
==== Front
Indian J Crit Care Med
Indian J Crit Care Med
IJCCM
Indian Journal of Critical Care Medicine : Peer-reviewed, Official Publication of Indian Society of Critical Care Medicine
0972-5229
1998-359X
Jaypee Brothers Medical Publishers

39130399
10.5005/jp-journals-10071-24734
Original Article
Quantium Consciousness Index and Quantium Noxious Index in Ketamine Subdose Administration Compared with Fentanyl and Midazolam in Postoperative ICU Patients: A Prospective, Observational Study
Masharto Alegra R 1https://orcid.org/0000-0002-6596-5263

Lubis Andriamuri P 2https://orcid.org/0000-0002-1962-3799

Bangun Chrismas G 3https://orcid.org/0009-0009-5236-8898

Wahyuni Arlinda S 4https://orcid.org/0000-0002-5265-4685

1–3 Department of Anesthesiology and Intensive Care, Faculty Medicine, Universitas Sumatera Utara, Medan, Indonesia
4 Department of Community Medicine, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia
Andriamuri P Lubis, Department of Anesthesiology and Intensive Care, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia, Phone: +62 8126078194, e-mail: andriamuri@usu.ac.id
6 2024
31 5 2024
28 6 581586
21 2 2024
08 5 2024
Copyright © 2024; The Author(s).
2024
https://creativecommons.org/licenses/by-nc/4.0/ © The Author(s). 2024 Open Access. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted use, distribution, and non-commercial reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Abstract

Aims and background

In postoperative patients in the intensive care units (ICUs), not only analgesics are needed but also sedation so that the patient can remain calm during treatment, especially patients with mechanical ventilation. By using the measurement parameters of the quantum consciousness index (qCON) and quantum noxious index (qNOX) in measuring the depth of sedation and adequacy of analgesics, the use of subdose ketamine instead of fentanyl and midazolam as sedative, analgesic agents can be performed as a new alternative to nociceptive monitoring methods with more objective results. This study aims to obtain results of comparing qCON and qNOX in postoperative patients by administering subdose ketamine compared with a combination of fentanyl and midazolam in RSUP Haji Adam Malik Medan.

Materials and methods

A randomized clinical trial with a double-blind approach has been used in this study. A total of 44 experimental samples were gathered and randomly split into two groups after meeting the criteria for inclusion. Group A administered a ketamine subdose, whereas Group B administered a mixture of fentanyl and midazolam. The research data obtained were tested using Statistical Product and Science Service (SPSS).

Results

There were differences in the median, minimum, and maximum values of qCON and qNOX in the groups given subdose ketamine and fentanyl and midazolam, but these were not statistically significant (p > 0.05) at T0, T1, and T2.

Conclusion

Administering a subdose of ketamine can provide sedation and analgesia comparable to fentanyl and midazolam.

How to cite this article

Masharto AR, Lubis AP, Bangun CG, Wahyuni AS. Quantium Consciousness Index and Quantium Noxious Index in Ketamine Subdose Administration Compared with Fentanyl and Midazolam in Postoperative ICU Patients: A Prospective, Observational Study. Indian J Crit Care Med 2024;28(6):581–586.

Keywords

Fentanyl
Intensive care units
Ketamine
Midazolam
Postoperative
qCON
qNOX
Subdose
==== Body
pmcHighlights

This study uses primary data, which is homogeneous based on the normality test, so it is considered appropriate to represent the population and reduce research bias. It was considered not to have much influence on hemodynamics. It was proven that there appeared to be no significant difference between the two groups.

Introduction

Postoperative patients often experience various problems, one of which is pain, with nearly 5 million postoperative patients being treated in intensive care units (ICUs) annually, and it estimated that 71% of these patients stated that they experienced pain while in treatment.1,2 It is important to note that, leading to increased patient morbidity and mortality, improper pain management in critical patients can increase respiratory, metabolic, and infectious complications, while, on the other hand, adequate pain management is linked to a relatively short duration of mechanical breathing, decreased nosocomial infection rates, and increased patient satisfaction with pain control.3,4

