COMPARATIVE STUDY OF THE EFFECTS OF INTRAOPERATIVE INFUSION OF LOW DOSE KETAMINE AND MAGNESIUM ON CONTROLLING POST OPERATIVE PAIN AND POST OP OPIOID CONSUMPTION AMONG THE PATIENTS UNDERGOING ORTHOPAEDIC SURGERIES AT DGH TRINCOMALEE
SUPERVISOR
Dr. Herath R. M. H. M. A. I. Consultant Anaesthetist. DGH Trincomalee
INVESTIGATORS Dr. Rimaz S. N. A. Dr. Nusra M. A. F Dr. Amarasooriya S.C. Dr. Cowshika K.TABLE OF CONTENTS1. INTRODUCTION
1.1 Background
Pain is defined as “An unpleasant sensory and emotional experience associated with actual orp otential tissue damage”. Postoperative pain is the commonest reason for delayed discharge and unanticipated hospital admission after ambulatory surgery.1
When pain is not treated accordingly it will become persistent, a vicious cycle of increasing disability and distress can occur2.Therefore alleviating the surgical pain from perioperative period will break the vicious cycle. Provision of multimodal analgesia with conventional opioids,
non-steroidal anti-inflammatory drugs, peripheral nerve blocks, intrathecal and epidural analgesics, ketamine are widely in use.
Shoulder surgery, elbow/hand surgery, were identified as the some procedures causing most
moderate to severe pain at 24 hr.1 As orthopaedic surgeries cause moderate to severe pain,provision of high doses of opioids in post-operative period leads to over dosage.
Delayed hyperalgesia may be produced by acute exposure to large doses of opioids. Tolerance to opioids is dose-dependent. Possible mechanisms for tolerance include alterations of the NMDA receptors
and its intracellular second messenger systems. In this regard, NMDA receptor antagonists such
as ketamine and magnesium block opioid tolerance1. Therefore to reduce post operative
consumption of opioids adding non opioid analgesics like Ketamine and Magnesium Sulphate
(Mg) is beneficial3.
NMDA receptors are ligand-gated ion channels that are unique in that channel activation requires
binding of the excitatory neurotransmitter, glutamate with glycine as an obligatory coagonist.
Ketamine inhibits activation of NMDA receptors by glutamate and decreases presynaptic release
of glutamate. In addition, Ketamine exerts effects at other sites including opioid receptors,
monoaminergic receptors, voltage-sensitive sodium and L-type calcium channels and neuronal
nicotinic acetylcholine receptors as well. Magnesium has anti nociceptive effects possibly due to
inhibition of calcium influx, antagonism of NMDA receptors and prevention of NMDA
signaling.
As pain is subjective, valid and reliable assessment of pain is essential for both clinical trials and
effective pain management. The nature of pain makes objective measurement impossible. Acutepain can be reliably assessed, both at rest (important for comfort) and during movement
(important for function and risk of postoperative complications), with one-dimensional tools
such as numeric rating PAIN scales (NRPS) or visual analogue scales (VAS). Both these are
more powerful in detecting changes in pain intensity than a verbal categorical rating scale. In
acute pain trials, assessment of baseline pain must ensure sufficient pain intensity for the trial to
detect meaningful treatment effects.7
1.2 Justification of study
There was a significant reduced post operative consumption of morphine by using low dose
ketamine infusion intra operatively. And the side effects such as hallucination, sedation,
headache, dizziness, respiratory depression and/or emergent reaction are less with the low rate of
infusion.5
Ketamine has been widely used as an adjuvant analgesic in a variety of perioperative pain
settings. Reductions of up to 20–25% in pain intensity and 30–50% in analgesic consumption up
to 48 h after surgery have been reported. An associated reduction in opioid-related adverse
effects such as decreased PONV was found.6
The provision of intraoperative analgesic with low dose of Ketamine and Mg are currently in
practice in other countries of world. Usage of those in SriLanka and peripheral hospitals like in
DGH Trincomalee is very minimal. Therefore it is a better timeline intervention to conduct this
research to asses and compare the effects of both Ketamine and Mg infusion the provide a
multimodal analgesia intraoperatively and gain a good outcome of reducing post operative opioid
consumption and its side effects like respiratory depression, nausea and vomiting2. LITERATURE REVIEW
This study is to assess the effectiveness of low dose of Ketamine and Magnesium sulphate
infusion on controlling the post-operative pain and opioid consumption. There are many
randomized controlled trials and systemic reviews on this aspect.
