A comparative study of intraperitoneal instillation of ketamine and magnesium sulphate for intraoperative and postoperative pain relief in patients undergoing laparoscopic cholecystectomy

 

Abstract               Background and Aims: Purpose of this study was to assess the intraperitoneal effect of ketamine and Magnesium sulphate (MgSO4) on hemodynamic response, *analgesic and antiemetic effects in patients undergoing elective laparoscopic cholecystectomy. Methods: 70 adult patients scheduled for elective laparoscopic cholecystectomy under general anaesthesia were randomly allocated in two groups: Ketamine intraperitoneum(KIP) group,in which 0.5mg/kg ketamine diluted in 30ml normal saline and Magnesium sulphate intraperitoneum(MIP) group in which 20ml 10 % MgSO4 diluted in 10ml normal saline was instilled intraperitoneally respectively. Time to first rescue analgesic and total rescue analgesic consumption were the primary outcomes studied. Results: Recovery characteristics in terms of Extubation time (5.51 ± 1.71 vs. 12.8 ±3.13) and Emergence time(12.8 ± 2.33 vs. 18.74 ± 2.99) were significantly longer in group MIP compared with group KIP. VAS scores were significantly lower in Group KIP during first 24 postoperative hours and the time to first analgesic requirement was longer in group KIP(6.37 ± 1.31hr) compared with group MIP (4.28 ± 1.44hr) and total dose of Diclofenac sodium consumption was significantly lower in group KIP in 24 postoperative hours. Postoperative sedation was significantly higher in group MIP compared with group KIP during first 2 postoperative hours. Retching, Nausea and Vomiting were significantly higher in group KIP(62.85%) compared with group MIP(34.28%). Conclusion: Intraperitoneal instillation of both ketamine and Mgso4 results in stable post-operative haemodynamic. Patients who received intraperitoneal ketamine experienced better analgesic profile, better recovery profile, lesser post-operative sedation compared to those who received MgSo4. However side effects like nausea vomiting were lesser in Group MIP as compared to Group KIP.

Key Words: Analgesia, cholecystectomy, intraperitoneal, laparoscopy,

 

 

 

INTRODUCTION

Laparoscopic cholecystectomy is usually preferred for chronic cholelithiasis as laparoscopic surgeries has a number of advantages over conventional open surgery. Although laparoscopic surgery have less pain tendency in comparison to open surgery due to absence of large incision, but still laparoscopic surgery have pain in postoperative period due to combination of parietal component at the trocar site and also due to visceral pain affecting sub diaphragmatic region and often referring to the right shoulder.¹ Postoperative pain depends on numerous factors like gas characteristics, duration of surgery, type of surgery, pressure of pneumoperitoneum, postoperative residual gas in the abdomen and any surgical trauma. Multimodal analgesic techniques are being used to decrease the pain intensity in postoperative periods like postoperative NSAIDS or opioid analgesia. Local anaesthetic administration after laparoscopic surgeries is effective but there is lack of consensus regarding dose, concentration site and manner of administration, but even some studies failed to show some effectiveness. NMDA receptor is an excitatory amino acid receptor that has been implicated in the modulation of prolonged pain. NMDA antagonists are useful in the reduction of acute postoperative pain and analgesic consumption. Magnesium sulphate inhibits calcium entry into cell through a non-competitive blockade of NMDA receptor. Intraperitoneal instillation of magnesium sulphate attenuates hemodynamic stress response to pneumoperitoneum and reduces postoperative pain and nausea and vomiting.²Ketamine is an NMDA receptor antagonist that blocks nociceptive input and reduces hyperalgesia³.Ketamine hasanti-inflammatory action and antioxidant. intraperitoneal instillation reduces postoperative pain and analgesic requirement. Our aim is to compare effect of Ketamine and Magnesium sulphate intraperitoneally in laparoscopic cholecystectomy for haemodynamic stability, intraoperative analgesic and antiemetic effect. The primary objective was to evaluate analgesic effect of intraperitoneal instillation of Ketamine and Magnesium sulphatein laparoscopic cholecystectomy. The secondary objective was to assess the effect of magnesium sulphate and ketamineon hemodynamic response and their antiemetic effects.