In a recent study, the use of the following tool is considered to be more objective because it shows a number/index, while the previous assessment of pain and sedation was carried out by subjective physical examination, where it was stated that the measurement of quantum consciousness index (qCON) and quantum noxious index (qNOX) is considered to be similar to Critical Care Pain Observation Tool or Ramsay Agitation Sedation Scale as a measure of sedation depth and analgesic adequacy. Conox is using electroencephalography (EEG) data as a new alternative to nociceptive monitoring methods, where the first parameter is qNOX to provide information about the depth of analgesia, and the second parameter is qCON to determine the depth of anesthesia which is similar to the bispectal index or entropy score.5,6

A common method for controlling postoperative pain is the use of either bolus opioids or patient controlled analgesia (PCA) for postoperative pain control. Fentanyl was the most common analgesic agent used followed by Tramadol and Paracetamol.7,8 However, as we know, the side effects of opioids are very large and have an impact on the length of treatment and patient recovery, so recent research using subdose ketamine shows that this drug can be a substitute for opioids with fewer side effects and is more cost-effective than opioids which are more difficult to access at the regional hospital.9

Therefore, based on the explanation above, we hope this study can assess qCON and qNOX in postoperative patients with subdose ketamine administration compared with patients with a combination of fentanyl and in the ICU of RSUP HAM. It is hoped that in this study, the authors can provide new sources and fresh air for further research and monitor future progress in providing analgesic sedation especially in postoperative patients in the ICU.

Materials and Methods

This is an analytic experimental study with a double-blind, randomized prospective cohort study method (double-blind randomized) with primary data sources obtained directly from examining patients in the ICU of RSUP HAM.

Research data were collected in the ICU room of H Adam Malik General Hospital from January to March 2023 in postoperative patients who had been intubated and met the inclusion criteria, implementing successive sampling until the number of study subjects was met. Randomization was carried out by volunteers using the randomization method. By splitting 44 people into two groups of 22 individuals each, a total of 44 samples were recorded. This study used the primary data followed, where Group A was given a subdose of ketamine and Group B was given a combination of fentanyl and midazolam.

The independent variable in this study was the administration of subdose ketamine with a combination of fentanyl and midazolam. At the same time, the dependent variable is the value of qCON and qNOX. Characteristics of the subjects in this study included age, sex, height, weight, body mass index (BMI), length of operation, and Physical Status-American Society of Anesthesiologist (PS-ASA).

For demographic data, descriptive statistical analysis using the Kolmogorov–Smirnov test was employed. Chi-square statistical analysis was performed for categorical data, while the t-test or Mann–Whitney U-test was executed for numerical data. An ANOVA test was then undertaken between the variables. The research data were statistically evaluated using the Windows Statistical Product and Science Service (SPSS) version 22.0. At p < 0.05, differences were considered statistically significant.

Results

Based on 44 respondents, there were 11 neurosurgery patients in the subdose ketamine group, 5 ob-gyn patients, 3 digestive surgery patients, 1 plastic surgery patient, 1 thoracic surgery patient, and 1 orthopedic surgery patient. Whereas in the fentanyl–midazolam group, there were 11 neurosurgery patients, 5 digestive surgery patients, 4 ob-gyn patients, 1 orthopedic surgery patient, and 1 urological surgery patient with a transfer range from completion of surgery to arrival at the ICU of 5–30 minutes.

Normal distribution numeric data are shown in mean ± SD. Numerical data with non-normal distribution are displayed in the median with minimum and maximum values. In this study, the characteristics of the research subjects were based on age with a p-value of 0.445, based on gender with a p-value of 0.750, based on height with a p-value of 0.145, based on weight with a p-value of 0.110, based on BMI with a p-value of 0.183, based on length of action with p-value = 0.887, and based on PS-ASA with p-value of 1.000. Showing that the subdose ketamine group and the fentanyl–midazolam group are homogeneous, so they are worth comparing (Table 1), it was found, based on the normality test of the above, that there were no significant differences in the two groups in terms of age, sex, height, weight, BMI, duration of action, and PS-ASA.

