|Year : 2014 | Volume
| Issue : 2 | Page : 42-48
Comparative evaluation of intraperitoneal bupivacaine, magnesium sulfate and their combination for postoperative analgesia in patients undergoing laparoscopic cholecystectomy
Smriti Anand1, Sukhminder Jit Singh Bajwa1, BB Kapoor1, Mukta Jitendera2, Hemant Gupta3
1 Department of Anaesthesiology and Intensive Care, Gian Sagar Medical College and Hospital, Ram Nagar, Banur, Punjab, India
2 Department of Anaesthesiology and Intensive Care, GMC, Jammu, India
3 Regional Hospital, Solan, Himachal Pradesh, India
|Date of Acceptance||02-Sep-2014|
|Date of Web Publication||21-Jan-2015|
Sukhminder Jit Singh Bajwa
House No-27-A, Ratan Nagar, Tripuri, Patiala
Source of Support: None, Conflict of Interest: None
Background: Various multimodal techniques have been employed time and again to allay visceral pain after laparoscopic cholecystectomy. Aim: The aim of this study was to assess and compare the postoperative pain relief in patients undergoing laparoscopic cholecystectomy with intraperitoneal administration of bupivacaine, magnesium sulfate and their combination. Materials and Methods: Patients were randomly divided into four groups of 20 each. Patients in group I "C" received 50 ml of 0.9% saline, group II "B" received 50 ml of 0.25% bupivacaine, group III "M" received 50 ml of 30 mg/kg magnesium sulfate, while patients in group IV "MB" received 0.125% of bupivacaine with 15 mg/kg of magnesium sulfate to a total volume of 50 ml after surgery. Postoperatively pain was assessed using visual analog scale (VAS) and postoperative pain (VAS > 3) was managed with intravenous tramadol 50 mg. Time to the first request of analgesia, the total number of analgesic doses of tramadol, the incidence and severity of postoperative shoulder pain in 24 h and presence of complications if any were noted. Results: Demographic profile of patients of all the four groups was comparable and statistically nonsignificant. Intraperitoneal instillation of 0.25% bupivacaine provided longest duration of analgesia for 541.5 131.48 min with a significant reduction in the number of doses of intramuscular tramadol in 24 h. Intraperitoneal instillation of 30 mg/kg magnesium sulfate provided analgesia for 82.25 35.37 min with no significant reduction in a number of doses of intramuscular tramadol in 24 h when compared to control. Intraperitoneal instillation of mixture of bupivacaine and magnesium sulfate in reduced doses, that is, 0.125% bupivacaine and 15 mg/kg magnesium sulfate provided analgesia for 305 65.64 min with a significant reduction in a number of doses of intramuscular tramadol in 24 h. There was reduced incidence and severity of shoulder pain, which was comparable in all the four groups. No significant side-effects were seen in any of the groups. Conclusion: Intrape-ritonel administration of bupivacaine, magnesium sulfate and their combination in reduced doses provides effective postoperative analgesia in laparoscopic cholecystectomy patients though their combination when the doses of both the drugs were reduced to half was less effective than bupivacaine group alone. Furthermore, bupivacaine and magnesium sulfate serve as useful adjuncts to postoperative analgesics.
Keywords: Bupivacaine, laparoscopic cholecystectomy, magnesium sulphate, postoperative analgesia
|How to cite this article:|
Anand S, Bajwa SS, Kapoor B B, Jitendera M, Gupta H. Comparative evaluation of intraperitoneal bupivacaine, magnesium sulfate and their combination for postoperative analgesia in patients undergoing laparoscopic cholecystectomy. Niger J Surg Sci 2014;24:42-8
|How to cite this URL:|
Anand S, Bajwa SS, Kapoor B B, Jitendera M, Gupta H. Comparative evaluation of intraperitoneal bupivacaine, magnesium sulfate and their combination for postoperative analgesia in patients undergoing laparoscopic cholecystectomy. Niger J Surg Sci [serial online] 2014 [cited 2019 Dec 12];24:42-8. Available from: http://www.njssjournal.org/text.asp?2014/24/2/42/149602
| Introduction|| |
Present day anesthesiology practice strives to bring more qualitative change so as to decrease the incidence of morbidity and side-effects during peri-operative period.  Intra-operative pain relief can be measured and assessed appropriately with the help of clinical acumen and availability of so many gadgets and can be relieved by administration of appropriate anesthetics and analgesic.  However, postoperative pain relief is highly desired, and services of anesthesiologists are available to a very limited extent during this period.