 

METHODS

After approval from Institutional Ethics Committee this prospective randomized double blind study was conducted at P.D.U. Medical College and Hospital, Rajkot. 70 patients of American society of Anaesthesiologists(ASA) physical status 1 and 2 in the age group of 18-65 years of either sex undergoing elective laparoscopic cholecystectomy under general anaesthesia were studied. The patient's history, clinical examination and investigation were carried out on the preoperative day. Patients refusal, cardiac, renal, hepatic or any systemic disease, known allergy to any drug, pregnant, lactating mothers were excluded from the study. Patients who needed conversion to open cholecystectomy or insertion of the drain at the end of the procedure were also excluded from the study. Preoperative assessment and fasting rules according to institution protocols were followed and also the patients were explained about the use visual analogue scale (VAS). On arrival to the operating room a peripheral 20G intravenous cannula under local anaesthesia was secured and Standard monitoring (electrocardiography, non-invasive blood pressure, oxygen saturation and end tidal CO2) were connected and baseline vital parameters recorded. Patients were premedicated intravenously with Glycopyrrolate 0.2mg, Fentanyl 1.5 microgram/kg, Ranitidine 50mg, Ondansetron 4mg.Preoxygenation with 100% oxygen was done for 3 min. General Anaesthesia was induced with Sodium thiopentone 5-7mg/kg and tracheal intubation facilitated by inj. vecuronium bromide 0.1 mg/kg and appropriate sized oral cuffed endotracheal tube was inserted. Anaestheisa was maintained using controlled ventilation with isoflurane 1.5 to 2.0% dial concentration and O2 : N2O in the ratio of 40:60 to maintain adequate anaesthesia and hemodynamic stability. Lung ventilation were controlled to maintain EtCo2 tension at 35±5 mm Hg.Vital parameters include HR, NIBP-systolic, diastolic and mean, EtCO2, SpO2 and ECG were monitored throughout the procedure. Incremental dose of vecuronium were given as per the requirement. In case of any episode of bradycardia that was HR< 50beats /min and hypotension that was 80mmHg was managed with i.v. atropine and i.v. mephentermine as per need. Patient was reversed with inj. Neostigmine and inj. Glycopyrrolate. Pneumoperitoneum was achieved by CO2 insufflations at the rate of 1L/min for the first min, then at the rate of 3-4L/min with a maximum IAP 15 mmhg. Patients will be randomly allocated into one of the two groups.

1)Ketamine intraperitoneum(KIP) Group(n=35 patients):0.5mg/kg ketamine diluted in 30 ml normal saline was injected intraperitonially.

2) Magnesium sulphate intraperitoneum (MIP)group(n=35 patients): 40mglkg magnesium sulphate in 30ml normal saline and patients were kept in the Trendelenburg position for 5-10 min then patients of both groups was put in anti-trendelenberg position with rising of the right shoulder. After the end of surgical procedures, discontinuation of Isoflurane,Fio2was increased to 100% and Glycopyrrolate 0.4mg and Neostigmine0.04-0.08mg/kg was used to antagonize the residual effect of Vecuronium bromide. After tracheal extubation the patients were transferred to recovery. Arterial pressure and heart rate were measured atinduction(baseline),after intubation, before pneumoperitoneum, every 10 min after pneumoperitoneum for 30 min, after extubation and before shifting from operation room. Time to extubation in min was defined as the time from the end of surgery to tracheal extubation. Surgical duration was defined as the time from skin incision to skin closure. Time of emergence was defined as the time to respond to a simple verbal command following discontinuation of isoflurane. Time of the first request of analgesia was defined as the time at which rescue analgesic was given if the VAS was 3 or more. Total analgesic requirement during first 24 postoperative hours were recorded. The pain was assessed with visual analogue scale(VAS),( 0=no pain to 10 the worst pain)VAS were recorded at 1st hr., 2nd hr., 4th hr,6th hr., 8th hr., 12 hr. and 24 hours postoperatively. If the VAS was 3 or more ,it was treated byinjection Diclofenac sodium(75mg).Nausea was assessed at the same interval of VAS using a scoring system (0-Retching,1-Nausea,2-Vomiting)Ramsay Sedation score was also assessed at same interval of VAS using 6 point score(1-Anxious,restless or both,2-cooperative,oriented and tranquill,3-responds to commands,4-Brisk response to stimulus,5-sluggish response to stimulus,6-no response to stimuli). Sample size was calculated based on a pilot study considering difference in time of 1st rescue analgesic dose of diclofenac sodium as 1.5 hrs. from completion of the surgery in both groups. Based on a previous study[ ] Standard deviation was taken as 3 and sample size was calculated to a total of 64.Considering a dropout rate of 10% we took 35 cases in each group and enrolled a total of 75 patients.The raw data was collected in MS EXCEL sheets and statistical analysis was done by Statistical Package for Social Sciences (SPSS version 20.0) using Student unpaired t-test..Quantitative data were expressed as mean± standard deviation (SD). Qualitative data were expressed as frequency and percentage.