Table 1 Characteristics of research subjects

Subject	Ketamine subdose	Fentanyl–Midazolam	p-value	
N = 22	N = 22	
Age	
  Mean ± SD	50.9 ± 13	46 ± 16.9	0.445*	
  Median	51	49	
  Range (min.–max.)	23.00−65.00	20.00−65.00	
Gender	
  Man	7	8	0.750*	
  Woman	15	14	
Height (cm)	
  Mean ± SD	162 ± 7.5	159 ± 6	0.145*	
  Median	162	160	
  Range (min.–max.)	150−173	150−172	
Weight (kg)	
  Mean ± SD	65.5 ± 9.89	59.1 ± 6.9	0.110*	
  Median	65	60	
  Range (min.–max.)	44−90	40−70	
BMI	
  Mean ± SD	24.7 ± 2.96	23.4 ± 2.5	0.183*	
  Median	24.35	23.5	
  Range (min.–max.)	19.00−33.00	17.3−26.6	
Action time (minutes)	
  Mean ± SD	218.6 ± 155.8	241 ± 177	0.887*	
  Median	150	180	
  Range (min.–max.)	60−720	60−600	
PS-ASA	
  III	22	22	1,000*	
*Independent t-test. BMI, body mass index; PS-ASA: Physical Status-American Society of Anesthesiologist

Systolic blood pressure, diastolic blood pressure, mean arterial pressure (MAP), heart rate, respiratory rate, and oxygen saturation have all been measured in this study. T0 is when both groups are 0 hours after drug administration, T1 is when both groups are 12 hours after drug administration, and T2 is when both groups are 24 hours after drug administration. In both treatment groups, from the baseline value (T0) of the hemodynamic variables it can be seen that there is no significant difference (Table 2).

Table 2 Hemodynamic change status table

Hemodynamic parameters	Ketamine subdose N = 22	Fentanyl + Midazolam N = 22	p.s	
Systolic (mm Hg)	
  0 hours after drug administration	129.1 ± 21.5	127.8 ± 22.2	0.843*	
  12 hours postoperatively	127.1 ± 19.0	124.0 ± 21.5	0.611*	
  24 hours postoperation	125.5 ± 17.3	120.0 ± 17.5	0.323*	
Diastolic (mm Hg)	
  0 hours after drug administration	72.8 ± 11.3	81.5 ± 15.0	0.037*	
  12 hours postoperatively	75.0 ± 9.4	77.7 ± 16.9	0.513*	
  24 hours postoperation	76.5 ± 10.2	73.2 ± 12.4	0.335*	
MAPs (mm Hg)	
  0 hours after drug administration	90.0 ± 15.9	94.2 ± 15.7	0.381*	
  12 hours postoperatively	92.5 ± 11.7	91.1 ± 17.8	0.751*	
  24 hours postoperation	92.5 ± 11.2	87.5 ± 12.5	0.168*	
Pulse rate (x/min)	
  0 hours after drug administration	97 ± 14.1	92.5 ± 21.1	0.403*	
  12 hours postoperatively	95.5 (61–126)	98 (60–149)	0.549**	
  24 hours postoperation	91.2 ± 15.2	96.4 ± 21.0	0.355*	
*Independent t-test

Researchers then measured the sedation parameter variables, which included qCON and qNOX in the two treatment groups at T0, T1, and T2 after drug administration. The two groups, both given subdose ketamine, and fentanyl–midazolam, had mean qCON and qNOX values that were not much different, and changes in their values also had a trend of increasing that was not much different in the two groups, as shown in Table 3.

Table 3 Types of sedation given – analgesics to qCON and qNOX values

Sedation parameters – analgesics	T0	T1	T2	
Ketamine subdose	
  qCON	63.5 (39–80)	68 (40–79)	72 (41–79)	
  qNOX	68 (40–78)	70 (42–78)	72 (44–80)	
Fentanyl–midazolam	
  qCON	57.5 (30–78)	68 (40–80)	72 (40–80)	
  qNOX	60 (40–75)	68 (45–79)	70 (42–80)	
qCON, quantum consciousness index; qNOX, quantum noxious index; T0, 0 hours after drug administration; T1, 12 hours after drug administration; T2, 24 hours after drug administration

The researcher then compared, with the Mann–Whitney U-test test, the differences in sedation parameter variables which included qCON and qNOX in both groups. The qCON value on subdose ketamine administration has a median value of 0 hours after administration of the drug 63.5 while in the group fentanyl–midazolam 57.5. As for the value of qNOX on, giving sub dose ketamine has a median value of 0 hours after drug administration 68 while in the group fentanyl–midazolam 60. In both treatment groups, from the baseline value (T0) of the hemodynamic variables, it can be seen that there is no significant difference. The same thing was also found at 12 hours postoperatively (T1) and 24 hours postoperatively (T2) with intravenous analgesic sedation drugs. It appears that there is no significant difference in the values of qCON and qNOX in the two groups on postmedication T0, T1, and T2 measurements (p > 0.05).

