 (L2–3, or L3–4) interspace with the patient in the sitting position skin disinfection with complete aseptic technique, skin infiltration with LA lidocaine 0.5 mL at the preselected intervertebral space below L2, the epidural (18-gauge Tuohy needle) was inserted and the epidural space identified using “air-loss of resistance technique” then, 25 mm × 120 mm gauge/length spinal needle was introduced through the epidural needle and advanced until the tip of the spinal needle is felt to penetrate the dura “dural click” confirmed by free flow or aspiration of cerebrospinal fluid (CSF), then the appropriate preprepared dose of fentanyl or nalbuphine followed by LA bupivacaine was injected according to the protocol sequence of drug injection in both groups then spinal needle was withdrawn and Tuohy needle was rotated 180°,,(site of the spinal needle dural puncture is away), followed by epidural needle position confirmation by aspiration for excluding blood or CSF aspiration then loss of resistance recheck to document that the Tuohy needle still in the epidural space, after that epidural bolus volume of placebo or dexamethasone to be injected according to the randomization protocol in both groups:
First group: Epidural placebo control group (Group P)
Intrathecal injection of preservative-free 20 μg fentanyl (Fentanyl Hameln 100 μg/2 mL ampoule, Sunny Pharmaceutical, 100Acre Industrial zone, Badr City, Egypt under license of Hameln Pharmaceutical, Germany). 100 μg fentanyl ampoule will be diluted up to 5 mL sterile saline 0.9% to get 20 μg/mL concentration then using a sterile 3 mL syringe to take 1 mL to be injected intrathecally followed by intrathecal injection of 3 mL (15 mg) of hyperbaric bupivacaine 0.5% (Marcaine spinal heavy 0.5% by Astra Zeneca, Buyukdere Cad. Yapi Kredi Plaza B Blok Kat: 3-4 Levent, Istanbul, Turkey), then epidural injection of placebo 15 mL volume of sterile saline 0.9%.
Second group: Epidural dexamethasone study group (Group D)
Intrathecal injection of preservative-free 0.6 mg nalbuphine (Nalbuphine 20 mg/2mL ampoule; SERB, Paris, France). 20 mg ampoule will be diluted up to 20 mL sterile saline 0.9% to get 1 mg/mL dilution then using an insulin syringe to take 0.6 mL and complete it to 1 mL volume with sterile saline 0.9% to be injected intrathecally followed by 3 mL (15 mg) of hyperbaric bupivacaine 0.5% intrathecal injection, Then epidural injection of 8 mg dexamethasone sodium phosphate (dexamethasone 8 mg/2 mL ampoule; Amriya Pharmaceuticals, Alexandria, Egypt) in 15 mL total volume using sterile saline 0.9%.
Anesthesia technique precautions
- Epidural bolus injection time should never exceed the range of 30 seconds to avoid intrathecal saddling and low fixation of the LA. After drugs injection, patients were immediately placed in the supine 5°–10° trendelenburg position, at 2-min intervals the spread of sensory analgesia to pinprick was done
- If at 4 min analgesia level had not reached the 8th thoracic dermatome, the Trendelenburg tilt to be increased further to an approximately 20° head down position so as to extend the sensory block to the fourth thoracic segment, patients in whom a T4 level of pinprick anesthesia could not be achieved were excluded, motor function was also assessed at 2-min intervals with use of the modified bromage scale.
Surgeons team included three senior surgeons
Charged in this present study for (a) assigning expert surgeons in lower abdominal oncology operations, (b) exclude surgeons who refuse sole regional anesthesia technique for lower abdominal operations, (c) collect surgeons opinion about the CSEA technique at the end of surgery according to the surgeon satisfaction score (0 = unsatisfied, 1 = satisfied, 2 = fully satisfied) assigned for this study.
Intraoperative complications management
Propofol IV infusion of 25 μg/kg/min (targeting conscious sedation).
Abdominal dragging pain
Surgical manipulation that unaccepted by the patient managed soon using multimodal analgesia regimen including; ketorolac slow injection in an IV bolus of 0.5 mg/kg plus bolus of nalbuphine of 0.1 mg/kg and number of patients that had this pain was recorded. If still in pain, general anesthesia to be induced and case to be excluded from the study replaced from the enrolled randomized cases and recorded as a number of patients with failed technique.
