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| ORIGINAL ARTICLE |
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| Year : 2022 | Volume
: 23
| Issue : 2 | Page : 131-137 |
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Comparison of ketamine–propofol (ketofol) versus midazolam–fentanyl for procedural sedation and analgesia in emergency care department: An open-label randomized controlled study
K Charishma Begum1, Kingsly Robert Gnanadurai2, Chandrappa Sreekanth2, DS Pushpa Latha3
1 Nandyal Critical Care Center, Nandyal, Andhra Pradesh, India
2 Department of Emergency Medicine, Bangalore Baptist Hospital, Bengaluru, Karnataka, India
3 Department of Anesthesia, Bangalore Baptist Hospital, Bengaluru, Karnataka, India
| Date of Submission | 30-Dec-2021 |
| Date of Decision | 16-Apr-2022 |
| Date of Acceptance | 28-Apr-2022 |
| Date of Web Publication | 29-Oct-2022 |
Correspondence Address:
Dr. K Charishma Begum
Nandyal Critical Care Center, Near Rythu Bazar, Ttd Road, Nandyal - 518 501, Andhra Pradesh
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/TheIAForum.TheIAForum_170_21
Background: Various anesthetic drugs are used for procedures conducted outside the operation theater. Very few studies are done in the emergency department to compare the combination of ketamine and propofol (ketofol) versus midazolam–fentanyl for procedural sedation and analgesia, thus we conducted this study to compare these drug combinations in terms of analgesic and sedation efficacy in the emergency department.
Materials and Methods: A prospective, open-label, randomized, comparative study was conducted on 60 patients, who were randomly assigned to the ketofol and midazolam–fentanyl groups (30 each) to compare these drugs in terms of sedation efficacy using modified Ramsay sedation score, pain scores using Visual Analog Scale, and alteration of hemodynamic, adverse effects such as respiratory distress and nausea. The mean pain score before and after the study was compared using paired t-test, and the difference between the two groups was assessed using Student's t-test. Chi-square test and Fisher's exact test were employed to compare the distribution of qualitative data.
Results: Our study showed that ketofol provides better analgesia as compared to the midazolam–fentanyl group because reduction in Visual Analog Scale scores was 1.27 ± 1.52 (mean ± standard deviation [SD]) in the ketofol group as compared to 3.07 ± 1.25 (mean ± SD) in the midazolam–fentanyl group. Ketofol 4.47±0.73 (mean ± SD) had a better modified Ramsay sedation score when compared to midazolam–fentanyl 3.47±0.90 (mean ± SD). There was reduction in systolic (from 119 ± 18.4 to 113.3 ± 18.81 mmHg) and diastolic blood pressure (from 72 ± 9.61 to 69.67 ± 10.33 mmHg) in the midazolam–fentanyl group during and after the procedure in comparison to the ketofol group where none had hypotension.
Conclusion: Results concluded that ketamine–propofol (ketofol) combination is safe and better in providing adequate analgesia and sedation than midazolam and fentanyl combination in the emergency room.
Keywords: Anesthesia, analgesics, drug combination, emergency department, sedation
How to cite this article:
Begum K C, Gnanadurai KR, Sreekanth C, Pushpa Latha D S. Comparison of ketamine–propofol (ketofol) versus midazolam–fentanyl for procedural sedation and analgesia in emergency care department: An open-label randomized controlled study. Indian Anaesth Forum 2022;23:131-7 |
How to cite this URL:
Begum K C, Gnanadurai KR, Sreekanth C, Pushpa Latha D S. Comparison of ketamine–propofol (ketofol) versus midazolam–fentanyl for procedural sedation and analgesia in emergency care department: An open-label randomized controlled study. Indian Anaesth Forum [serial online] 2022 [cited 2023 Mar 28];23:131-7. Available from: http://www.theiaforum.org/text.asp?2022/23/2/131/359842 |
| Introduction | |  |
Procedural sedation and analgesia play a vital role and are challenging in the emergency department. Many procedures in the emergency room are painful and require analgesia. Procedural sedation and analgesia help in minimizing pain and anxiety of the patient and increase the success rate of the procedure.[1] Many drugs used for procedural sedation and analgesia in the emergency room vary in their duration of action. Hence, duration of sedation and procedure should be considered for administration of adequate dosage and monitoring purpose.[2] The drugs used in common are midazolam, fentanyl, propofol, ketamine, etomidate, and ketamine–propofol combinations. They are used in various combinations to reduce complications and to reach the goals of procedural sedation and analgesia. The standard drug combination used is midazolam and fentanyl. Midazolam is a benzodiazepine sedative and fentanyl is an opioid analgesic. The combination of these drugs has additive effects in adverse events. Ketofol is the combination of ketamine and propofol, in which they antagonize each other's adverse effects. Combination of these two drugs helps in reducing the dosage of drugs required for sedation and also minimizes their respective adverse effects while maintaining sedation efficacy.[3],[4]
Hypothesis of our study was that ketofol provides better sedation and analgesia when compared to midazolam–fentanyl. Hence, the primary objectives of our study were to compare the two groups in terms of sedation efficacy and analgesia. We also compared them in terms of alteration in hemodynamics and incidence of adverse events as secondary objectives.