Laparoscopic cholecystectomy is now an established form of treatment for patients with symptomatic gallstones. Interestingly, the type of pain after laparoscopy differs considerably from that seen after laparotomy. Although it is the belief of patients that laparoscopy has ushered a pain-free era, the fact remains that patients complain more of visceral pain after laparoscopy in contrast to parietal pain experienced in laparotomy.  Also, the incidence of postoperative shoulder pain due to diaphragmatic irritation by residual carbon-dioxide following laparoscopic surgery may reach up to 80%.  Inadequately treated pain may lead to splinting, loss of sighing and decrease in vital capacity, and these may contribute to postoperative pulmonary morbidity. Various multimodal approaches have, therefore, been tried to ameliorate postoperative pain. These include parenteral analgesics, local infiltration with local anesthetics, epidural and intrathecal opioids and local anesthetics, interpleural and intercostals nerve blocks as well as intraperitoneal routes that in turn has been explored with local anesthetics and opioids. In order to get an instant relief, polypharmacy is commonly practiced which can be potentially harmful to the patient and can lead to re-admission.  It has been appreciated that multiple glutamate receptors are expressed on peripheral nerve terminals, and these may contribute to peripheral nociceptive sensation,  which elucidates the possibility of the use of peripheral N-methyl-D-aspartate (NMDA) receptor antagonists like magnesium sulfate to allay pain.  Clinically, intraperitoneal NMDA receptor antagonist magnesium sulfate with bupivacaine reduced postoperative shoulder pain and postoperative analgesic requirements. ,
However, some studies have failed to report analgesic effects of intraperitoneal topical administration of bupivacaine and magnesium sulfate. The present study was, therefore, conducted to evaluate the postoperative analgesic efficacy of intraperitoneal magnesium sulfate and bupivacaine alone, and a combination of both the drugs in reduced doses and their usefulness as adjuncts to postoperative analgesics.
| Materials and methods|| |
The present study was conducted over a period of 1-year from 2012 to 2013 on 80 patients of ASA-I, of either sex, in the age group 20-60 years, undergoing elective laparoscopic cholecystectomy. Before enrolment for the study, all the patients were informed about the aims, methods, anticipated benefits and potential hazards of the study. An informed written consent from the patients and approval from local ethics committee were obtained. Patients with allergy to amide anesthetics, acute cholecystitis, previous abdominal surgery, those on magnesium therapy or in whom surgery was converted to conventional cholecystectomy due to any reason were excluded from the study.
Preanesthetic check-up was done the day before surgery and included a detailed history and complete general physical and systemic examination. Baseline values of pulse, blood pressure and respiratory rate were recorded. Basic demographic characteristics like age, sex and weight were noted. Routine investigations included hemoglobin, clotting time, bleeding time, X-ray chest, electrocardiogram (ECG), renal function tests, serum electrolytes, blood sugar and liver function tests. Patients were kept fasting overnight and were premedicated with tablet alprazolam - 0.25 mg at bed time. Injection glycopyrrolate - 0.2 mg and injection tramadol - 50 mg were given intramuscularly 45 min before surgery.
Using a sealed envelope technique, patients were randomly allocated to one of the four groups of 20 each according to the composition of intraperitoneal instilled solution. In group I "C", patients received 50 ml of 0.9% saline (control), in group II "B" patients received 50 ml of 0.25% bupivacaine, in group III "M" patients received 50 ml of 30 mg/kg of magnesium sulfate, whereas in group IV "MB" patients received 0.125% of bupivacaine with 15 mg/kg of magnesium sulfate to a total volume of 50 ml.
In the operation theater, intravenous (IV) line was established. Monitors to measure heart rate, noninvasive systolic blood pressure, diastolic blood pressure, mean blood pressure, oxygen saturation and ECG were attached.
