|Year : 2021 | Volume
| Issue : 1 | Page : 79-85
Premedication with clonidine and dexmedetomidine as multimodal analgesia for overnight stay laparoscopic cholecystectomy: A randomized comparative study
Navneeta Bisht, Thrishul Muniraju, Ashar Hasan, Vivek Kumar, Dhrubajyoti Bhaumik
Department of Anaesthesiology, Sambhunath Pundit Hospital, Kolkata, West Bengal, India
|Date of Submission||28-May-2020|
|Date of Acceptance||01-Jul-2020|
|Date of Web Publication||22-Feb-2021|
Dr. Navneeta Bisht
Department of Anaesthesiology, Sambhunath Pundit Hospital, Kolkata - 700 020, West Bengal
Source of Support: None, Conflict of Interest: None
Background: Pain due to pneumoperitoneum after laparoscopic cholecystectomy (LC) may contribute to prolong hospital stay, patient discomfort, and failure of the surgery as an ambulatory procedure. A balanced multimodal analgesia regimen consisting of premedication with selective alpha-2 agonists is gaining popularity for postoperative pain relief for multiple surgeries. Although both clonidine (CLO) and dexmedetomidine (DEX) belong to this group, DEX is seen to have more selective α2 action and better sympatholytic properties. The present study aims to assess the coanalgesic effect of premedication with CLO and DEX for LC, done as an overnight stay procedure, and to compare their efficacy.
Methodology: This was a prospective, randomized, single-blinded comparative study, conducted between July 2015 and July 2016. A total of 80 patients undergoing LC were randomly assigned to either CLO or DEX groups (n = 40). The patients were premedicated with low-dose (1 μg/kg) bolus intravenous drugs before induction according to the allotted group. Effect of individual drugs on the postoperative visual analog scale (VAS) score was noted, hemodynamic status was monitored, and analgesic-sparing effect to a multimodal analgesic regimen comprising intraoperative fentanyl and postoperative tramadol was noted.
Results: VAS scores at 15 min postextubation, the number of patients required rescue analgesia, and the number of injections required were all found significantly low with DEX. Systolic as well as diastolic blood pressure was significantly lower in the DEX group.
Conclusions: Although both the drugs were effective for short hospital stay LC, early pain relief and better hemodynamic stability were seen with DEX. Thus, routine premedication with DEX for ambulatory LC may be recommended.
Keywords: Ambulatory surgery, clonidine, dexmedetomidine, laparoscopic cholecystectomy, multimodal analgesia
|How to cite this article:|
Bisht N, Muniraju T, Hasan A, Kumar V, Bhaumik D. Premedication with clonidine and dexmedetomidine as multimodal analgesia for overnight stay laparoscopic cholecystectomy: A randomized comparative study. Indian Anaesth Forum 2021;22:79-85
|How to cite this URL:|
Bisht N, Muniraju T, Hasan A, Kumar V, Bhaumik D. Premedication with clonidine and dexmedetomidine as multimodal analgesia for overnight stay laparoscopic cholecystectomy: A randomized comparative study. Indian Anaesth Forum [serial online] 2021 [cited 2021 May 9];22:79-85. Available from: http://www.theiaforum.org/text.asp?2021/22/1/79/309835
| Introduction|| |
Laparoscopic cholecystectomy (LC) is a frequently performed surgery worldwide, and constant efforts are made to perform this procedure as an ambulatory or outpatient procedure. Pain due to pneumoperitoneum still may be significant after LC, which may contribute to prolong hospital stay and patient discomfort. A balanced multimodal analgesia regimen is gaining popularity for postoperative pain relief as it maximizes the efficacy of the regimen and reduces the side effects of individual drugs., Premedication with α2 agonists such as clonidine (CLO) and dexmedetomidine (DEX) has been used in multiple surgeries as adjuvant drugs for multimodal analgesia.,,
Although both CLO and DEX belong to selective α2 agonists, DEX has been seen to have more selective α2 activities and more effective sedative and analgesic actions than CLO. Moreover, DEX has been used preferentially for premedication for different surgeries for its better sympatholytic properties.,,,
Although the use of these drugs in LC has been published in several literature earlier, routine use of them for an overnight stay and short-duration surgeries has not been practiced widely. It is also not very clearly established which one of these drugs is more suitable for LC as they have a very similar pharmacokinetic property. LC, aiming constantly aiming to reduce hospital stay, emphasizes the establishment of a routine and balanced multimodal analgesic regimen.