Side effects reported in this study, such as postoperative nausea-vomiting (PONV), nausea, vomiting, and emergence reactions, and that were mainly related to the sub dose of ketamine and the use of opioids, were also not found. Using a rescue dose of the analgesic Paracetamol drips 1000 mg was also not used because all respondents did not reach qNOX >80 (Table 4).

Table 4 Comparison of changes in qCON and qNOX values between groups

Sedation parameters	Ketamine subdose N = 22	Fentanyl – Midazolam N = 22	p.s	
qCON	
  0 hours after drug administration	63.5 (39–80)	57.5 (30–78)	0.052*	
  12 hours postoperatively	68 (40–79)	68 (40–80)	0.472*	
  24 hours postoperation	72 (41–79)	72 (40–80)	1,000*	
qNOX	
  0 hours after drug administration	68 (40–78)	60 (40–75)	0.094*	
  12 hours postoperatively	70 (42–78)	68 (45–79)	0.539*	
  24 hours postoperation	72 (44–80)	70 (42–80)	0.287*	
*Mann–Whitney test. qCON, quantum consciousness index; qNOX, quantum noxious index

Discussion

Following the research of Masharto et al. that the overall postsurgery in the ICU was 18%, with 23% being patients related to nerves, based on 44 respondents in both groups, the majority were 22 neurosurgery patients, 9 ob-gyn patients, and 8 digestive surgery patients, and the rest were plastic surgery, thoracic surgery, orthopedic surgery and urological surgery patients with a transfer range from completion of surgery to arrival at the ICU ranging from 5 to 30 minutes.10

Another study by Harsha et al. showed that of all postoperative patients in the ICU, the majority were neurosurgical 27.58%, followed by gastrosurgical and peripheral surgery patients each 18.39%, ENT surgery 12.64%, thoracic surgery 5.74%, urological surgery 4.59%, and gynecological surgery 2.29%.6

Hemodynamic responses in both groups in this study were in balanced hemodynamic conditions. Hemodynamics can be more stable due to using the CONOX monitor, which, because it uses applied mathematics as a diagnostic and analytical too, measures qCON and qNOX values for objective monitoring of pain and sympathetic responses.11 In line with the study of Jehosua et al., incidents of blood pressure and pulse that exceeded or decreased by 20% from baseline were half as rare as the control group, with the two treatment groups having a mean value of the hemodynamic component that was not much different.5

In most cases, hypotension arises during induction, whereas elevations in blood pressure or heart rate emerge after intubation or extubation. In patients in the ICU, hemodynamic responses can experience turmoil during routine care, installation of life-support devices such as intubation and ventilators, use of NGT, or urine tubes, pain responses due to comorbidities and postsurgery, anxiety, and agitation, which have an impact on direct complications in the form of increased oxygen consumption, lengthening the treatment period, length of recovery, and weaning from the ventilator to post-traumatic stress disorder.6 In general practice, opioid overdose can cause death or disability, while overuse of these drugs can also cause drowsiness, sedation, respiratory distress, urine retention, nausea/vomiting, ileus, or pruritis are all possible outcomes. Early opiate symptoms of withdrawal, such as anxiety, nervousness, lacrimation, nasal congestion, diaphoresis, sleeplessness, frequent yawning, and muscular pains, are also common and may be experienced by patients after discontinuation of a drug overdose. Opioid drug use can increase patients’ risk of addiction and substance use disorders. Late opioid withdrawal symptoms involve diarrhea, stomach cramps, piloerection, nausea, and vomiting, as well as tachycardia, hypertension, pupil dilatation, and impaired vision.5