 

RESULTS

There were no significant differences in either the demographic data or duration of surgery between the two groups.(TABLE 1)

Table 1: Patient's demographic data and duration of surgery

Data are expressed as mean (SD)

 

Table 2: Comparison of heart rate among two groups

Table 2 shows that there was no statistically significant difference between the two groups until 10 min after creation of pneumoperitoneum. However HR was significantly lower in Group MIP than in Group KIP at 10, 20,30 ,45 min after pneumoperitoneum. After 45 min the HR values in Group KIP became similar to baseline whereas in Group MIP the values were still lower therefore there was statistically significant difference between the two groups until 120 min.

Table 3: Comparison of blood pressure among two groups

Table 3 shows that there was no statistically significant difference in MAP between the two groups until 10 min after creation of pneumoperitoneum. However MAP was significantly lower in Group MIP than in Group KIP at 10, 20, 30 ,45 min after pneumoperitonium.After 45 min the MAP values in Group KIP became similar to baseline whereas in Group MIP the values were still lower therefore there was statistically significant difference between the two groups until 120 min.

                                                                     

Table 4: VAS and analgesic profile during first 24 post-operative hours

Data are presented as mean (SD),VAS - visual analogue score (0-10),p <0.01

Table 4 shows that at 1 hour post-op patients in both the groups were pain free. Mean pain scores were significantly lower in Group KIP when compared with Group MIP during the first 8 hours. Patients in Group KIP became pain free by 12 hours post-op and those in Group MIP became pain free by 24 hours post-operatively. Time to first analgesic requirement was longer in Group KIP (6.8 ± 1.5h) than in Group MIP ( 4.77± 1.94h). Furthermore, patients in KIP group required less dose of Diclofenac sodium in the first 24 hour of post-operative period (72.72± 12.85) compared to MIP group (117.19±37.2) (P < 0.0001)

Table 5: Recovery characteristics

Recovery characteristics in terms of extubation time(12.8±3.13vs. 5.51±12.8h)and emergence time (18.74 ± 2.99 vs. 12.8±2.33 h) were significantly longer in Group MIP compared with Group KIP.

 

Table 6: Ramsay sedation score

Data are expressed as mean (SD),Ramsay sedation score(1-6),significant P value.

Ramsay sedation scores were significantly higher in group MIP when compared with group KIP during first 2 postoperative hours(P < 0.0001).

 

 

 

 

 

Table 7: Nausea/vomiting score during first 24 post operative hrs

Retching, Nausea and Vomiting were significantly higher in group KIP (62.85%) compared with group MIP (34.28%) in first 6 postoperative hours. There were no postoperative side effects attributable to the Ketamine and Magnesium sulphate such as Bradycardia and Hypotension.

 

DISCUSSION

Laparoscopic surgical procedures usually require the creation of a capnoperitoneum by peritoneal insufflations of pressurized dry co2 which along with the direct surgical touching by instruments initiate an acute phase stress protein release, that predisposes the peritoneum and organ structures to inflammation, resulting in pain perceived by the patient.