The present study aims to assess the coanalgesic effect of premedication with CLO and DEX for LC, done as an overnight stay procedure, and to compare their efficacy.
This single-blinded randomized controlled study aimed to compare the effect of intravenous (IV) DEX with CLO for postoperative pain relief after LC.
| Materials and Methods|| |
After approval by the institutional ethical committee, this prospective randomized comparative study was conducted between July 2015 and June 2016 as per the standard ethical practice and CONSORT guidelines. A total of 80 patients attending the preanesthetic check-up clinic of our hospital for elective LC, preferably as an overnight stay procedure, were included in this study.
Patients having bodyweight between 50 and 70 kg, aged between 18 and 60 years, and ASA Class I and II undergoing elective LC under general anesthesia (GA) were assessed. Patients with known allergy to the drug, ischemic heart disease, and valvular heart diseases were excluded. Patients with hypertension on treatment with beta-blockers or CLO, renal dysfunction, pregnancy and lactation, and elevated liver enzymes were excluded from the study. Any surgery exceeding 120 min, conversion to laparotomy for any unavoidable reasons, and intraoperative bleeding needing resuscitation were also excluded from the present analgesic regiment.
The patients were randomly allocated to two groups using a computer-generated random number table: The designated CLO group (n = 40) and DEX group (n = 40) received CLO or DEX IV bolus injection during premedication, respectively [Figure 1].
|Figure 1: CONSORT diagram showing the flow of participants through each stage of a randomized trial|
Click here to view
Patients fulfilling the selection criteria were selected for the study and briefed the nature of the study and explained the anesthetic procedure. Written informed consent was obtained from the patient. A thorough preanesthetic evaluation was performed by taking history and clinical examination and recorded on a predesigned and pretested study pro forma. Before surgery, the study drug was prepared in 50 ml syringes in 1 μg/ml dilutions with 0.9% normal saline. After shifting the patient to the operating room, monitors for electrocardiography, noninvasive blood pressure, and pulse oximeter were attached. An 18G IV cannula was secured for IV fluids and drug administration. Basal readings of heart rate (HR), mean arterial pressure (MAP), systolic blood pressure (SBP), diastolic blood pressure (DBP), and SpO2 were recorded. HR, MAP, SBP, DBP, and SpO2 were monitored before, during, and after the surgery. End-tidal CO2 was monitored intraoperatively. The prepared drug is given as IV infusion at a dose of 1 μg/kg bolus over 15 min using a syringe driver during premedication, according to the allotted group.
Patients were administered with injection fentanyl 100 μg for analgesia. Preoxygenation was done for 3 min. Patients were induced with injection propofol 2 mg/kg, and endotracheal intubation was facilitated with injection vecuronium 0.1 mg/kg. Patients were intubated using an appropriate-sized endotracheal tube and maintained on O2:N2O (33:66) and isoflurane 1%. HR <50 beats/min was treated with atropine 0.6 mg IV. All patients were ventilated with a tidal volume of 6–8 ml/kg at a rate of 14 breaths per minute with volume-controlled continuous mandatory ventilation. Following induction, pneumoperitoneum was achieved with CO2. Intraoperatively, injection paracetamol 1 g was given IV. At the end of the operation, the CO2 carefully evacuated.
After the surgery, residual neuromuscular block was reversed with injection glycopyrrolate 0.01 mg/kg and injection neostigmine 0.05 mg/kg, and patients were maintained on IV paracetamol 1 g 8 hourly for pain relief. Patients were instructed to use a visual analog scale score (VAS score: 0–10, where 0 = no pain and 10 = worst pain) for pain measurement. Postoperatively, patients' vitals and VAS score were monitored. The VAS score, HR, and BP were measured at 15 min and 1, 2, and 4 h after extubation.
If patients had VAS (>4/10), 50 mg tramadol was given as IV bolus as a rescue analgesia with prior medication with 4 mg ondansetron. Total opioid demand in the first 24 h was calculated for the study.