| Materials and Methods | | |
A prospective, open-label, randomized (sealed opaque envelopes, computer-generated randomization), comparative study was conducted in the emergency department. This study was approved by the institutional review board (Registration number: EM/136/2016), patients or legally authorized relatives were informed about the study procedure, and written informed consent was taken. A total of 60 patients aged more than 18 years, who reported to emergency department with painful conditions, and who required sedation and analgesia for diagnostic or therapeutic management of either gender were included in the study [Figure 1]. Patients with American Society of Anesthesiologists physical status classification Grade more than 3, patients with known allergy to study drugs, increased intracranial pressure, psychosis, or any history of psychiatric illness, or patients on any psychiatric drugs were excluded from the study. Patients were randomized to either of the two groups based on computer randomization; allocation concealment was done using sealed opaque envelopes. Thirty patients were randomly assigned to the ketofol group and thirty patients were assigned to the midazolam–fentanyl group. The procedures which are done in emergency room were fracture–dislocations requiring closed reduction, immobilization, and intercostal chest drainage insertions.
The drug was prepared by the primary investigator in the emergency room. We used a combination of 10 ml of 10 mg/ml ketamine and 10 ml of 10 mg/ml propofol to give 20 ml of ketofol 10 mg/ml. Thus, ketofol 10 mg/ml contains ketamine 5 mg/ml and propofol 5 mg/ml (1:1). Midazolam and fentanyl were loaded in separate labeled syringes. Injection midazolam syringe contained 5 ml (1 mg/ml). Injection fentanyl syringe contained 2 ml (50 μg/ml). Pre procedural assessment was done by principal investigator. It includes heart rate, respiratory rate, blood pressure, oxygen saturation and pain scores. Visual analog scale [Figure 2]a was used to measure pain score. The hemodynamic variables such as heart rate, respiratory rate, and oxygen saturation were measured continuously and blood pressure was measured every 5 min. The time of administration of the drug (TA), time of onset of action (TO), and duration of the procedure (TD) were noted by the staff nurse. Efficacy of sedation was monitored by the principal investigator in accordance with the modified Ramsay sedation score. Visual analog score was measured preprocedure as baseline and postprocedure after recovery of the patient from sedation. Modified Ramsay sedation score was measured during the procedure after onset of sedation. | Figure 2: (a) Visual analog pain distress scale. (b) Mean visual analog pain score comparison
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The dose of ketofol given was 0.75–1.5 mg/kg of each drug in titrated doses to achieve an adequate level of sedation. Midazolam was administered in doses of 0.06–0.1 mg/kg and fentanyl at doses of 1–2 μg/kg. The need for additional boluses was considered the need for additional boluses was considered when there was movement under sedation, grimacing of face, or when adequate sedation and analgesia was not achieved. If adequate sedation was not achieved, midazolam boluses in titrated doses were given. If facial grimacing appears or if patient complains of pain additional boluses of fentanyl was given. Injection naloxone was kept on standby in the crash cart for symptoms of fentanyl overdose. Adverse events during the procedure such as hypotension, desaturation, nausea, vomiting, and agitation were identified by the principal investigator. The hypotension was defined as systolic blood pressure of <90 mmHg. Desaturation was defined as oxygen saturation <92% anytime during the procedure. Hypotension was treated with intravenous fluid boluses of 20 ml/kg. Desaturation was corrected by oxygen supplementation with an oxygen mask. Nausea and vomiting were treated with anti-emetics and emergence reactions with benzodiazepines. After the procedure, the time of sedation was recorded by the staff nurse. It was defined as the time from the first administration of the study drug to the time of first purposeful verbal response by the patient (TF). The time of recovery (TR) was noted when the patient returns to baseline mental status. The hemodynamic variables were checked immediately after completion of the procedure, at the time of first purposeful verbal response and at the time of recovery. Pain scores were measured with visual analog scores after the recovery when the patient returns to baseline mental status. The patients were discharged in stable condition when sensorium returned to baseline level. In the case of complications and adverse events, the patients were treated with appropriate measures as mentioned above. The plan of admission to the hospital was made if there was a failure of the procedure or the patient had a respiratory compromise requiring mechanical ventilation.