Perioperative intravenous magnesium sulfate at very high doses has been reported to reduce
postoperative morphine consumption but not postoperative pain scores (Albrecht et al., 2013)
Perioperative infusion of Mg was associated with a decrease in postoperative opioid
consumption and a decrease in visual analog scale pain scores up to 4-6 hours after surgery
(Murphy et al. 2013) In lower abdominal surgery with magnesium supplementation, patients
required 30% less morphine in the postoperative period compared with control patients (Albrecht
et al. 2013) and also post-operative use of magnesium sulfate reduces opioid consumption for
pain after thoracotomy operations (De Oliveira et al.2013)
Usage of ketamine bolus dose (0.2 mg/kg) intravenously, followed by continuous infusion of
ketamine (0.05 mg/kg/h) decreased postoperative pain and analgesic consumption in the first 48
hours after surgery along with longer pain free period compared to patients who were given
magnesium sulfate bolus dose (50 mg/kg) intravenously, followed by continuous infusion of
magnesium sulfate (10 mg/kg/h).(Ibrahim et al., 2020)
The total consumption of morphine, and additional analgesic requirements were less, while the
satisfaction level of patients were higher when using Ketamine. Ketamine is still one of the most
advantageous adjuvant drugs for treating postoperative pain. (Arikan M et al,2016). Low-dose
ketamine should be used in painful orthopaedic surgical procedures, especially total joint
replacement, as it shows an opioid-sparing effect at 24 and 48 h, and decreased pain perception
at 48 h. A suggested dose based on the evidence is 0.5 mg /kg bolus; longer procedures (>90
min) might warrant an infusion of 2-5 microgram/ kg/ min.
Though we have plenty of trials and reviews on the effects of low dose infusion of Ketamine and
Mg as their usage are very well implemented in those countries, in our country there is lack of
evidence for their usage in controlling post operative pain and opioid consumption.3. OBJECTIVES
3.1 General objective:
To compare the effects of intra operative usage of intravenous low dose infusion of Ketamine
and Mg on controlling the post operative pain and post operative opioid consumption among the
patients undergoing orthopedic surgeries at DGH Trincomalee
3.2 Specific Objectives
1. To assess the effects of intra operative IV low dose Ketamine infusion on post operative pain.
2. To assess the effects of intra operative IV low dose Ketamine infusion on post operative
opioid consumption
3. To assess the effects of intraoperative infusion of Mg on post operative pain.
4. To assess the effects of intraoperative infusion of Mg on post operative opioid consumption.
5. To compare the effects of both low dose of Ketamine infusion and Mg infusion in alleviating
post operative pain and opioid consumption.
6. To compare the effects of both Ketamine and Mg infusion to the effects conventional
morphine on requirement of post operative opioid consumption.4. METHEDOLOGY
4.1 Study design
Prospective …………….
4.2 Study area
This study is going to be conducted among the orthopaedic patients who is awaiting for surgeries
in Trincomalee District.
4.3 Study period
This study is going to be conducted from January 2022 to ……
4.4 Study population
This study is to assess the effect of intra operative intravenous Ketamine and Mg infusion on
post operative pain and opioid consumption. So this study includes the population of patients
waiting for orthopedic surgeries who needs General Anesthesia for the relevant surgeries.
4.4.1 Inclusion criteria
All male and female, ASA I – II, Orthopedic surgical patients awaiting surgeries under
GA at DGH Trincomalee Operation theatre
4.4.2 Exclusion criteria
1. Patients who deny giving consent for study.
2. Patients who deny giving consent for General Aneasthesia.
3. Patients with ASA III and more than III
4. Previously participated study participants will be excluded from the second chance.
5. Pediatric patients with Age less than 18years.
6. Patients who are waiting for short surgical procedures.4.5. Sampling
4.5.1 sample size
N = Z2 x P (1-P) / d2
N - Sample size
Z - Z value for 95% confidence interval (1.96)
P - Anticipated population proportion ()
d - Precision (0.05)
N = Z2 x P (1-P) / d2
N = (1.96)2 x () / (0.05)2
4.5.2 Sampling method
DGH Trincomalee is the only institution where subspecialty of orthopedic surgery is
available for the Trincomalee District. So the study population of all the orthopedic
patients who are waiting for their surgeries to be done have to go undergo pre-operative
assessment through the anesthetic team of DGH Trincomalee. So all eligible samples
will to be collected.
4.6 study instruments
1. Post-operative Pain assessment through 100mm numeric rating pain scale (NRPS).
2. Questionnaires for patients’ socio demographic data with the informed written consent for the
participation of study.
3. Questionnaire includes the vital parameters indicating pain such as HR, BP, RR and NRS score
which is assessed at the post op period of 0, 4, 8, 12 and 24hours.4.8. Data collection method
Study population is randomly divided into 3 groups. One group who is going to have intra operative
low dose of ketamine infusion (K group), second one is going to have intravenous Magnesium
infusion (M group) and third group will be receiving conventional morphine (control group).
