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ORIGINAL ARTICLE
Year : 2021  |  Volume : 22  |  Issue : 1  |  Page : 67-72
 

Effect of low dose ketamine on perioperative analgesia in patients undergoing open abdominal hysterectomy - A double-blind, randomized, placebo-controlled trial


1 Department of Anaesthesia, Christian Medical College, Vellore, Tamil Nadu, India
2 Department of Anesthesiology & Perioperative Medicine, Penn State Health College of Medicine, Hershey, Pennsylvania, USA
3 Department of Biostatistics, Christian Medical College, Vellore, Tamil Nadu, India

Date of Submission13-Jun-2020
Date of Acceptance04-Aug-2020
Date of Web Publication22-Feb-2021

Correspondence Address:
Dr. Ramamani Mariappan
Department of Anaesthesia, Christian Medical College, Vellore - 632 002, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/TheIAForum.TheIAForum_80_20

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  Abstract 


Background: Low-dose ketamine can provide effective perioperative analgesia while reducing its side effects. This study aims to estimate the effect of a low dose of ketamine administered preemptively and during the surgery on postoperative opioid requirement and the incidence of side effects of ketamine.
Methods: This prospective, double-blind, randomized control trial enrolled 60 adult women (>18 years) scheduled for open abdominal hysterectomy. All patients received general anesthesia using a standard protocol. Patients were randomized to receive 0.2 mg/kg of ketamine as bolus before induction of anesthesia, followed by an infusion of 0.002 mg/kg/min for the duration of surgery (Group K) or an equivalent volume of 0.9% saline (Group C). The primary outcome was to compare the morphine requirement over the 24 h postoperatively between the two groups. The secondary outcomes were to compare the intraoperative morphine requirement, and the incidence of side effects of ketamine.
Results: The intraoperative morphine requirement was significantly less (P = 0.006) in those who received ketamine (6.5 ± 1.5 mg) compared to the placebo (7.67 ± 1.7 mg). The 24-hour morphine requirement was less in the Group K (7.87 ± 4.7 mg) compared to Group C (9.2 ± 4.5 mg), but was not statistically significant. The incidence of hallucination and nystagmus was significantly higher in the ketamine group, but it lasted <2 h.
Conclusion: The preemptive and the intraoperative infusion of low-dose ketamine decreases the morphine requirement intraoperatively but not during the postoperative period.


Keywords: Analgesia, hysterectomy, ketamine, pain management


How to cite this article:
Mariappan R, Cherian VT, Joy M, Selvaraj K G. Effect of low dose ketamine on perioperative analgesia in patients undergoing open abdominal hysterectomy - A double-blind, randomized, placebo-controlled trial. Indian Anaesth Forum 2021;22:67-72

How to cite this URL:
Mariappan R, Cherian VT, Joy M, Selvaraj K G. Effect of low dose ketamine on perioperative analgesia in patients undergoing open abdominal hysterectomy - A double-blind, randomized, placebo-controlled trial. Indian Anaesth Forum [serial online] 2021 [cited 2021 May 10];22:67-72. Available from: http://www.theiaforum.org/text.asp?2021/22/1/67/309839





  Introduction Top


Postoperative pain, although transient, does have significant consequences during the immediate postoperative period with regard to morbidity, wound healing, and time to discharge, and it also the quality of life.[1],[2] Inadequate postoperative pain relief can cause activation of the N-methyl-D-aspartate (NMDA) receptors in the dorsal column and lead to chronic pain syndrome and also opioid dependence.[1] Therefore, there is a renewed interest in the perioperative use of ketamine, an NMDA receptor antagonist. Studies have shown that intraoperative and postoperative administration of low dose ketamine reduces the intensity of pain and opioid consumption after surgery.[3],[4],[5],[6] The aim of this study was to determine if the preemptive administration of a low dose of ketamine before and during the surgery decreases the requirement of analgesics after open abdominal hysterectomy. The primary outcome of the study was to compare the opioid requirement during the first 24 h after the surgery. The secondary outcomes were to compare the intraoperative morphine requirement, the need for additional analgesics postoperatively, and to monitor the incidence of complications associated with ketamine such as hallucinations and nystagmus.