After preoxygenating the patient with 100% oxygen, induction was carried out in all patients with IV propofo l - 2 mg/kg. Trachea was intubated with oral cuffed endotracheal tube after giving succinylcholine - 1.5 mg/kg and intermittent positive pressure ventilation was done with oxygen (O 2 ), nitrous oxide (N 2 O) and isoflurane. Intra-operative muscle relaxation was achieved by injection vecuronium 0.08 mg/kg IV as and whenever required. End-tidal carbon-dioxide (EtCO 2 ) was monitored after intubation. Ventilation was adjusted to maintain normocapnia (EtCO 2 around 35-40 mmHg). IV 10 mg metaclopromide, 75 μg palonosetron as well as intramuscular 75 mg diclofenac sodium were given following intubation in all patients. A nasogastric tube was introduced, and the laparoscopic procedure was carried out in a standard fashion. Intra-abdominal pressure was maintained between 10 and 12 mmHg. After the removal of gall bladder, intraperitoneal instillation of the total volume of 50 ml of the prepared solution in the above mentioned doses was carried out under both the copulae of diaphragm guided by the camera and the patients were kept in Trendelenburg position until the end of the procedure (10-15 min). After skin closure local infiltration of each port site with 3-5 ml of bupivacaine - 0.25% was done. Reversal of residual neuromuscular blockade was achieved with IV neostigmine 0.05 mg/kg and glycopyrrolate - 0.01 mg/kg. Extubation was done after thorough oropharyngeal suctioning. The nasogastric tube was removed after recovery from anesthesia. Intra-operative monitoring consisted of pulse rate, noninvasive blood pressure, ECG and pulse oximetry.
Postoperative pain was assessed using visual analog scale (VAS), consisting of 10 cm scale representing varying intensity of pain from 0 cm (no pain) to 10 cm (worst imaginable pain). Postoperative pain (VAS > 3) was managed with injection tramadol 50 mg intramuscular. The postoperative assessment of pain was done by the resident doctor on duty who was blinded to the study arm to which the patient belonged.
The following parameters were evaluated in all studied groups:
- Time to the first request of analgesia (i.e. the time that elapsed between extubation and first analgesic dose)
- The total number of analgesic doses of intramuscular tramadol - 50 mg in 24 h following extubation
- The incidence and severity of postoperative shoulder and arm pain for 24 h
- Complications such as cardiovascular, respiratory and neurological side-effects as well as nausea and vomiting, allergic reactions and miscellaneous side-effects if any were looked for in the intraoperative and postoperative period.
To detect difference in duration of postoperative analgesia of 30 min between the groups for Type I error of 0.05 and power of the study at 80%, a sample size of 18 patients was required in each group. However, we selected 20 patients in each group for better validation of the results. The data were analyzed with the help of computer software Microsoft Excel and SPSS (Chicago) version 15.0 for Windows. The results were reported as mean and standard deviation for quantitative variables and percentage for qualitative variables. Statistical significance among mean differences was evaluated using one-way analysis of variance. Bonferroni's t-test was employed post-hoc to assess intergroup significance. P <0.05 (two-tailed) was considered as statistically significant. Analysis was performed according to the intention to treat principle.
| Results|| |
All the four groups were comparable with respect to age, weight, sex and mean duration of surgery [Table 1]. However, the mean duration between extubation and first analgesic dose was 34.75 ± 14.37 min in group I "C," 541.5 ± 131.48 min in group II "B," 82.25 ± 35.37 min in group III "M" and 305 ± 65.54 min in group IV "MB" statistically the difference between them being highly significant [Table 2]. When the intergroup comparison was done among each group, the results were again statistically highly significant [Table 3]. The mean number of intramuscular tramadol doses in 24 h following extubation in Group I "C" was 3.45 ± 0.6, in group II "B" was 1.85 ± 0.81, in group III "M" was 3.2 ± 0.69 and group IV "MB" was 2.5 ± 0.82. Statistically, the difference was highly significant [Table 3]. When the intergroup comparison was done the difference between each group was again statistically significant except between group I "C" and group III "M" where the result was statistically nonsignificant [Table 4]. The incidence of shoulder pain was comparable in all the four groups, peaking after 18 h, however ranging in severity from 2 to 4 using VAS [Table 5]. Nausea and vomiting were the only side-effect reported in all the four groups the difference being statistically insignificant.
