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Year : 2017  |  Volume : 18  |  Issue : 1  |  Page : 3-8

Postoperative analgesia in laparoscopic surgeries with small dose of preemptive ketamine: A comparative study of three small doses

Department of Anesthesia, BJ GMC, Pune, Maharashtra, India

Date of Web Publication27-Jun-2017

Correspondence Address:
Vaijayanti Nitin Gadre
303-C Aarav, Opposite Y.C. Chavan Natyagruha, Behind Mhatoba Mandir, Kothrud, Pune - 411 038, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/TheIAForum.TheIAForum_41_16

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Introduction: Preemptive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine inhibits central sensitization in response to peripheral nociception. The purpose of our study was to compare efficacy of three small doses of ketamine for improving postoperative analgesia after laparoscopic surgeries.
Materials and Methods: A total of 120 patients of American Society of Anesthesiologists physical status I–II undergoing laparoscopic surgeries were randomly allocated into four groups. Groups 1, 2, and 3 received intravenous ketamine in dose of 1, 0.75, and 0.5 mg/kg, respectively, and control Group 4 received isotonic saline 30 min before incision. Variations in heart rate and mean arterial pressure were noted, and response to pain at rest and at deep breathing was studied over 24 h. Fentanyl 0.5 μg/kg was used for rescue analgesia.
Results: Visual analog scale score was significantly low in Groups 1, 2, and 3 as compared to control Group 4. 66.7% of patients in Group 4 required rescue analgesia at 24 h which was significantly higher (P < 0.0001) than that in Groups 1, 2, and 3 (26.67%, 20.00%, and 36.67%, respectively). Total number of analgesic doses required was only 32 in Group 3 as compared to Groups 2, 1, and 4, wherein it was 36, 40, and 78, respectively.
Conclusion: Preemptive administration of ketamine decreases postoperative analgesic requirement with satisfactory hemodynamic stability and no side effects in 0.5 mg/kg dose.

Keywords: Ketamine, postoperative analgesia, preemptive analgesia

How to cite this article:
Gadre VN, Dhokte NS. Postoperative analgesia in laparoscopic surgeries with small dose of preemptive ketamine: A comparative study of three small doses. Indian Anaesth Forum 2017;18:3-8

How to cite this URL:
Gadre VN, Dhokte NS. Postoperative analgesia in laparoscopic surgeries with small dose of preemptive ketamine: A comparative study of three small doses. Indian Anaesth Forum [serial online] 2017 [cited 2019 Nov 21];18:3-8. Available from: http://www.theiaforum.org/text.asp?2017/18/1/3/208967

  Introduction Top

Perioperative noxious stimuli trigger central sensitization resulting in intense postoperative pain. The pain due to laparoscopic surgery is associated with peritoneal stretching by insufflation and diaphragm irritation. N-methyl-D-aspartate (NMDA) receptor antagonist ketamine is useful in reducing pain and analgesic requirement if given before the onset of noxious inputs.[1] This study evaluated the effects of three small doses of ketamine given before incision on the time required for first rescue analgesic, total number of analgesic doses, hemodynamic stability, and side effects.

  Materials and Methods Top

After the approval of Ethical Committee, a double-blind, randomized, prospective study was conducted in 120 American Society of Anesthesiologists Grade 1 and 2 patients of both sexes and aged between 18 and 50 years. Patients undergoing various laparoscopic surgeries under standard general anesthesia (GA) technique were included in the study. Pregnant and nonconsenting patients were excluded from the study.