  Methods Top


This double-blind, randomized, placebo-control clinical trial was approved by the Institutional Review Board (IRB number 5587). All American Society of Anesthesiologists Grade 1 and 2 women over 18 years of age, scheduled for open abdominal hysterectomy were eligible to be enrolled in this study. Patients with significant comorbidities such as cardiovascular, hepatic, renal, neurological or psychiatric disease, and those allergic to ketamine were excluded. All the eligible participants were explained about the study the day before surgery and those willing to participate were asked to sign a written consent before enrolling them into the study.

At the time of planning of this study, due to the paucity of studies using ketamine infusion intraoperatively, the study by Snijdelaar et al.[7] was used to calculate the sample size. Based on this data to achieve a power of 80% with a α-error of 5%, the calculated sample size was 23. A computer-generated randomization list in blocks of 10 was created, and the allocation concealment was ensured by enclosing the group allocation in sequentially numbered opaque envelopes.

To maintain blinding and concealment of allocation, a consultant anesthesiologist, who was not involved in the study or the perioperative care of the patient, was asked to open the randomization envelop, 30 min before induction of anesthesia, and loaded the study drug in a 50 ml syringe (BD®). For the Group K, 50 mg of ketamine was diluted to 50 ml with 0.9% saline to make a concentration of 1 mg/ml, whereas for Group C, 50 ml of 0.9% saline was loaded in the 50 ml syringe. The anesthesiologist managing the patient, and the members of the study team were blinded to the contents of the syringe.

The participants were randomized into two groups. Patients in Group K (ketamine) received 0.2 mg/kg of racemic ketamine before induction of anesthesia followed by an infusion of 0.002 mg/kg/min for the duration of the surgery. The patients in Group C (control) received 0.9% saline in equivalent volumes.

A uniform anesthetic protocol was followed for all the participants except for the study intervention. On the day of surgery, all patients were premedicated with oral diazepam 0.2 mg/kg (up to a maximum of 10 mg) 90 min before the induction of anesthesia, as per the standard of practice. In the operating room, an 18 G intravenous (IV) cannula was placed, and an infusion of lactated Ringer's was started. After placing the standard anesthesia monitors (electrocardiogram [ECG], noninvasive blood pressure, SpO2) and recording the baseline values, 0.2 ml/kg of study drug from the 50 ml syringe was administered over 15 min. All the patients were induced and intubated as per the standard of care at our institution. After recording the postintubation hemodynamic values, the infusion of the study drug was started at the rate of 0.002 ml/kg/min and continued for the duration of the surgery. Anesthesia was maintained with 50% N2O in oxygen and Isoflurane. The management of patient, in terms of dose of morphine, depth of anesthesia, and use of vasopressors to maintain hemodynamic stability was at the discretion of the consultant anesthesiologist. At the end of surgery, ondansetron (4 mg) was administered IV and the infusion of the study drug was stopped. The muscle relaxation was reversed with neostigmine (50 μg/kg) and atropine (20 μg/kg), and the endotracheal tube was removed when the patient met the extubation criteria. The duration between stopping the infusion and extubation was labelled “wake-up” time. The patient was then transferred to the postanesthesia care unit (PACU) as per the standard of care.

In the PACU, the blood pressure, the ECG, and the SpO2 were monitored for all the patients as were the level of sedation (1 – awake; 2 – drowsy but responding to voice; 3 – drowsy and unresponsive to verbal stimuli; 4 – drowsy and unresponsive to verbal or tactile stimuli) and pain on the Visual Analog Scale 0–10 (VAS). The patient was observed for side effects of ketamine, namely hallucinations and nystagmus. If the patient was restless and had an incomprehensible speech, without hypoxemia (SpO2<90) or pain, it was recorded as hallucination. Any rapid, to-and-fro movement of the eye was recorded as nystagmus. Any complaints of nausea and vomiting were also recorded. In the postoperative period, when the patient complained of significant pain, intramuscular morphine (0.1 mg/kg) was given, which could be repeated after 6 h if required. However, if analgesia was required before that, ketorolac 30 mg could be administered intramuscularly as per the standard of practice. The time to the first dose of morphine was recorded.