Data analysis
Sample size was derived as the proportion of subjects with Ramsay sedation score above 4 was 87% in the ketofol group and 41.9% in the midazolam–fentanyl group with 95% confidence interval with respect to the study done by Nejati et al.[5] Based on these findings, sample size was calculated to 60 with 80% power. The mean pain score before and after the study was compared using paired t-test, and the difference between the two groups was assessed using Student's t-test. Chi-square test and Fisher's exact test were employed to compare the distribution of qualitative data. Statistical significance was accepted at value < 0.05. Continuous variables were presented as means (standard deviation [SD]). Statistical analyses were performed using the Statistics Package for Social Scientists, Windows version 16.0.
| Results | | |
This study was conducted on total 60 patients (30 in each group) [Figure 1]. The mean age in the ketofol group was 37.8 ± 13.9 (mean ± SD) years and in the midazolam–fentanyl group was 45.9 ± 21.98 (mean ± SD) years. The female-to-male ratio was same in both the study groups, but males 21 (50%) outnumbered the females 9 (50%). Ketofol 1.27 ± 1.52 (mean ± SD) was found to have more reduction in Visual Analog Scale scores after procedure compared to midazolam–fentanyl 3.07 ± 1.25 (mean ± SD), which shows that ketofol provides better analgesia [Figure 2]b. The two groups were compared using modified Ramsay sedation scores, and found that, group ketofol 4.47±0.73 (mean ± SD) had a better sedation score than midazolam–fentanyl 3.47±0.90 (mean ± SD) group [Table 1] and [Table 2]. | Table 1: Changes in vital signs and characteristics of sedation during procedural sedation anesthesia
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 | Table 2: Mean difference of Visual Analog Scale score and Modified Ramsay sedation score
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There was a drop in systolic (from 119 ± 18.4 to 113.3 ± 18.81 mmHg) [Figure 3]a and diastolic blood pressure (from 72 ± 9.61 to 69.67 ± 10.33 mmHg) [Figure 3]b in the midazolam–fentanyl group during and after the procedure, but the difference was not statistically significant. No significant bradycardia or tachycardia [Figure 4], or apnea [Figure 5a], was noted in either of the groups. Oxygen saturation was well maintained in the ketofol group than in the midazolam–fentanyl group [Figure 5]b and [Table 1]. | Figure 3: (a) Comparison of mean SBP, (b) Comparison of mean DBP. DBP: Diastolic blood pressure, SBP: Systolic blood pressure
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 | Figure 5: (a) Comparison of mean respiratory rate, (b) Comparison of mean oxygen saturation (SpO2)
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Additional boluses were given in 5 (16.5%) patients in both the study groups if there was any movement under sedation like grimacing or complaining of pain which was indicative of inadequate sedation. One (3.3%) patient in the ketofol group and three (10%) patients in the midazolam–fentanyl group had inadequate ventilation and were corrected with airway repositioning maneuvers. The ketofol group has shorter sedation times 17.5 ± 6.63 (mean ± SD) when compared to midazolam–fentanyl 24.7 ± 11.1 (mean ± SD), and the difference was statistically significant. Desaturation in 4 (66.7%) patients and hypotension in 2 (100%) patients were associated with the midazolam–fentanyl group. Agitation and emergence reactions were seen in 2 (100%) patients of the ketofol group who required midazolam boluses to control the reaction [Table 3]. | Table 3: Changes in characteristics of sedation during procedural sedation anesthesia
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| Discussion | | |
In this open-labelled randomized controlled study on 60 patients, we compared ketamine–propofol combination with midazolam–fentanyl combination for procedural sedation and analgesia in the emergency care department. After procedure, reduction in Visual Analog Scale scores was better in ketofol 1.27 ± 1.52 (mean ± SD) group when compared to midazolam-fentanyl 3.07 ± 1.25 (mean ± SD). This indicates ketofol provides better analgesia. Modified Ramsay sedation score for ketofol 4.47 ± 0.73 (mean ± SD) had a better score when compared to midazolam–fentanyl 3.47±0.90 (mean ± SD). In midazolam and fentanyl group the systolic (from 119 ± 18.4 to 113.3 ± 18.81 mmHg) and diastolic (from 72 ± 9.61 to 69.67 ± 10.33 mmHg) blood pressures were reduced during and after the procedures, while in ketofol group none had hypotension.