All patients were shown the visual analog scale (VAS) and explained that it will be the tool for measuring the postoperative pain. Patients who were unable to understand the VAS and those with allergic or psychiatric disorders were also excluded from the study. All patients were premedicated with tablet diazepam 10 mg and tablet ranitidine 150 mg night before surgery. The patients were randomly allocated using computer-generated random numbers and concealed opaque envelops into four groups; Groups 1, 2, and 3 received intravenous (IV) ketamine 1 mg/kg, 0.75 mg/kg, and 0.5 mg/kg, respectively, and Group 4 received isotonic saline. The study drug was drawn and diluted to a fixed volume of 10 ml by the anesthesiologist not involved in study. On the operation table, baseline vital parameters were recorded; IV access obtained and patients were premedicated with IV 0.03 mg/kg midazolam, 0.1 mg/kg ondansetron, and 5 μg/kg glycopyrrolate. After preoxygenation with 100% oxygen for 3 min, anesthesia was induced with thiopentone sodium 4–6 mg/kg till abolition of eyelash reflex. Injection fentanyl 1 μg/kg IV was given immediately after induction. Endotracheal intubation was done with proper size tube using suxamethonium 1.5 mg/kg for facilitating intubation. The study drug diluted to 10 ml volume was administered IV by the anesthesiologist not participating in the study, about 30 min before incision. Anesthesia was maintained with oxygen and N2O (50:50), isoflurane 2%–4%, and vecuronium bromide 0.2 mg/kg. Intraoperatively, heart rate (HR), blood pressure, electrocardiogram, temperature, end-tidal carbon dioxide, and oxygen saturation were monitored. Neostigmine 0.04 mg/kg and glycopyrrolate 0.01 mg/kg IV were given to reverse the neuromuscular blockade after completion of surgery. Postoperatively, HR, mean arterial pressure (MAP), and pain intensity and/or relief were monitored. The time 0 h for postoperative monitoring was taken from the shifting of patients to the recovery room. VAS score for pain was noted every 15 min for 1st h and then hourly for the next 4 h. Patients were visited at 12 h and at 24 h postoperative. Injection fentanyl 0.5 μg/kg was given as IV bolus for rescue analgesia started when VAS ≥4–5 and was repeated when necessary. For first 24 h, only fentanyl supplemental analgesia was given and after that other analgesics, if required, were added.

Data analysis was performed using IBM SPSS version 20.0 USA and MS Excel 2010. Categorical variables were presented as frequency and percentages while continuous variables were presented as mean (standard deviation) or median. In comparing categorical variables, Chi-square test for two groups or Kruskal–Wallis test for more than two groups of categorical data was used. Independent sample t-test was employed in assessing statistical significance of two continuous variables. One-way ANOVA with post hoc analysis of Bonferroni was used for statistical comparison of continuous variables involving four study groups. At 95% confidence interval, P< 0.05 was considered statistically significant.

  Results Top

A total of 120 patients were randomly allocated into four groups of thirty each. Patients undergoing laparoscopic procedures under GA were included in the study. To evaluate the pain of laparoscopy in postoperative period, VAS score was explained to the patients preoperatively.

Demographic parameters showed that mean age in Group 1 was not statistically different as compared to other three groups. Mean age in Group 2 was significantly higher than that in Group 4; patients in Groups 3 and 4 showed statistically significant age difference [Table 1] and [Figure 1]. Weight of patients in all four groups was comparable [Table 1].
Table 1: Demographic parameters in study groups

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Figure 1: Distribution of patients according to age

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Overall percentage of males (59.17%) included in the study was higher than that of females (40.83%) [Table 1]. HR changes assessed at different timelines in study groups showed mean baseline (P = 0.008), and at premedication, HR was significantly higher in Group 1 as compared to Group 4. HR at induction, intubation, and test drug administration did not vary in Groups 1 and 2 compared to Group 4. HR at induction in Group 3 showed statistically significant difference compared to Group 4 (P = 0.001). HR at reversal was significantly lower in Group 3 (74.73 ± 5.29) compared to Group 4 (80.60 ± 6.87, P= 0.004) and that at extubation was significantly higher in Group 4 (85.47 ± 5.04) compared to Group 1 (80.80 ± 7.23, P= 0.004). Postoperative HR showed significantly higher values in Group 1 when compared to Group 4 at all timelines during 24 h postoperative period (P < 0.0001 for all timeline comparison). The HR in Groups 2 and 3 was not significantly different at any timeline when compared with Group 4 [Figure 2].
Figure 2: Changes in heart rate over time in the study groups

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Changes in MAP over different timeline in the study groups are shown in [Figure 3]. Mean value of MAP in all four groups was found to be lowest (86.24) in Group 3 and highest (92.28) in Group 2. [Table 2] shows the statistical calculations for the application of ANOVA; the statistical explanation indicates that higher value of computed F-ratio strongly suggests significant difference in MAP in the four study groups.
Figure 3: Changes in mean arterial pressure over time in the study groups

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Table 2: Mean values of mean arterial pressure and statistical calculation for application of ANOVA