Once the patients were awake and stable, they were transferred to the ward where the monitoring was continued. The blood pressure, heart rate, pain score, sedation level, and presence of hallucinations or nystagmus were recorded at regular intervals. Twenty-four hour after the surgery, the study anesthesiologist interviewed the patient and asked them to grade their level of satisfaction with the control of their postoperative pain, on a scale of 0–10, with 10 being the most satisfied. The score was grouped as good (8–10), moderate (4–7), and poor (0–3) for analysis.

Statistical analysis

All the statistical analyses were performed using IBM SPSS Statistics for Windows, Version 21.0. Armonk, NY: IBM Corp. Continuous variables which follow normality were expressed in terms of mean and standard deviation, and otherwise, median with inter-quartile range was presented. The categorical variables were reported using frequencies and percentages. t-test was used for the analysis of continuous data with normal distribution and Mann–Whitney U-test for data with skewed distribution. The Chi-square test was performed for the categorical variables. To see the difference in VAS score over a period, Generalized Estimating Equations (GEE) analysis was done. All tests were two-sided at the α =0.05 level of significance.


  Results Top


Out of 65 eligible patients, 60 were enrolled in the study and their data included in the final analysis. The consort flow diagram is given in [Figure 1]. The demographics of the two groups were comparable.[Table 1] The patients in Group K received 25.7 ± 6.6 mg of ketamine during their surgery.
Figure 1: Consort flow diagram

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Table 1: The baseline demography of the participants enrolled in the two groups and the monitored variables

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The “wake-up” time was 7.6 ± 3.78 min for Group C and 7.9 ± 6.07 min for Group K. The intraoperative morphine requirement was significantly (P = 0.006) higher for those in Group C (7.67 ± 1.7 mg) compared to the patients in Group K (6.5 ± 1.5 mg). The pain was well controlled in the study population, and the pain score was comparable between the two groups at all time points during the first 24 hour after surgery [Figure 2]. The GEE analysis did not show any statistically significant difference in VAS score between the two groups over a period of 24 h (P = 0.080). During the 24-h postoperative period, the morphine requirement was higher in Group C (9.2 ± 4.5 mg) compared to Group K (7.87 ± 4.7 mg), but this difference was not statistically significant. Postoperatively, the median time to the first dose of morphine was 345 min for Group K compared to 240 min for Group C. However, due to the wide variation, this difference was not statistically significant. The number of patients who received rescue analgesia (ketorolac 30 mg) was similar between the two groups (n = 9).
Figure 2: Pain score (Visual Analog Scale 0–10) at various time intervals during the first 24-h postoperative perio

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The depth of sedation was comparable between the groups at all time points during the first 24 h. The incidence of hallucination and nystagmus was high in the ketamine group which was statistically significant with the P = 0.021 and 0.003, respectively [Table 2]. Both these side effects were noted only during the first 2 h after extubation. Although a greater number of patients in ketamine group had postoperative nausea and vomiting (PONV) compared to placebo, it was not statistically significant [Table 2]. Regarding the level of satisfaction, 11 (36%) patients in Group K and 5 (16%) in Group C graded it “good” while the rest graded it “moderate.” This difference was not statistically significant (P = 0.14). None of the participants graded their level of satisfaction as “poor.”
Table 2: Incidence of adverse effects between the two groups