Ketamine is an NMDA receptor antagonist with sedative, analgesic and anti-inflammatory action. The NMDA receptors have a role in central sensitization. The blunting of central sensitization has played an important role in the prevention and treatment of both postoperative pain and chronic pain.⁴ Evidence also suggests that NMD Areceptors located in the peripheral tissue(intraperitoneal) and viscera play an important role in nociception and peripheral sensitization.⁵Activation of peripheral NMDA receptors causes the Ca-dependent release of proinflammatory substance p and produces nociceptive behavior. Peripheral injection of NMDA receptor antagonists attenuates pain associated with neuropathic pain or inflammation.⁶ The study performed by Soad S.A EL Gaby et al⁷ showed that KIP 0.5 mg/kg was associated with significant decrease in NRS and analgesic dose requirement postoperatively; this could be explained by peripheral NMDA receptor. Our study also showed that similar results, VAS score were significantly lower in group KIP compared with group MIP during the first 6 postoperative hours. Time to first analgesic consumption was longer in KIP group compared with group MIP. Total dose of rescue analgesics in 24 postoperative hours was also lower in group KIP compared with group MIP. Magnesium sulphate is an antagonist of NMDA receptor and its associated channels and decreases calcium influx to the cell and hence has an important role in neuronal signaling and pain processing in the central nervous system.⁸In our study we found that Patients who received MgSo4 had stable hemodynamic parameters throughout the intra-operative period until extubation as compared to those who received ketamine. Both HR and MAP were significantly lower in Group MIP as compared to Group KIP.Magnesium produces vasodilatation by acting directly on blood vessels, and high dose magnesium attenuates vasopressin stimulated vasoconstriction and normalizes sensitivity to vasopressin.^[9] Similar findings were recorded by Rania M et al^[10] who found that administration of 20 ml 10 % MgSO4 intraperitoneally compared with 20ml 0.9% normal saline intraperitoneally in patients undergoing laparoscopic cholecystectomy resulted in better hemodynamics. This may be because magnesium induces hypotension directly by vasodilatation and indirectly by sympathetic blockade and inhibition of catecholamine release. In our study we found that patients of both the groups experienced sufficient analgesia upto 4 hours post op but patients who received Ketamine intraperitoneally had lower pain scores for 8 hours post op as compared to those who received MgSo4 and the difference was statistically significant. Time to first rescue analgesic was longer and total requirement of analgesic were also lower in patients who received Ketamine intraperitoneally as compared to those who received MgSo4 intraperitoneally. Ahmad M.Shawky et al.¹¹ in their study showed that VAS scores were lower in ketamine group than in saline group after 1 hour as it was (1(0.75) VS 4(2)) respectively and even after 24 hours (0(0) VS 1(0)) respectively. Moharari et al.¹² reported that intraperitoneal instillation of 0.5mg/kg ketamine in elective laparoscopic cholecystectomy significantly reduces the postoperative pain and the analgesic requirement. Time to first analgesic requirement was longer in Group KIP than in Group MIP. Furthermore, patients in KIP group required less dose of Diclofenac sodium in the first 24 hr. of post-operative period compared to MIP group. Similar to our study M.Abdel. Rouf et al¹³  in their study showed that the time to first request of analgesia in groups C(control), B( Bupivacaine 0.25%), MB(30 mg/kg magnesium sulphate in bupivacaine 0.25%), and KB(1 mg/kg ketamine in bupivacaine 0.25%) were 15.33 (5.1) min, 35.23 (4.8) min, 130.34 (6.8) min and 132.13 (5.9) min, respectively, with significantly longer duration (P < 0.05) in groups MB and KB compared to either group C or group B and that of Group KB was longer than that of group MB and also Dose of intravenous PCA morphine consumed at 0-6 h, 6-12 h, 12-18 h, 18-24 h, and 0-24 h following extubation were significantly lower in groups MB and KB compared to either group C or group B (P < 0.05).But in our study we avoided bupivacaine and its complications of wrong injection and its toxicity. By blocking NMDA receptor, MgSO4 decreases postoperative pain due to blockage of both somatic and visceral pain fibers. MgSO4 blocks the release of catecholamines from both adrenergic nerve terminals and adrenal gland, in addition carboperitoneum causes noxious stimulation which leads to the release of glutamate and aspartate, which bind to various subclasses of excitatory amino acid receptors, including the N-methyl D-aspartate (NMDA) receptor. Activation of NMDA receptors leads to calcium and sodium influx into the cell, with an efflux of potassium and initiation of central sensitization and windup. Magnesium blocks NMDA channels in a voltage-dependent way and produces analgesia. Since NMDA receptor is considered one of the main mechanism for post-operative pain ketamine produces non-competitive NMDA receptor antagonism to produce analgesia. In our study patients recovery profile was longer in group MIP compared with group KIP. Both extubation time and emergence time were significantly longer in group MIP.MgSo4 competes with calcium ions in synaptic junctions and prevents the release of presynaptic acetylcholine, prolonging the effects of neuromuscular blocker agents. Also sedation was significantly higher in group MIP when compared with group KIP during first 3 hours. This sedation may be due to the depressant effect of MgSO4 on central nervous system and antagonism of NMDA receptors. In our study, there was a significant reduction in the incidence of retching, nausea and vomiting in group MIP compared with group KIP. Magnesium blocks NMDA receptors, which lie in both emetic pathways and structures associated with the final common pathway for vomiting. Limitation of the study were that magnesium concentration in serum were not studied. Pre-emptive analgesic effect of Fentanyl could have partly contributed to the overall analgesia. More number of studies should therefore be conducted on a larger scale comparing the efficacy of two different drugs of the same class to reduce postoperative pain.

 

CONCLUSION

Intraperitoneal instillation of both ketamine and Mgso4 results in stable post-operative haemodynamics. Patients who received intraperitoneal ketamine experienced better analgesic profile with lesser VAS scores, longer duration of analgesia, lower requirement for rescue analgesic, better recovery profile, lesser postoperative sedation compared to those who received MgSo4. However side effects like nausea vomiting were lesser in Group MIP as compared to Group KIP.

 

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