From the measurement of sedation parameter variables which include qCON and qNOX in the two treatment groups at T0, T1, and T2 after drug administration. The two groups that were given sub dose ketamine and fentanyl–midazolam had mean values of qCON and qNOX that were not much different and changes in their values also had a tendency to increase that was also not much different in the two groups. This shows that both groups’ qCON and qNOX values are at an adequate level for postoperative sedation – analgesia in the ICU, which ranges from 75 to 60, classified as adequate sedation, and being fully responsive to pain stimuli. In fact, according to the Peripheral Arterial Disease Guidelines from AHA/ACC 2016, it is stated that maintaining an adequate dose of light sedation can reduce the time to wean from the ventilator, extubation, and length of ICU stay.12 The qCON and qNOX measurements can detect movement in response to noxious stimuli, while qNOX detects more movement than qCON. This is possible since an increase in qNOX is a straightforward EEG response to noxious stimuli in the form of pain, but a rise in qCON is a subsequent result of stimulation. In a study of 140 patients under general anesthesia who were scheduled to take propofol, the qCON index was found to be better at predicting a loss of consciousness, such as loss of verbal commands and eyelash reflex, than the qNOX index, whereas the qNOX index was found to be better at predicting responses to noxious stimuli. Furthermore, supporting the theory that reaction to stimuli recovers faster than awareness recovery, the qNOX index increased more rapidly at the conclusion of the surgery.13

This study did not show a significant difference in the values of qCON and qNOX in the two groups at the time of measurement 0 hours after drug administration (T0), when both groups were 12 hours after drug administration (T1), and when both groups were 24 hours after drug administration (T2). Both qCON and qNOX are considered to be effective at measuring levels of sedation and pain in intubated patients in the ICU as a way of central nervous system monitoring, which very well predicts noxious stimuli, however, as has been demonstrated with various EEG monitors, this can be influenced by the use of muscle relaxants.6,14

Likewise, the known side effects of ketamine, such as hallucinations, delirium, depression, nightmares, and PONV, did not appear in this study. Following the study by Ali et al., it is even more beneficial in patients who are opioid-dependent and opioid-tolerant but does not rule out the possibility that these psychomimetic side effects increase with stress responses such as acute psychosis, patients with cardiovascular disease, pregnant women with delayed gastric emptying, impaired liver function, increased intracranial pressure, and increased intraocular pressure.15,16

Likewise, in the research of Wang et al., Gelmanas et al. and Samuel et al., however, in our current study, it was proven that the sedation and analgesic effects that resulted from subdose ketamine and fentanyl–midazolam administration did not, without side effects, differ much. This can be a breath of fresh air in the future, bearing in mind that the use of opioids is expected to decrease; in fact, it is still not new to science outside of anesthesiology and intensive care therapy, so the cost of using opioids can be reduced, even replaced, by ketamine which is also more easily found in type C hospitals in remote areas.16–19

In a study by Jehosua et al., it was found that in the group that did not use a CONOX-type EEG monitoring tool, there were more side effects of anesthesia, such as higher intraoperative hemodynamic turmoil, postoperative cognitive disorder, intraoperative awakening, PONV, to moderate to severe pain while in the recovery room.5 Ren et al.'s study showed that the anxiety score (HAD-A) and depression score (HAD-D) in the postoperative group with colorectal cancer who were given subdose ketamine 5 minutes before a single bolus operation also had a higher Quality of Recovery-40 (QoR-40) level, as well as levels of anxiety and depression and IL-6, IL-8, and TNF-α, being lower.20 In other studies, it was also found that postoperative fatigue syndrome (POFS) as measured by the identity consequence fatigue scale, namely complaints such as fatigue, lack of enthusiasm, lack of appetite, sleep disturbances, depressed mood, laziness to move in patients with subdose ketamine seems to improve and so patients recover faster.21

Our research aims to measure pain objectively with a tool that shows the level of pain and awareness based on the appropriate numerical value so that, in addition to using drugs that are more efficient and effective, patients are also expected to recover faster, and the side effects of drugs are more minimal. If not recovered, these patients will resultingly have a longer rehabilitation time, weakening the patient's ability to work, with even difficulty extubating in intubated patients, reducing the quality of life, and increasing patient care costs, especially in patients who are tolerant to opioids and reducing the risk of chronic postoperative pain. In Aribawa et al.'s study, the application of ketamine administration can also be done using the PCA method so that patients can provide analgesics according to the subjective complaints they feel.22,23