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VAS at rest and at deep breathing at different timeline in study groups was assessed using Kruskal–Wallis (nonparametric test) test. Minimum, maximum, and median values with P value were calculated [Figure 4] and [Figure 5]. VAS scores were significantly low in all three groups compared to control group till 4 h postoperatively (P < 0.001). At 12 h, no statistically significant difference was observed at rest (P < 0.129) but at deep breathing; it was significantly lower in Groups 2 and 3 (3.30 ± 0.46) compared to control Group 4 (4.53 ± 0.50), (P < 0.001). At 24 h, all three groups had significantly lower VAS scores at rest (3.33 ± 1.24, 2.87 ± 1.07, 3.60 ± 1.27 in Groups 1, 2, and 3, respectively, P< 0.001) but not at deep breathing (4.27 ± 0.45, 4.3 ± 0.46, 4.3 ± 0.46, P= 0.001) compared to control Group 4 (4.67 ± 0.47 at rest and 4.9 ± 0.80 at deep breathing) [Figurs 4] and [Figure 5].
Figure 4: Visual analog scale at rest in postoperative period

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Figure 5: Visual analog scale during deep breath in postoperative period

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[Table 3] shows time of receiving rescue analgesia with fentanyl in different groups. Highest number of patients in Group 4 required rescue analgesic with a maximum of 78 dosages, compared to Groups 1 (40), 2 (36), and 3 (32) (P < 0.0001). At 1 h, 6.67% of patients in Group 4 needed rescue analgesia, whereas none of the patients in Groups 1, 2, and 3 required analgesia as the mean VAS score was 2.33–3.33 [Figure 4] and [Figure 5]. The onset of requirement of rescue analgesia in Group 4 was at 1 h (compared to 2, 1.75, and 3 h in Groups 1, 2, and 3, respectively) and rescue analgesic doses required up to 4 h was 48. The number of rescue analgesic doses required up to 12 h at different timeline during the study period (1, 1.25, 1.5, 1.75, 2, 3, and 4 h, respectively) in control Group 4 was 2, 3, 10, 5, 10, 12, and 6. Total number of analgesic doses up to 12 h was 32, 30, 21, and 58 in Groups 1, 2, 3, and 4, respectively. Requirement of rescue analgesic at 24 h was significantly higher (P < 0.0001) in Group 4 (66.67%) compared to Groups 1 (26.67%), 2 (20.00%), and 3 (36.67%) [Table 3]. VAS in Group 4 at 4 h was 4.03 ± 0.669 at rest and 4.67 ± 0.75 at deep breath whereas that in Groups 2 and 3 was significantly low statistically (2.7 ± 1.11 and 3.77 ± 0.43 in Group 2 and 2.43 ± 0.817 and 3.77 ± 0.43 in Group 3 at rest and at deep breath, respectively) [Figure 4] and [Figure 5].
Table 3: Rescue analgesia with fentanyl in different groups

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  Discussion Top

Adequate postoperative pain relief is an integral part of anesthesia management. Postsurgical pain can be treated effectively with both strong analgesia and prevention of central sensitization. The goal of preemptive analgesia is to avoid pathological modulation of the central nervous system (CNS). Animal experiments demonstrate [2] that high-frequency stimulus applied to sciatic nerve produced Aβ and C-fiber primary afferent stimulation and long-term potentiation (LTP). A negative focus of long latency (90–120 ms) and high threshold (10–25 V) was recorded at superficial dorsal horn (C-evoked potential) and continued to occur for a prolonged period (LTP). High-dose ketamine 5 mg/kg given 1 h after the LTP stimulation produced no effect; combination of bolus ketamine and bolus fentanyl given before the stimulus produced 40% reduction in C-evoked potentials and LTP was fully blocked, whereas single-dose fentanyl alone given before stimulation produced 37% reduction in C-evoked potentials and no effect on LTP.

In this study, we have compared three doses, 1, 0.75, and 0.5 mg/kg of ketamine given in combination with fentanyl 1 μg/kg before surgical incision, and the effects on postoperative pain and analgesic requirements were studied for 24 h. We assessed VAS at rest and at deep breathing [Figure 4] and [Figure 5]. The hemodynamic parameters were also studied in groups under evaluation as an indirect reflection of pain control.

In our study, 6.67% patients in Group 4 needed rescue analgesia at 1 h while patients in the study groups did not require analgesia as the VAS score was 2.33–3.33.