During pre operative assessment by the anaesthetic team, if a patient accepts for the study with the
consent, NRPS will be explained by the researchers and the socio demographic data will be
collected. Once the surgery is over, at the postoperative interval of 0, 4, 8, 12 and 24 hours pain will
be assessed. Meanwhile the opioid usage and the dosage given at post op period will be added to the
data.
4.9 Data Analysis
After completing data collection, data will be entered using Microsoft Excel software. A coding
system will be used to convert the raw data in to a processor friendly mode. After reviewing all the
questionnaires modifications will be done to the coding system to enhance effectiveness..
Then entered data will be applied in to calculations to derive scientific meaningful inferences.
Percentages and proportions will be calculated using counts. Design of the research requires a
statistical data analyzer that is designed to perform well with population based data. Therefore
Statistical Package for Social Sciences (SPSS) software will be used for the analysis of data as well
as manual calculations.5. ETHICAL CONSIDERATION
5.1. Ethical clearance
Research proposal will be submitted to the ethical review committee through the department of
community and family medicine, faculty of health care and sciences, university of Batticaloa and
the ethical clearance will be obtained to carry out this research project.
Then the permission for the data collection will be obtained from the director DGH Trincomalee
and the Consultant Orthopedic Surgeon.
Informed written consent forms will be provided to each study participants. Consent form will
provide information of Purpose of the study, Expected duration, Participant’s right to withdraw
from study whenever preferred, Research benefits and Potential risks, and the Limits of
confidentiality. The patients may withdraw their consent at any point of the research. Their
decision to withdraw consent will be respected if a patient refuses to take part in the study.
5.2. Confidentiality
5.2.1. Ensuring Confidentiality
Confidentiality will be maintained throughout the study and the data will not be given to
any third party. Confidentiality of all records is guaranteed and they will go by a serial
number and not by name.
5.2.2. Access to personal data
The principal investigators and the supervisor will have access to data collected during
the study.
5.5.3.Storage of Data
The filled questionnaires and consent forms will be stored safely in a safety locker with
one principal investigator having access for one year from the data collection date. Also,
the information will be stored in a personal computer of one principal investigator in a
password protected folder for one year from data collection date.
5.5.4.Data Disposal
The filled questionnaire forms will be disposed by burning after one year from the data
collection date6. References
1. McGrath B. Elgendy H. Chung F. Kamming Curti.B. King.S. Thirty percent of patients have moderate to severe pain 24 hr after ambulatory surgery: a survey of 5,703 patients. Can J Anesth 2004; 51: 886–91
2. Wilkinson P. Pain management programme (bja) BJA vol 17, issue 1, jan 2021pages 10 – 15 3. Mohamed Elaysed Hassan. Effects of magnesium sulphate with ketamine infusion on
intraoperative and post operative analgesia in in cancer breast surgeries: a randomized double trial
4. Yu-Ning Peng, MD, Fung-Chang Sung, PhD, The use of intravenous magnesium sulfate on postoperative analgesia in orthopedic surgery. A systematic review of randomized controlled trials 5. Sarvjeet Kaur. Effect of intraoperative infusion of low-dose ketamine on management of postoperative analgesia
6. Shankar Ramaswamy. Non-opioid-based adjuvant analgesia in perioperative care. Continuing Education in Anaesthesia, Critical Care & Pain j Volume 13 Number 5 2013
7. H. Breivik. Assessment of pain, British Journal of Anaesthesia 101 (1): 17–24 (2008)
8. Muge Arikan, Bilge Aslan, Osman Arikan. Comparison of the effects of Magnesium and Ketamine on post-operative pain and morphine consumption. A double blind randomized controlled clinical study, Acta Cirurgica Brasileira - Vol. 31 (1) 2016 - 67
9. Mark Riddell. J. Low-dose ketamine in painful orthopaedic surgery: a systematic review and meta-analysis: British Journal of Anaesthesia, 123 (3): 325 - 334 (2019)
10. Murphy J.D, Paskaradevan J: Analgesic efficacy of continuous intravenous magnesium infusion as an adjuct to morphine for postoperative analgesia: A systemic review and meta analysis. M. E. J. Anaesth 22(1), 2013
11. Albrecht E, Kirkham K. R,: Peri operative intravenous administration of Magnesium sulphate and postoperative pain: a meta analysis. Anaesthesia 68, 79–90, 2013.
12. Ibrahim A.E.R.M, Tarek A.E.S.S.: Comparative study between intravenous Ketamine or Magnesium sulfate or both on postoperative morphine consumption after major abdominal surgery: Al-Azhar Med. J( Medicine ) Vol. 49(4), October, 2020, 1965 - 1980