Sedation score was measured immediate postoperatively as per Ramsay sedation score (1: Patient anxious, agitated, or restless, 2: Cooperative, oriented, and tranquil, 3: Responds to commands only, 4: Exhibits brisk response to a light glabellar tap or loud auditory stimulus, 5: Sluggish response to a light glabellar tap or loud auditory sound, 6: No response).
The postoperative analgesic effects of preoperative IV DEX and CLO to our usual multimodal analgesic regimen of opioid analgesic (fentanyl) intraoperatively and paracetamol and milder opioid-like tramadol postoperatively have been evaluated. The outcomes in the two groups were compared regarding pain scores and opioid-sparing effects. Secondary outcomes such as hemodynamic parameters in the postoperative period were also compared in two groups.
Calculation of sample size of this study is based on the study published by Samantaray et al., in 2012 where it was presumed that postoperative VAS scores after preinduction administration of CLO would be 30mm when compared with 45 mm in the placebo group with a standard deviation (SD) of 20 mm at all time points. For the results to be of statistical significance with α = 0.05 and β = 0.90, one needed to recruit 37.33 patients in each group. To increase the power of the study and to compensate for any possible dropouts, we enrolled 40 patients in each group. Therefore, keeping n = 40 in each group, the total sample size was taken as 80.
All data were recorded and noted on Master Charts and were analyzed at the end of the study. Data were expressed as mean ± SD, and comparisons were made using the unpaired t-test. Nominal or ordinal variables were compared using the Chi-square test. P < 0.05 was considered statistically significant.
All the statistical analyses were done with (IBM Corp. Released 2013. IBM SPSS Statistics for Windows, Version 20.0.1 Armonk, NY, USA) and Graph Pad Prism version 5 (San Diego, California).
| Results|| |
The demographic profile of our patients was comparable in both the groups to mean age, sex distribution, body weight, and ASA grade [Table 1]. The VAS score at 15 min, the total number of rescue analgesia in 24 h, and the time of requirements were significantly low in the DEX group [Table 2], [Table 3] and [Figure 2]. Statistically significant and favorable low SBP was noted in the DEX group [Table 4]. Our analgesic regimens effectively controlled pain, and all the patients were discharged the next day with oral medications.
|Figure 2: Distribution of number of rescue analgesia per patient in 24 h|
Click here to view
The mean postoperative sedation score was 3.425 ± 1.299 and 3.125 ± 0.8825 in the CLO and DEX group, respectively. The difference was not statistically significant (P = 0.2305).
| Discussion|| |
Mean VAS score was significantly low at 15 min postoperatively in the DEX group. There were also significantly less requirements of rescue analgesia and total number of doses per patient in 24 h in the DEX group. SBP was significantly low in DEX at 1, 2, and 4 h after surgery than CLO group. LC is one of the frequently performed surgeries worldwide in the present time. The surgery has been facilitated as an ambulatory or outpatient procedure, and continuous efforts are made to reduce the operative stay of routine surgery, improve patient comfort, and promote early recovery.
Pain after LC, though significantly less than an open procedure, has been attributed particularly to pneumoperitoneum. However, pain after LC is multifactorial and includes humoral biochemical response related to stress and inflammation, besides stretching of the peritoneum by CO2 insufflation and residual pneumoperitoneum. Pain may sometimes be a source of delayed recovery and prolong hospital stay and has been seen as a major concern for the success of an ambulatory LC. Several surgical modifications such as low-pressure insufflation (10–12 mmHg), saline lavage and suction, port site local anesthetic infiltration, and evacuation of pneumoperitoneum have been adopted to reduce such pain. However, a combination of several analgesics in the pre-, intra-, and the post-operative period has been noted useful to further optimize the analgesic effect, and the involvement of an anesthetist become imperative for this purpose.