Nausea and vomiting
Treated by metoclopramide 10 mg, if resistant IV bolus ondansetron 4 mg, with the treatment of hypotension if present.
Mean arterial blood pressure (MAP) <65 mmHg, will be managed using ephedrine bolus doses of 6 mg, fluids and blood transfusion according to events and requirements.
Heart rate (HR) <60 beat/min will be managed by atropine bolus of 0.5 mg.
Desaturation (SaO2<90%) will be managed by increase oxygen face mask flow up to 10 L/s and dealing with the airway according to the situation targeting a patient airway with breathing comfort and O2 saturation >94%. In case of any respiratory depression, emergency airway equipment's and drugs for resuscitation for airway management and ventilation were kept ready.
Postoperative pain will be assessed by VAS every1 h 1st 4 readings then at 6 h, 12 h, 18 h, and 24 h and managed by background IV ketorolac 0.5 mg/kg with maximum bolus dose of 30 mg within 6 h, plus IV nalbuphine 10 mg bolus dose on need if (VAS ≥ 3) after ketorolac injection, postoperative vomiting managed by IV boluses of metoclopramide (10 mg/dose), then IV bolus ondansetron (4 mg/dose) if resistant vomiting to metoclopramide. Postoperative hypotension, bradycardia, and desaturation to be managed same as intraoperative method.
Outcome variables and data recording
Time to 1st analgesic request (minutes).
Postoperative VAS every every1 h 1st 4 readings then at 6 h, 12 h, 18 h, and 24 h. T4 sensory blockade time (time taken from the end of injection to loss of pinprick sensation at T4 dermatome-nipple level), S1 sensory regression time (time taken for sensory block to regress to S1 dermatome level), time to modified bromage Score 0 (time required for motor blockade return to modified bromage Grade 0 from the time of onset of motor blockade). Total IV dose of rescue analgesic nalbuphine in milligram during first postoperative 24 h. Nausea and vomiting incidence. Number of patients that had abdominal dragging pain. Number of failed cases in each group (due to persistent intraoperative abdominal pain, nausea, and vomiting despite all analgesics or excess IV boluses of sedation which compromise the conscious level of the patient indicating failure of this anesthesia technique and shift to general anesthesia and consequently case cancelled from this study reported, and replaced by another one). Hemodynamics (HR and mean arterial pressure MAP]) were recorded basal then every 1 h intraoperative then every 6 h for the postoperative 24 h. Patient satisfaction score using four graded scale (poor, fair, good, and excellent) was recorded. Surgeon satisfaction score (0 = unsatisfied, 1 = satisfied, 2 = fully satisfied) recorded at the end of the operation by head surgeons in charge.
Sample size calculation
According to a previous study with a mean time to 1st analgesic request in intrathecal nalbuphine group (259.20 ± 23.2 min) compared to intrathecal fentanyl group (235.1 ± 15.15 min) was statistically significant between groups (P < 0.05), we will need to study 15 experimental individuals and 15 controls to detect this difference. Considering Type I error of 0.05 and Type II error 0.05 and power 0.95 and drop out of 10%, so we needed 17 subjects in each group having a total sample size = 34.
The collected data were coded, processed, and analyzed using SPSS program statistical package version 16 (IBM Corporation, Armonk, NY). The normality of distribution was tested for normality by two-sample Kolmogorov–Smirnov test, Shapiro–Wilk nonparametric tests and histograms. Normally distributed numerical data were presented as mean and standard deviation and their comparison in both groups was performed using Student's t-test. Nonparametric data presented as median and range, or number and percent, categorical data presented as frequency and percentage will be compared using crosstab Chi-square test. All data will be considered statistically significant if P < 0.05.
| Results|| |
Fifty patients were enrolled for the present study. Seven patients declined the study, three patients with physical status ASA Class III, five patients their surgeons refused regional anesthesia, and one patient had elevated liver enzymes with coagulopathy. All of these patients were removed from the study. The remaining 34 patients were allocated into the groups of this study and their results were analyzed [Figure 1]. The patient's demographic characteristics and operative duration showed no significant differences between both studied groups [Table 1].
|Figure 1: The flow diagram of patient progress through the randomized trial|
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Regarding hemodynamics, neither HR nor MAP recorded any significant difference between both groups all over the study time points whether basal, intraoperative or postoperative.