|Table 3: Time between extubation and first analgesic dose: Intergroup comparison (Bonferroni's t-test) |
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|Table 4: Number of intramuscular tramadol doses at VAS>3 in first 24 h following extubation |
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|Table 5: Number of intramuscular tramadol doses at VAS>3 in first 24 h following extubation: Intergroup comparison (Bonferroni's t-test) |
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| Discussion|| |
The present day anesthesiology practice has improved tremendously as a result of the adoption of evidence-based medicine and patient-centered approach.  A deeper understanding of the bio-psychosocial perspectives and enhanced knowledge of the various pharmacogenomic, pharmacokinetic and pharmacodynamic characteristics associated with anesthesiology has been revolutionizing the anesthesia specialty. , Even though, laparoscopy is a commonly performed procedure, postoperative morbidity and discomfort is a huge drawback especially when it is performed on a day care basis. Literature is replete with evidences where different researchers have tried time and again with variable success to overcome such limitations.
The present study was based on these principles so as to achieve better patient comfort during the postoperative period. Mean duration between extubation and first analgesic dose in group II "B" that is, in which 125 mg of bupivacaine (50 ml of 25%) was instilled was 541.5 ± 13.48 min (approximately 9 h). Literary evidence also supports pain relief up to 8 h postoperatively upon intraperitoneal instillation of 100 mg of bupivacaine. , However, certain studies have negated the analgesic potential of intraperitoneal administration of bupivacaine. Utilizing either 0.25% bupivacaine or 0.5% lignocaine, Rademaker et al.  failed to demonstrate any reduction in postoperative pain, which could be due to the fact that instillation of local anesthetic in the supine position prevented its flow over the coelic plexus and phrenic nerve endings. Schenin et al.  used a lower concentration of 0.15% bupivacaine when compared to the present study in which 0.25% bupivacaine was used. In group III "M" mean duration between extubation and first analgesic dose were 82.25 ± 35.37 min, the possible mechanism of analgesia being NMDA receptor antagonism. Comparable results have been reported with magnesium sulfate in certain studies though the route of administration was parenteral. , In group IV "MB" (0.125% bupivacaine that is, 62.50 mg with 15 mg/kg magnesium sulfate) the mean duration between extubation and first analgesic dose was 305 ± 65.64 min, that is, approximately 5 h. The doses of bupivacaine and magnesium sulfate when given in combination in this group were reduced to half to assess whether in reduced dosages they exerted additive effects than when given individually in double doses. Intraperitoneal instillation of 50 mg of bupivacaine (20 ml of 0.25%) has been shown to provide mean duration of analgesia of 2 h.  In the present study, the prolonged duration of analgesia can be attributed to the co-administration of magnesium sulfate (15 mg/kg) with bupivacaine as elucidated in clinical researches., While doing the intergroup comparison, the duration between extubation and first analgesic dose was maximum in Group II "B", followed by Group IV "MB", followed by Group III "M" and least in the control group, that is, Group I "C" [Table 3]. All these studies have somewhat followed the principles of evidence made medicine and logical empiricism with a quest to achieve a better pain-free postoperative period. 
Intraperitoneal co-administration of ketamine (1 mg/kg) or magnesium sulfate (30 mg/kg) with 0.25% bupivacaine has been found to provide better pain relief than intraperitoneal bupivacaine (0.25%) alone. , This is in contrast to the present study which is attributable to the fact that in the present study half of the doses, that is, 0.125% bupivacaine and 15 mg/kg of magnesium sulfate were used.