In our study, ketofol gave a better level of modified Ramsay sedation score of 4.47±0.73 (mean ± SD) when compared to midazolam–fentanyl 3.47±0.90 (mean ± SD).[4] These results are in consistency with the study by Nejati et al. where 87.1% in the ketofol group had a modified Ramsay sedation score between 4 and 6 and midazolam–fentanyl 58.1% had a score of 3 or less.[5] Willman and Andolfatto showed that ketofol had better sedation efficacy and lesser requirement for additional boluses during the procedure. The sedation efficacy can be related to the synergy between the drugs.[6] In the present study, visual analog pain scores postprocedure were less with ketofol (1.27 ± 1.52) when compared to midazolam–fentanyl (3.07 ± 1.25).[7] This is similar to the study where Amir Nejati et al. showed that ketofol had better analgesia where 83.9% had completely painless procedure and 16.1% had comparatively less pain with visual analog scores of ≤6, whereas in the midazolam–fentanyl group, only 29% had visual analog scores ≤6.[5] This property of better analgesia is because of combination where ketamine acts as analgesic by inhibiting glutamate and thereby nociceptive pathway.[8] Ketofol maintained hemodynamic stability in the procedures during and after the sedation. The hemodynamic stability of the ketofol is due to the opposing effects of ketamine and propofol. Propofol inhibits sympathetic vasoconstrictor nerve activity, thereby causing hypotension and bradycardia.[9] Ketamine stimulates the sympathetic system, increasing heart rate, and blood pressure. These antagonizing effects of ketamine and propofol will make the combination a better agent maintaining hemodynamic stability. In the midazolam–fentanyl group, there was a drop in systolic blood pressure. This is consistent with the study done by Christe et al., which showed that midazolam was associated with drop in mean arterial pressure.[10] This might be because of the decrease in systemic vascular resistance by the drug. Hence, when administered in hypovolemic patients, the decrease in blood pressure will be enhanced. In our study, we observed desaturation in the elderly age group. Desaturation was 15.3% and 7.1% in the midazolam–fentanyl group and the ketofol group, respectively. These are consistent with 16.3% and 6.2% in midazolam–fentanyl and ketofol, respectively, in a study conducted by Nejati et al.[5] This is due to the fact that midazolam when combined with opioids increases the incidence of respiratory depression. Ketamine in the ketofol group maintains the airway patency and muscle tone. In our study, among the patients who had hypoxia, two of them may have been related to acute alcohol intoxication, as they required increased effective doses of drugs for sedation. This might be due to cross-tolerance between anesthetic drugs.[11] In our study among the 11 elderly patients in both the groups, four patients had adverse events, which was statistically significant [Table 4]. This is inconsistence with the study done by Heuss et al., which showed that as the age increases, the sensitivity to the drugs increases making them susceptible for adverse events.[12] In the present study, two patients had emergence reactions in the ketofol group and they required midazolam to control the agitation. Lemoel et al. showed that there was a significant reduction in emergence reactions and emesis among the patients who received ketofol when compared to ketamine alone. The emergence reactions are usually self-limited and can be treated with benzodiazepines or antipsychotics.[13] | Table 4: Comparison of adverse events in patients and age of the patient
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The drug doses required for additional boluses were less in the ketofol group in our study. This is in consistence with the study done by Willman and Andolfatto, which showed that 96.5% of the procedures did not require adjunctive medication in the ketofol group. It is probably due to the better sedation efficacy of ketofol as a combination.[6]
We observed that ketofol had a faster onset of sedation than the midazolam–fentanyl group which is statistically significant which is inconsistence with the study where Kurdi and Deva showed that ketofol of 1:1 and 1:2 had onset of action of the drug at 1.59 min and 0.58 min, respectively.[14] The recovery times were noted postprocedure where we observed that ketofol has faster recovery rates. This can be attributed to its lipophilic nature of the drugs. In our study, we observed prolonged sedation time in the midazolam–fentanyl group (24.7 ± 11.1), which is statistically significant. The faster recovery times in ketofol can be attributed to the lipophilic nature of the drugs. Current guidelines of procedural sedation American Society of Anesthesiologists in 2018 recommend providing supplemental oxygen to prevent hypoxemia unless specifically contraindicated.[15] We did not provide supplemental oxygen unless indicated. Oxygen therapy was given to the patient in the case of adverse events of inadequate ventilation and desaturation.