Control of pain is of utmost importance in LC as per the Enhanced Recovery After Surgery (ERAS) Protocol. ERAS is a multiple evidenced-based strategy for early discharge of the patients after surgery and is followed by most of the centers. ERAS needs a combined effort and teamwork involving a surgeon and the anesthetist. Anesthesiologist plays an important role in preoperative patient preparation and counseling, intraoperative choice of anesthesia for early recovery, as well as postoperative fluid and pain management, and reduction of postoperative complications, such as nausea-vomiting and prolonged sedation. Pain management in ERAS is very important as an appropriate choice of techniques and medications enables individual patients an early discharge such as choice of epidural block and continuous nerve block could not facilitate, instead an oral medication combined with field block with long-acting drugs and adjuvants may be. Multimodal analgesia has been gaining popularity for postoperative pain reduction after a variety of surgeries. A combination of different drugs not only increases the efficacy of the regimen but also reduces the side effect of individual components. Selective alpha-2 agonists are used in modern anesthesia because of several benefits such as conscious sedation, attenuation stress response, hemodynamic stabilization, sedation, reduction of anesthetic drug requirements, and coanalgesic property.,, The use of CLO and DEX as analgesics has been discussed in several literature earlier. DEX or CLO or both are selective α2-adrenergic receptor agonists with a coanalgesic property.
Premedication with CLO blunts the stress response to intubation and surgical stimuli and decreases the requirements of narcotic and analgesic drugs. Besides, CLO raises the cardiac baroreceptor reflex sensitivity to increase SBP and thus stabilizes blood pressure in operative hypotension.
DEX and CLO play a vital role as an adjuvant used for ERAS. The shorter duration of action and conscious sedation allow early recovery from anesthesia with systemic medications and early mobilization after surgery.
DEX is eight times more specific for α2 adrenoceptors than CLO. The ratio of α2:α1 activity is 1620:1 and 220:1 for DEX and CLO, respectively., The specificity of DEX for the α2 receptor, especially for the 2A subtype of this receptor, causes it to be a much more effective sedative and analgesic agent than CLO. DEX modulates the hemodynamic changes induced by pneumoperitoneum by inhibiting the release of catecholamine and vasopressin. Several studies have been conducted on this sympatholytic effect of premedication with DEX.,,, The sedative and anxiolytic properties of DEX, as well as sympatholytic characteristics, make this drug of particular interest for premedication.,,
Due to sedative and coanalgesic effect of these drugs, they are increasingly used for analgesia for a variety of purposes including procedures in ICU, short duration sedations and surgeries, and laparoscopic procedures and even complex procedures such as sleeve gastrectomy and coronary bypass surgery.,,,, The reduction in pain and opioid consumption may decrease the incidence of side effects such as postoperative nausea, vomiting, and respiratory depression, hasten the postoperative recovery, and reduce the length of hospital stay. They also found to improve the hemodynamic condition of the patients related to this surgery.
In the present study, our analgesic regimen of a combination of preoperative fentanyl and premedication with low-dose IV α2 agonists, intra- and post-operative IV paracetamol and IV tramadol as rescue analgesia in the postoperative period effectively controlled overnight pain. All the patients were discharged on the next day with oral medications.
In the present study, VAS at 15 min was found to be significantly low at 15 min with DEX (P = 0.0195). At 1, 2, and 4 h, VAS scores were comparable in both the groups. The results are similar to some earlier meta-analysis., Therefore, it is noted that both CLO or DEX may be used effectively to reduce the postoperative pain of LC in the early postoperative period (<4 h).
A second important result that we got from our study is the opioid-sparing effect of both the drugs by combining the results of the number of patients who required rescue analgesia and the total number of opioids (tramadol) injections demanded in 24 h. Seventeen out of 40 patients in the CLO group whereas 7/40 patients in the DEX group required tramadol as rescue analgesia in a 24-h postoperative period, and the difference was statistically significant (P = 0.0146). The total demand for tramadol injection was also lower and statistically significant with the DEX group (P = 0.0356) [Table 3] and [Figure 2].