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  Discussion Top


This randomized, placebo-controlled clinical trial has shown that the administration of a bolus and infusion of low-dose ketamine in patients undergoing open hysterectomy significantly decreased the intraoperative requirement of morphine. Although, the dose of morphine needed during the first 24 h after surgery was also reduced, it was not statistically significant. Snijdelaar et al.[7] used a low-dose infusion of S-ketamine during the surgery and continued it postoperatively as a patient-controlled analgesia (PCA) and were able to demonstrate a decrease in morphine requirement of 25 mg. Since the use of ketamine infusion in an unmonitored ward is not the usual practice in our institution, it was not continued postoperatively. Therefore, it is evident from this study that the benefits of the administration of racemic ketamine during the surgery do not extend into the postoperative period to counteract the nociceptive inputs continuing during the postoperative period. Another reason for this difference could be that racemic ketamine is half as potent compared to s-ketamine.[8]

Inadequate control of postoperative pain has shown to stimulate the endocrine and the sympathetic nervous system leading to a stress response resulting in poor wound healing and delayed discharge from the hospital.[1],[2] It may also lead to a chronic pain syndrome. Since nociceptive inputs from the surgical wound continue during the postoperative period, the repeated stimulation of the dorsal horn neurons of the spinal cord leading to central sensitization.[7] This has been shown to be mediated through NMDA receptor activation. Ketamine, being an NMDA receptor antagonist, would prevent this central sensitisation, thereby helps in treating both acute[3],[4],[5],[6] and chronic pain.[9],[10]

Ketamine in anesthetic doses produces profound analgesia, but it has psychedelic side effects, which may be dose dependent.[11] Several studies have demonstrated the role of NMDA receptor antagonist in the postoperative pain relief and this has rekindled the interest in use of ketamine.[3],[4],[6],[12] Studies have shown that the administration of even a single dose before surgery reduces the opioid requirement, has antidepressant effects, and improves patient satisfaction.[13],[14],[15] Similar to other reports, this study has also demonstrated a significant reduction in intraoperative opioid requirement and improved patient satisfaction with a low dose of ketamine.[3],[4],[5],[7],[16]

However, it did not reduce the requirement of morphine postoperatively. One of the reasons could be the intermittent bolus administration of a fixed dose of morphine instead of the use of an IV PCA for postoperative pain control, which could have delineated the difference in morphine requirement more precisely.

Ketamine in anesthetic dose (1–2 mg/kg) is associated with sedation and sympathetic stimulation.[17] However, in the subanesthetic doses as used in this study, these side effects were not clinically significant as demonstrated by no delay in “wake-up” time and comparable hemodynamic vital signs to those in Group C. Group K had a higher incidence of PONV, but it was not statistically significant. However, other side effects such as hallucinations and nystagmus were more frequent among those who received ketamine, but these were short-lasting. Clattenburg et al.[18] also found similar results.

Limitations of this study

  1. Since the postoperative morphine requirement was low, a larger sample size would be needed to show a statistically significant difference between the two groups
  2. The use of a PCA to administer morphine for postoperative analgesia could have better delineated the morphine requirement between the two groups.


This study has brought out a question whether the postoperative morphine requirement would have been decreased if an infusion of low-dose ketamine were to be continued into the postoperative period. As per current standard of care, this would require the patient be monitored in a high-dependency unit and consequently increasing the cost of hospitalization and manpower. Further studies could try to answer the question and to investigate if an infusion of low-dose ketamine is safe to be administered to a postoperative patient being managed in a hospital ward.


  Conclusion Top


The administration of a low-dose ketamine before induction of anesthesia and continued as an infusion during the intraoperative period reduces the morphine requirement intraoperatively but does not significantly reduce the postoperative morphine requirement.

Financial support and sponsorship

Internal Fluid research grant was obtained to conduct the study (IRB minute number 5587).