Based on the discussion above, this study uses primary data, which is homogeneous based on the normality test, so it is considered appropriate to represent the population and reduce research bias. It was considered not to have much influence on hemodynamics, as most respondents were postoperative neurosurgery patients with a transfer period from the operating room to the ICU ranging from 5 to 30 minutes. Side effects were not found in intubated postoperative patients in the ICU, where, according to the results of statistical tests, it was proven that there appeared to be no significant difference between the two groups. This meant that the use of subdose ketamine was considered equivalent or could replace the fentanyl–midazolam combination. Likewise, in qCON and qNOX measurements at T0, T1, and T2, there were not many significant differences with values ranging from 60 to 75, which means that the patient is still in adequate sedation and has a full pain response. Hopefully, for future research, this scientific work can be a reference for comparing different types of drugs with a larger number of respondents so that there will be more significant comparisons between the two groups, especially in the group given the sedative analgesic drug fentanyl–midazolam compared with subdose ketamine. While there is no controversy so far, although the use of ketamine in patients with intracranial disorders still require more supporting research, which is certainly very much needed, starting from when is the right time to use CONOX, the therapeutic dose that can be used for each patient, and the criteria according to the type of surgery and the patient's condition.

Conclusion

Administering a subdose of ketamine can provide sedation and analgesia comparable to fentanyl and midazolam.

Clinical Significance

The strength of this research is that it is the first time it has been held at Faculty of Medicine Universitas Sumatera Utara; then the assessment of the CONOX tool is objective so that it is very applicable as an assessment of pain and level of consciousness, and the drugs used are also easy to get anywhere. The limitation is that the CONOX device is not yet considered a mandatory assessment for pain and awareness, so the equipment and probes/electrodes must be purchased first.

Authors Contributors

Alegra R Masharto: Conceptualization, Methodology, and Software.

Andriamuri P Lubis: Data curation, Writing – Original draft preparation, and Supervision.

Chrismas G Bangun: Visualization and Investigation.

Arlinda S Wahyuni: Validation, Writing – Reviewing and Editing.