Limitations of the study
This is a single-center study and did not include pediatric population. The TR from sedation was noted but not statistically compared. Hence, we are unable to conclude which group has faster recovery. The modified Aldrete scores were not taken as discharge criteria.
| Conclusion | | |
Based on our study results, we conclude that ketofol provides better sedation and analgesia when compared to the midazolam–fentanyl combination. Hemodynamic stability was better maintained and incidence of adverse events was less in the ketofol group. Hence, it is preferable to use ketofol as the agent of choice with appropriate hemodynamic monitoring for procedural sedation and analgesia in the emergency department.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
| References | | |
| 1. | Sih K, Campbell SG, Tallon JM, Magee K, Zed PJ. Ketamine in adult emergency medicine: Controversies and recent advances. Ann Pharmacother 2011;45:1525-34.  |
| 2. | Adams D, Dervay KR. Pharmacology of procedural sedation. AACN Adv Crit Care 2012;23:349-54. |
| 3. | Arora S. Combining ketamine and propofol (”ketofol”) for emergency department procedural sedation and analgesia: A review. West J Emerg Med 2008;9:20-3. |
| 4. | Ramsay MA, Savege TM, Simpson BR, Goodwin R. Controlled sedation with alphaxalone-alphadolone. Br Med J 1974;2:656-9. |
| 5. | Nejati A, Moharari RS, Ashraf H, Labaf A, Golshani K. Ketamine/propofol versus midazolam/fentanyl for procedural sedation and analgesia in the emergency department: A randomized, prospective, double-blind trial. Acad Emerg Med 2011;18:800-6. |
| 6. | Willman EV, Andolfatto G. A prospective evaluation of “ketofol” (ketamine/propofol combination) for procedural sedation and analgesia in the emergency department. Ann Emerg Med 2007;49:23-30. |
| 7. | Cline ME, Herman J, Shaw ER, Morton RD. Standardization of the visual analogue scale. Nurs Res 1992;41:378-80. |
| 8. | Aroni F, Iacovidou N, Dontas I, Pourzitaki C, Xanthos T. Pharmacological aspects and potential new clinical applications of ketamine: Re-evaluation of an old drug. J Clin Pharmacol 2009;49:957-64. |
| 9. | Rathwell JP, Rosow CE. Intravenous sedatives and hypnotics. In: Stoelting's Pharmacology and Physiology in Anaesthetic practice. 5 th ed., Ch. 5. New York: Wolters Kluwer; 2015. p. 160-8. |
| 10. | Christe C, Janssens JP, Armenian B, Herrmann F, Vogt N. Midazolam sedation for upper gastrointestinal endoscopy in older persons: A randomized, double-blind, placebo-controlled study. J Am Geriatr Soc 2000;48:1398-403. |
| 11. | Chapman R. Alcohol and anaesthesia. Contin Educ Anaesth Crit Care Pain 2009;9:10-3. |
| 12. | Heuss LT, Schnieper P, Drewe J, Pflimlin E, Beglinger C. Conscious sedation with propofol in elderly patients: A prospective evaluation. Aliment Pharmacol Ther 2003;17:1493-501. |
| 13. | Lemoel F, Contenti J, Giolito D, Boiffier M, Rapp J, Istria J, et al. Adverse events with ketamine versus ketofol for procedural sedation on adults: A double-blind, randomized controlled trial. Acad Emerg Med 2017;24:1441-9. |
| 14. | Kurdi MS, Deva RS. A comparison of two different proportions of ketofol with fentanyl-propofol for sedoanalgesia for tubal sterilisation by mini laparotomy: A randomised double-blindtrial. J Obstet Anaesth Crit Care 2015;5;84-9. |
| 15. | Practice Guidelines for Moderate Procedural Sedation and Analgesia 2018: A Report by the American Society of Anesthesiologists Task Force on Moderate Procedural Sedation and Analgesia, the American Association of Oral and Maxillofacial Surgeons, American College of Radiology, American Dental Association, American Society of Dentist Anesthesiologists, and Society of Interventional Radiology. Anesthesiology 2018;128:437-79. |
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2], [Table 3], [Table 4]
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