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Gan TJ. Poorly controlled postoperative pain: Prevalence, consequences, and prevention. J Pain Res 2017;10:2287-98.  Back to cited text no. 1
    
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Sinatra R. Causes and consequences of inadequate management of acute pain. Pain Med 2010;11:1859-71.  Back to cited text no. 2
    
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Brinck EC, Tiippana E, Heesen M, Bell RF, Straube S, Moore RA, et al. Perioperative intravenous ketamine for acute postoperative pain in adults. Cochrane Database Syst Rev 2018;12:CD012033.  Back to cited text no. 3
    
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Jouguelet-Lacoste J, La Colla L, Schilling D, Chelly JE. The use of intravenous infusion or single dose of low-dose ketamine for postoperative analgesia: A review of the current literature. Pain Med 2015;16:383-403.  Back to cited text no. 4
    
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Guillou N, Tanguy M, Seguin P, Branger B, Campion JP, Mallédant Y. The effects of small-dose ketamine on morphine consumption in surgical intensive care unit patients after major abdominal surgery. Anesth Analg 2003;97:843-7.  Back to cited text no. 5
    
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Wang L, Johnston B, Kaushal A, Cheng D, Zhu F, Martin J. Ketamine added to morphine or hydromorphone patient-controlled analgesia for acute postoperative pain in adults: A systematic review and meta-analysis of randomized trials. Can J Anaesth 2016;63:311-25.  Back to cited text no. 6
    
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Snijdelaar DG, Cornelisse HB, Schmid RL, Katz J. A randomised, controlled study of peri-operative low dose s(+)-ketamine in combination with postoperative patient-controlled s(+)-ketamine and morphine after radical prostatectomy. Anaesthesia 2004;59:222-8.  Back to cited text no. 7
    
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Arendt-Nielsen L, Nielsen J, Petersen-Felix S, Schnider TW, Zbinden AM. Effect of racemic mixture and the (S+)-isomer of ketamine on temporal and spatial summation of pain. Br J Anaesth 1996;77:625-31.  Back to cited text no. 8
    
9.
Cohen SP, Bhatia A, Buvanendran A, Schwenk ES, Wasan AD, Hurley RW, et al. Consensus guidelines on the use of intravenous ketamine infusions for chronic pain from the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists. Reg Anesth Pain Med 2018;43:521-46.  Back to cited text no. 9
    
10.
Kang C, Cho AR, Kim KH, Lee EA, Lee HJ, Kwon JY, et al. Effects of intraoperative low-dose ketamine on persistent postsurgical pain after breast cancer surgery: A prospective, randomized, controlled, double-blind study. Pain Physician 2020;23:37-47.  Back to cited text no. 10
    
11.
Rajan S, Hassain A, Puthenveettil N, Kumar L. Efficacy and safety of low-dose ketamine as an adjunct analgesic and amnesic during caesarean section under general anaesthesia. Indian J Anaesth 2015;59:653-7.  Back to cited text no. 11
[PUBMED]  [Full text]  
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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. 12
    
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Kasputytė G, Karbonskienė A, Macas A, Maleckas A. Role of ketamine in multimodal analgesia protocol for bariatric surgery. Medicina (Kaunas) 2020;56:96. doi:10.3390/medicina56030096.  Back to cited text no. 13
    
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Zanos P, Moaddel R, Morris PJ, Riggs LM, Highland JN, Georgiou P, et al. Ketamine and ketamine metabolite pharmacology: Insights into therapeutic mechanisms. Pharmacol Rev 2018;70:621-60.  Back to cited text no. 14
    
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Katz J. Pre-emptive analgesia: Evidence, current status and future directions. Eur J Anaesthesiol Suppl 1995;10:8-13.  Back to cited text no. 15
    
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Guignard B, Coste C, Costes H, Sessler DI, Lebrault C, Morris W, et al. Supplementing desflurane-remifentanil anesthesia with small-dose ketamine reduces perioperative opioid analgesic requirements. Anesth Analg 2002;95:103-8.  Back to cited text no. 16
    
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Kohrs R. Ketamine: Teaching an old drug new tricks.-PubMed-NCBI [Internet]. Available from: https://www.ncbi.nlm.nih.gov. [Last accessed on 2020 May 18].  Back to cited text no. 17
    
18.
Clattenburg EJ, Hailozian C, Haro D, Yoo T, Flores S, Louie D, et al. Slow infusion of low-dose ketamine reduces bothersome side effects compared to intravenous push: A double-blind, double-dummy, randomized controlled trial. Acad Emerg Med 2018;25:1048-52.  Back to cited text no. 18
    


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