The mean number of doses of intramuscular tramadol in 24 h were 3.45 ± 0.6 in group I "C", 1.85 ± 0.81 in group II "B", 3.2 ± 0.69 in group III "M" and 2.5 ± 0.82 in group IV "MB", the results being highly significant [Table 4]. Studies have shown a significant reduction in analgesic consumption between the groups up to 24 h upon intraperitoneal administration of local anaesthetics. ,
Mean number of doses of intramuscular tramadol in group III "M" was 3.2 ± 0.69 which when compared to group I "C" was nonsignificant (P > 0.05). However, it was more than group II "B" (P < 0.001; highly significant) and group IV "MB" (P < 0.05, significant). This was in concordance with results of Bhatia et al.  who observed that intraoperative parenteral administration of 50% magnesium sulfate (50 mg/kg) though resulted in pain relief and comfort in the first postoperative hour, did not significantly decrease the postoperative analgesic consumption. However, researchers have reported lesser requirement of rescue analgesics in contrast to the present study  which could be attributable to parentral route of drug administration in contrast to the intraperitoneal route in the present study.
Mean number of doses of intramuscular tramadol in 24 h in group IV "MB" were 2.5 ± 0.82, which was lower when compared with group I "C" and group III "M", but higher than group II "B". Researchers have observed that intraperitoneal co-administration of bupivacaine with magnesium sulfate resulted in better postoperative pain relief , and lesser rescue analgesics than bupivacaine alone. Greater requirement of rescue analgesics in group III "MB" than the bupivacaine group in the present study could be attributed to the usage of half the doses when given in combination.
In all the groups patients reported shoulder pain after 18 h. However, the incidence of shoulder pain in all the groups was statistically nonsignificant. Also, the severity of shoulder pain ranged from 2 to 4 in all the groups the difference again being statistically insignificant [Table 6]. Apart from small incidence of nausea and vomiting no other side-effects were noted.
This is in accordance with Lee et al.  who reported that patients experienced shoulder pain within 24 h after surgery. Also, the overall incidence of shoulder pain in the present study was 23.75%. As against 35-60% , reported in certain studies. The reduced incidence and severity of the shoulder pain in present study could be due to careful emptying of pneumoperitoneum. Moreover, saline irrigation and suctioning was done at the end of procedure before the instillation of the prepared drugs. It has been suggested that carbon-dioxide is converted to carbonic acid on the moist peritoneal surfaces during laparoscopic cholecystectomy, and it is a strong irritant to diaphragm leading to referred shoulder and neck pain.  Washing the diaphragmatic surface by a sizeable amount of saline dilutes the carbonic acid and hence reduces the severity of diaphragmatic irritation. 
The reduced incidence and severity of shoulder pain could also be attributed to the instillation of the prepared solution in head down position  and under both the hemidiaphragms.  Other factors like a low pressure insufflation  slow rate of insufflation  and use of preemptive antiinflammatory medication  could have also contributed to the lower incidence and severity of shoulder pain.
Incidence of nausea and vomiting was 20% in group I "C", 10% in group II "B", 15% in group III "M" and 10% in group IV "MB," which was comparable in all the groups. This could be attributed to the prophylactic administration of palonosetron 75 μg to all the patients in the present study. Palonosetron is a novel 5-HT3 antagonist, which has a prolonged duration of antiemetic effect. 
Although, in the present study, the blood levels of administered drugs were not estimated, no major systemic side-effects were recorded in the patients using bupivacaine (50 ml of 0.25% or 0.125%) and magnesium sulfate (30 mg/kg). Higher doses of bupivacaine have been used safely. , Doses up to 150 mg of bupivacaine are presumed to be fairly safe.  Also bupivacaine concentration in blood remain low following its instillation.  Moreover, several reports have shown that range of mean plasma concentrations (0.92-1.14 μg/ml) after the intraperitoneal administration of plain bupivacaine (100-150 mg) is well below the toxic concentration of 3 μg/ml.  The doses of bupivacaine used in the present study were lower than those thought to cause systemic toxicity. Also, higher doses of magnesium sulfate have been used by safely. ,,
| Conclusion|| |
Intraperitoneal instillation of bupivacaine, NMDA receptor antagonist, that is, magnesium sulfate used alone or in combination in reduced dosages is an effective and safe method of providing prolonged postoperative analgesia for patients undergoing laparoscopic cholecystectomy though the combination of magnesium sulfate and bupivacaine in halved doses was less effective than the bupivacaine group alone. Moreover, both the drugs bupivacaine as well as magnesium sulfate serve as adjuncts to analgesics used in the postoperative period. Moreover, both the drugs serve as adjuncts to analgesics used in the postoperative period.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]