As regards CSEA block characteristics, time to sensory block to T4 was significantly shorter with Group D (P = 0.029), there were significantly longer times to sensory regression to S1 (P <0.0001), modified bromage Score 0 (P = 0.002), and 1st analgesic request (P < 0.0001) in Group D compared to Group P [Table 2]. Moreover, postoperative VAS recorded significant decrease in the 1st 4 h values with Group D compared to Group P (P < 0.05) while 6 h, 12 h, 18 h and 24 h recorded no significant differences between both groups [Table 3]. IN addition, the total IV nalbuphine dose in 1st postoperative 24 h was significantly lower in D Group (P = 0.007) with the incidence of nausea and vomiting was also significantly lower in that group (P = 0.026). The number of patients had intraoperative abdominal dragging pain was significantly higher with Group P (P = 0.034) [Table 4].
|Table 4: Complications, total postoperative nalbuphine dosage, incidence of patients had intraoperative abdominal dragging pain|
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There was no significant difference between both groups regarding the incidence of headache (P = 0.545). No reported case in either group had failed block [Table 4]. The patient satisfaction score was significantly higher with Group D (P = 0.024) [Table 5]. The surgeon satisfaction was significantly higher with Group D compared to Group P (P = 0.043) [Figure 2].
|Figure 2: Group P = Epidural placebo control group. Group D = Epidural dexamethasone study group. Surgeon satisfaction was significantly higher with Group D compared with Group P (P = 0.043)|
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| Discussion|| |
In this present study, CSEA utilizing intrathecal nalbuphine with epidural dexamethasone as adjuvant analgesics to the LA bupivacaine 0.5% has improved the blockade criteria, duration, with lower number of patients who had dragging abdominal pain and resulted in significant prolongation of time to 1st analgesic request with significant decrease in VAS during 1st four postoperative hours. Moreover, Group D recorded a lower incidence of nausea and vomiting and the postoperative rescue analgesic nalbuphine utilization was reduced, all of these outcomes were reflected on significant increase in both patient and surgeon satisfaction that was significantly higher with Group D compared to Group P, simultaneously there were hemodynamic stability and acceptable comparable postoperative side effects as headache in between groups.
Visceral pain due to peritoneal traction during surgical manipulation even if still only pain without hemodynamic drawbacks sometimes necessitate sedation and even induction of general anesthesia. A fact that surgical manipulation on abdominal contents, visceral ligaments, and peritoneum produces abdominal visceral pain that may be associated with sever vagal stimulation that would produce reflex bradycardia and hypotension. Culebras et al. documented that intrathecal nalbuphine 0.8 mg provides good intraoperative and early postoperative analgesia without side effects. Epidural volume injection (even if placebo saline) after intrathecal LA injection would increase the upward spread of the intrathecal LA and explain by that increased volume within the extradural space leads to decrease in CSF volume in the caudal subarachnoid space with cephalic shift of LA within the CSF.
The explanation for significant increase in time to 1st analgesic request with significant decrease in the postoperative 1st 4 h VAS in Group D in comparison to Group P is that the combination of epidural 8 mg dexamethasone in 15 mL volume, with optimized dose of intrathecal 0.6 mg nalbuphine kappa opioid receptor agonist potentiated bupivacaine intraoperative analgesia via preventing dragging visceral pain transmission (kappa opioid receptor analgesic role in visceral pain prevention) during surgical manipulations. Another cornerstone point is that the epidural 15 mL volume injection after spinal bupivacaine nalbuphine injection would augment the cephalic spread of the spinal anesthesia dermatome coverage, in line with this explanation Culebras et al. documented that intrathecal nalbuphine 0.8 mg provides good intraoperative and early postoperative analgesia without side effects. Added to the epidural steroid dexamethasone analgesia level and quality improvement. Epidural 8 mg dexamethasone dose is probably more effective than lower doses to control moderate to severe postoperative pain, this dose is surgically safe neither produced delayed wound healing nor elevated blood glucose level. In accordance to our result as regard analgesia, Thomas and Beevi revealed that epidural dexamethasone is significantly more effective than IV dexamethasone to reduce postoperative pain and morphine consumption.