A favorable opioid- and analgesic-sparing effect has been described with DEX. It is seen that with DEX, a statistically significant decrease in opioid consumption was observed from the second postoperative hour until the 24 h, while with CLO, the decrease was from the 12–24 h postoperatively. The frequency of demand for rescue analgesia and total analgesic consumption is also significantly less in DEX than in CLO.,
In our study, the mean time of requirement of rescue analgesia for DEX was 341.35 min postsurgery and for CLO was 302.14 min [Table 3] and [Figure 3]. However, the time difference between both was found to be insignificant (P = 0.5637). The minimum time of demand for rescue analgesia was 51 min with CLO postoperatively and was 125 min with DEX, which was more than double the time of demand in the CLO group. This delay in minimum time requirement for rescue analgesia was observed in our study, which is suggested by some other studies also., Hence, a decrease total analgesic consumption in the early postoperative period, comparable VAS score, and time of requirements of analgesics establishes better analgesic-sparing profile of DEX for LC also.
Furthermore, this study also demonstrates that the hemodynamic parameters in the postoperative period were significantly better than CLO. It is important to note that many studies suggest bradycardia with DEX intraoperatively or in the early postoperative period; however, in our study, none of the patients required any treatment for bradycardia or hypotension in the postoperative period. The difference in the effects of DEX on HR and blood pressure in our study may also be attributed to the high selectivity and specificity of DEX to the alpha-2 agonist receptors than CLO [Table 4].
Our findings support the earlier observations of the beneficial role of premedication of both CLO and DEX on the postoperative pain. However, this study shows that DEX is efficacious than CLO in reducing opioid demand, following LC in the early postoperative period. This could be because of the more specific action of DEX on α2 adrenoceptors, which might have a significant role in post-LC pain. Hence, our study suggests to include DEX to a multimodal analgesic regimen for LC and possible benefit in ambulatory and daycare surgeries.
Our study was not a double-blinded study and did not include a control group. In this study, we used bolus doses of DEX and CLO. We did not use a maintenance dose throughout the intraoperative period. Moreover, the study was conducted on a small size of the population. Including a larger population would give better results and more clarification.
This study involved ASA Physical Status Class I and II patients suitable for overnight stay surgery only. Therefore, we cannot emphasize the results from our study on ASA Physical Status Class III and IV patients, e.g., patients with uncontrolled hypertension and/or uncontrolled diabetes mellitus, who otherwise may be considered poor candidates for an ambulatory procedure. This study emphasizes the use of this regimen for an ambulatory procedure, rather than a routine LC procedure.
| Conclusions|| |
Although both CLO and DEX have been shown to improve postoperative pain and reduce requirements of analgesics in a variety of surgeries, DEX has been found more effective than CLO for LC for early pain relief. Better hemodynamic stability is seen with DEX, which may be an important aspect after surgery. Thus, routine premedication with DEX for ambulatory LC may be recommended.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Joris JL. Anesthesia for laparoscopic surgery. In: Miller RD, editors. Miller's Anesthesia. 7th
ed. Philadelphia: Churchill Livingstone; 2010. p. 2185-202.
Michaloliakou C, Chung F, Sharma S. Preoperative multimodal analgesia facilitates recovery after ambulatory laparoscopic cholecystectomy. Anesth Analg 1996;82:44-51.
Naja ZM, Khatib R, Ziade FM, Moussa G, Naja ZZ, Naja AS, et al
. Effect of clonidine versus dexmedetomidine on pain control after laparoscopic gastric sleeve: A prospective, randomized, double-blinded study. Saudi J Anaesth 2014;8:S57-62.
Gupta S, Pratap V. Addition of clonidine or dexmedetomidine to ropivacaine prolongs caudal analgesia in children. Indian J Pain 2014;28:36-41. [Full text]
Blaudszan G, Lysakowaski C, Nadia E, Tramor MR. Effect of perioperative systemic α2 agonists on postoperative morphine consumption and pain intensity: Systematic review and meta-analysis of randomized controlled trials. Anaesthesiology 2012;116:1312-22.
Srivastava U, Sarkar ME, Kumar A, Gupta A, Agarwal A, Singh TK, et al
. Comparison of clonidine and dexmedetomidine for short-term sedation of intensive care unit patients. Indian J Crit Care Med 2014;18:431-6.
] [Full text]
Anjum N, Tabish H, Debdas S, Bani HP, Rajat C, Anjana Basu GD. Effects of dexmedetomidine and clonidine as propofol adjuvants on intra-operative hemodynamics and recovery profiles in patients undergoing laparoscopic cholecystectomy: A prospective randomized comparative study. Avicenna J Med 2015;5:67-73.