Orcid

Alegra R Masharto https://orcid.org/0000-0002-6596-5263

Andriamuri P Lubis https://orcid.org/0000-0002-1962-3799

Chrismas G Bangun https://orcid.org/0009-0009-5236-8898

Arlinda S Wahyuni https://orcid.org/0000-0002-5265-4685

Source of support: Nil

Conflict of interest: None
==== Refs
References

1. Raja SN Carr DB Cohen M Finnerup NB Flor H Gibson S et al. The revised International Association for the Study of Pain definition of pain: Concepts, challenges, and compromises Pain 2020 161 9 1976 1982 10.1097/j.pain.0000000000001939 32694387
2. Michaelides A Zis P Depression, anxiety and acute pain: Links and management challenges Postgrad Med 2019 131 7 438 444 10.1080/00325481.2019.1663705 31482756
3. Cohen M Quintner J Rysewyk SV Reconsidering the International Association for the study of pain definition of pain Pain Rep 2018 3 2 e634 10.1097/PR9.0000000000000634 29756084
4. Small C Laycock H Acute postoperative pain management Br J Surg 2020 107 2 e70 e80 10.1002/bjs.11477 31903595
5. Jehosua BY Suarjaya IPP Hartawan IU Senapathi TGA The use of CONOX as a guide to the general anesthesia on laparotomy patients compared with standard clinical care – A pilot study Neurol Spinale Med Chir 2021 4 2 51 54 10.36444/nsmc.v4i2.158
6. Harsha MS Bhatia PK Sharma A Sethi P Comparison of quantium consciousness index and richmond agitation sedation scale in mechanically ventilated critically Ill patients: An observational study Indian J Crit Care Med 2022 26 4 493 497 10.5005/jp-journals-10071-24183
7. Deol HS Surani SR Udeani G Inter-rater reliability of the Ramsay Sedation Scale for critically-ill intubated patients Cureus 2019 11 10 e6021 10.7759/cureus.6021 31824789
8. Chawla R Myatra SN Ramakrishnan N Todi S Kansal S Dash SK Current practices of mobilization, analgesia, relaxants and sedation in Indian ICUs: A survey conducted by the Indian Society of Critical Care Medicine Indian J Crit Care Med 2014 18 9 575 584 10.4103/0972-5229.140146 25249742
9. Raff M Belbachir A El-Tallawy S Ho KY Nagtalon E Salti A et al. Intravenous oxycodone versus other intravenous strong opioids for acute postoperative pain control: A systematic review of randomized controlled trials Pain Ther 2019 8 1 19 39 10.1007/s40122-019-0122-4 31004317
10. Masharto AR Lubis B Irina S Correlation between mortality risk factor and death rate of ICU patient in H. Adam Malik Hospital in 2021 Int J Innov Sci Res Technol 2022 7 6 5 11 10.5281/zenodo.6641506
11. Tanggono A Sinardja CD Suarjaya IPP Oxycodone as a replacement to opioid to facilitate tracheal intubation Bali J Anaesthesiol 2020 4 4 208 209 10.4103/BJOA.BJOA_117_20
12. Gerhard-Herman MD Gornik HL Barrett C Barshes NR Corriere MA Drachman DE et al. 2016 AHA/ACC guideline on the management of patients with lower extremity peripheral artery disease: Executive summary: A report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines Circulation 2017 135 12 e686 e725 10.1161/CIR.0000000000000470 27840332
13. Kaur A Mehta N Gupta S Intraoperative nociception monitoring by qNOX score using three different doses of fentanyl JK Sci 2021 23 4 185 190 Available from: https://journal.jkscience.org/index.php/JK-Science/article/view/85
14. Jensen EW Valencia JF Lopez A Anglada T Agustí M Ramos Y et al. Monitoring hypnotic effect and nociception with two EEG-derived indices, qCON and qNOX, during general anaesthesia Acta Anaesthesiol Scand 2014 58 8 933 941 10.1111/aas.12359 24995461
15. Ali H Ismail AA Wahdan AS Low-dose ketamine infusion versus morphine infusion during abdominoplasty to change the postoperative pain profile Anesth Pain Med 2020 10 6 e108469 10.5812/aapm.108469 34150574
16. Wang J Xu Z Feng Z Ma R Zhang X Impact of ketamine on pain management in cesarean section: A systematic review and meta-analysis Pain Physician 2020 23 2 135 148 32214291 32214291
17. Gelmanas A Vitartaite M Tamosiunas R Macas A Low-dose ketamine for acute postoperative pain treatment. Saiz-Sapena N Granell-Gil M Ketamine Revisited – New Insights into NMDA Inhibitors USA IntechOpen 2022 10.5772/intechopen.100415
18. Samuel H Aweke S Tuni J Effect of low-dose intravenous ketamine on postoperative pain following cesarean section under spinal anesthesia: A prospective cohort study, Ethiopia Ann Med Surg (Lond) 2022 77 103570 10.1016/j.amsu.2022.103570 35432988
19. Radvansky BM Shah K Parikh A Sifonios AN Le V Eloy JD Role of ketamine in acute postoperative pain management: A narrative review Biomed Res Int 2015 2015 749837 10.1155/2015/749837 26495312
20. Ren Q Hua L Zhou X Cheng Y Lu M Zhang C et al. Effects of a single sub-anesthetic dose of ketamine on postoperative emotional responses and inflammatory factors in colorectal cancer patients Front Pharmacol 2022 5 13 818 822 10.3389/fphar.2022.818822
21. Zhao L Zhang H Cheng H Effect of a single sub-dose of ketamine on postoperative fatigue syndrome in colorectal cancer patients undergoing radical laparoscopic surgery: A double-blind, pilot study J Affect Disord 2022 1 312 146 151 10.1016/j.jad.2022.06.029
22. Gorlin AW Rosenfeld DM Ramakrishna H Intravenous sub-anesthetic ketamine for perioperative analgesia J Anaesthesiol Clin Pharmacol 2016 32 2 160 167 10.4103/0970-9185.182085 27275042
23. Aribawa IGNM Senapathi TGA Wiryana M Sinardja IK Budiarta IG Widnyana IMG et al. The effectiveness of patient controlled analgesia (PCA) morphine-ketamine compared to patient controlled analgesia (PCA) morphine to reduce total dose of morphine and Visual Analog Scale (VAS) in postoperative laparotomy surgery Bali J Anest 2017 1 2 31 34 10.15562/bjoa.v1i2.11