Total number of analgesic doses at 24 h was also very high in the control group, compared to the study groups. In a study by Singh et al.,[3] the VAS score was 4.1–4.35 and verbal numerical rating was 1.85–2.15 at 1 h and mean time to receive rescue analgesia was 0.375 h in the control group versus 2.1, 1.85, and 1.98 h, respectively, in three study groups with preemptive ketamine in small doses. In the present study, none of the patients experienced hallucinations, nausea, or vomiting, whereas Singh et al. reported the incidence to be 10% and 15%–20% in different groups.

Effect of ketamine on single and repeated nociceptive stimuli was sought on placebo-controlled 12 human volunteers by experimentally studying pain, threshold tolerance, and electrophysiological withdrawal techniques. 0.5 mg/kg bolus ketamine followed by 9 μg/kg/min 20 min infusion was found to decrease response to high-intensity pain. Repetitive painful stimuli such as cautery and laser showed marked hypoalgesia because ketamine blocked the ion channel open to continuous barrage of stimuli. Unlike ketamine, isoflurane anesthesia was found to depress reflexes to single painful stimulus only and those to repeated stimuli were not affected.[4]

Preemptive ketamine in small dose of 0.15 mg/kg was found effective by Kwok et al.[5] According to them, although the duration of analgesia of a small dose given IV did not last long, the preemptively administered dose blocked postoperative painful stimuli effectively by preventing central sensitization.

Tissue trauma causes activation of C-fibers, release of glutamate, a major excitatory neurotransmitter in the CNS, which activates NMDA receptors. Repetitive painful stimuli of surgery activate more receptors resulting in increased central sensitization, LTP, and more postoperative pain. Low-dose ketamine given before stimulus blocks central sensitization and prevents LTP by blocking ion channels in open state, thus preventing hyperexcitability and postoperative pain.[6]

Ketamine also shows synergistic and additive interaction with opioids. Therefore, adding a small dose to intraoperative multimodal analgesic regimen becomes an important adjunct to improve postoperative analgesia and functional outcome.[7]

  Conclusion Top

We conclude that preemptive ketamine has definitive role in reducing postoperative pain and analgesic requirement in patients undergoing laparoscopic surgeries. A low dose of 0.5 mg/kg was devoid of any adverse effects and hemodynamic changes. Hence, it is an optimal dose for preemptive analgesia in patients undergoing laparoscopic surgeries.

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Conflicts of interest

There are no conflicts of interest.

  References Top

McCartney CJ, Sinha A, Katz J. A qualitative systematic review of the role of N-methyl-D-aspartate receptor antagonists in preventive analgesia. Anesth Analg 2004;98:1385-400.  Back to cited text no. 1
Benrath J, Brechtel C, Stark J, Sandkühler J. Low dose of S+-ketamine prevents long-term potentiation in pain pathways under strong opioid analgesia in the rat spinal cord in vivo. Br J Anaesth 2005;95:518-23.  Back to cited text no. 2
Singh H, Kundra S, Singh RM, Grewal A, Kaul TK, Sood D. Preemptive analgesia with Ketamine for laparoscopic cholecystectomy. J Anaesthesiol Clin Pharmacol 2013;29:478-84.  Back to cited text no. 3
[PUBMED]  [Full text]  
Arendt-Nielsen L, Petersen-Felix S, Fischer M, Bak P, Bjerring P, Zbinden AM. The effect of N-methyl-D-aspartate antagonist (ketamine) on single and repeated nociceptive stimuli: A placebo-controlled experimental human study. Anesth Analg 1995;81:63-8.  Back to cited text no. 4
Kwok RF, Lim J, Chan MT, Gin T, Chiu WK. Preoperative ketamine improves postoperative analgesia after gynecologic laparoscopic surgery. Anesth Analg 2004;98:1044-9.  Back to cited text no. 5
Menigaux C, Fletcher D, Dupont X, Guignard B, Guirimand F, Chauvin M. The benefits of intraoperative small-dose ketamine on postoperative pain after anterior cruciate ligament repair. Anesth Analg 2000;90:129-35.  Back to cited text no. 6
Menigaux C, Guignard B, Fletcher D, Sessler DI, Dupont X, Chauvin M. Intraoperative small-dose ketamine enhances analgesia after outpatient knee arthroscopy. Anesth Analg 2001;93:606-12.  Back to cited text no. 7


  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]

  [Table 1], [Table 2], [Table 3]


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