] [Full text]
Kumar S, Kushwaha BB, Prakash R, Jafa S, Malik A, Aggarwal J, et al
. Comparative study of effects of dexmedetomidine and clonidine premedication in perioperative hemodynamic stability and postoperative analgesia in laparoscopic cholecystectomy. Internet J Anaesth 2014;33:1-8.
Samantaray A, Rao MH, Chandra A. The effect on post-operative pain of intravenous clonidine given before induction of anaesthesia. Indian J Anaesth 2012;56:359-64.
] [Full text]
Barazanchi AWH, MacFater WS, Rahiri JL, Tutone S, Hill AG, Joshi GP, et al
. Evidence-based management of pain after laparoscopic cholecystectomy: A PROSPECT review update. Br J Anaesth 2018;121:787-803.
Joris JL, Chiche JD, Canivet JL, Jacquet NJ, Legros JJ, Lamy ML. Hemodynamic changes induced by laparoscopy and their endocrine correlates: Effects of clonidine. J Am Coll Cardiol 1998;32:1389-96.
Reves JG, Glass PS, Lubarsky DA, McEvoy MD, Martinez-Ruiz R. Intravenous anaesthetics. In: Miller RD, editors. Miller's Anesthesia. 7th
ed. Philadelphia: Churchill Livingstone ; 2010. p. 751-7.
Jalonen J, Hynynen M, Kuitunen A, Heikkilä H, Perttilä J, Salmenperä M, et al
. Dexmedetomidine as an anesthetic adjunct in coronary artery bypass grafting. Anesthesiology 1997;86:331-45.
Gertler R, Brown HC, Mitchell DH, Silvius EN. Dexmedetomidine: A novel sedative-analgesic agent. Proc (Bayl Univ Med Cent) 2001;14:13-21.
Sharma R, Gupta R, Choudhary R, Singh Bajwa SJ. Postoperative analgesia with intravenous paracetamol and dexmedetomidine in laparoscopic cholecystectomy surgeries: A prospective randomized comparative study. Int J Appl Basic Med Res 2017;7:218-22.
Chilkoti GT, Kumar M, Mohta M, Saxena AK, Sharma N, Singh J. Comparison of postoperative analgesic efficacy of low-dose bolus intravenous dexmedetomidine and intraperitoneal dexmedetomidine with bupivacaine in patients undergoing laparoscopic cholecystectomy: A randomised, controlled trial. Indian J Anaesth 2019;63:106-13.
] [Full text]
Manne GR, Upadhyay MR, Swadia V. Effects of low dose dexmedetomidine infusion on haemodynamic stress response, sedation and post-operative analgesia requirement in patients undergoing laparoscopic cholecystectomy. Indian J Anaesth 2014;58:726-31.
] [Full text]
Khare A, Sharma SP, Deganwa ML, Sharma M, Gill N. Effects of dexmedetomidine on intraoperative hemodynamics and propofol requirement in patients undergoing laparoscopic cholecystectomy. Anesth Essays Res 2017;11:1040-5.
] [Full text]
Singh S, Nazir N. A comparative study of effect of dexmedetomidine in dose of 0.7 μg/kg and clonidine in doses of 2 μg/kg as premedication before general anaesthesia. Int J Res Med Sci 2016;4:3365-9.
Taittonen MT, Kirvelä OA, Aantaa R, Kanto JH. Effect of clonidine and dexmedetomidine premedication on perioperative oxygen consumption and haemodynamic state. Br J Anaesth 1997;78:400-6.
Kumari S, Agrawal N, Usha G, Talwar V, Gupta P. Comparison of oral clonidine, oral dexmedetomidine, and oral midazolam for premedication in pediatric patients undergoing elective surgery. Anesth Essays Res 2017;11:185-91.
] [Full text]
Panchgar V, Shetti AN, Sunitha HB, Dhulkhed VK, Nadkarni AV. The effectiveness of intravenous dexmedetomidine on perioperative hemodynamics, analgesic requirement, and side effects profile in patients undergoing laparoscopic surgery under general anesthesia. Anesth Essays Res 2017;11:72-7.
] [Full text]
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4]