Intrathecal anesthesia blockade quality in this present study showed a significant increase in both sensory and motor recovery from the block in Group D in comparison to Group P, this could be attributed to the combined epidural 8 mg dexamethasone in 15 mL volume with intrathecal nalbuphine analgesia effect that potentate and fasten the LA bupivacaine blockade up spread and potency. In line with this Hefni et al. proved that single 8 mg bolus dose of epidural dexamethasone is probably more effective than lower dose to control moderate to severe postoperative pain. Furthermore, this dose is not associated with increased glucose level or delayed wound healing, also Viscusi et al. documented that higher doses of the epidurally injected dexamethasone leads to decreased rate of drug mobilization from the epidural space and allow for more effective dexamethasone tissue concentration leading to more prolonged effective postoperative pain control. In line with this, Naghipour et al. proved that dexamethasone added to bupivacaine prolongs the duration of epidural analgesia. Waldron et al. documented that single IV perioperative dose of dexamethasone had small but statistically significant analgesic benefits.
Postoperative side effects such as headache, hypotension, and bradycardia in the present study were comparable in between both groups with lower incidence of nausea and vomiting in Group D, this can be explained by the epidural antiemetic dexamethasone, simultaneously with intrathecal kappa opioid agonist Mu antagonist “nalbuphine” has its antiemetic effect and signs about the use of Mu-opioid analgesics such as morphine, sufentanil, fentanyl which are documented to be dose-dependent emesis inducing drugs. Epidural administration of drugs leads to rapid vascular uptake that provides access to the chemoreceptive trigger zone through the bloodstream. Peak plasma concentrations may be achieved within 5–15 min and systemic concentrations often approach those obtained after a similar intramuscular dose. In accordance to our result, Wang et al. documented a long time back that IV administration of dexamethasone 8 mg may be valuable for preventing epidural morphine-related postoperative vomiting. Another supporting opinion, epidural dexamethasone had almost the same analgesic potency as fentanyl when added to LA bupivacaine with opioid-sparing and antiemetic effects. Nalbuphine affinity to k-opioid receptors results in analgesia, sedation, and cardiovascular stability with minimal respiratory depression. Nalbuphine improves the quality of perioperative analgesia and provides reasonably potent analgesia for visceral nociception.,
Why nalbuphine and its (0.6 mg intrathecal dose) specifically in this present study?
Answer is for the fact that kappa receptor agonist reduced visceral pain. Mukherjee et al. recommend 0.4 mg as the optimal dose of nalbuphine if used intrathecally along with 12.5 mg 0.5% hyperbaric bupivacaine in patients undergoing lower limb orthopedic surgeries, which requires lower level of spinal anesthesia blockade than lower abdominal and pelvic surgery as in our study, so our higher dosing protocol of both nalbuphine and bupivacaine (0.6 mg nalbuphine and 15 mg 0.5% bupivacaine) are both logic to be suitable for attaining a perfect T4 anesthesia to cover the abdominal peritoneal traction induced visceral pain and also 0.8 mg intrathecal nalbuphine was documented to produce more side effects with the same analgesic outcome equal for both doses. In opposition to Mukherjee et al. long time back Culebras et al. documented that intrathecal nalbuphine 0.8 mg provides good intraoperative and early postoperative analgesia without side effects.
The current study had some limitations. First, no patient-controlled analgesia machine available to be used as controlled rescue postoperative analgesia. Second, coagulopathy and thrombocytopenia in cancer patient is frequent, hinders CSE technique inapplicable. Third, the small sample size of the study. We recommend these limitations to be considered in the future.
| Conclusion|| |
CSE technique as a sole anesthetic technique utilizing epidural dexamethasone with optimized doses of intrathecal nalbuphine prolonged intrathecal bupivacaine intraoperative analgesia, with lower incidence of dragging pain associated with surgical manipulation during lower abdominal oncology operations with intraoperative hemodynamic stability, and less postoperative pain, less rescue analgesic utilization, all that could recommend this anesthetic technique for patients undergoing lower abdominal oncology operations.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]