Emergency. 2018; 6 (1): e57 OR I G I N A L RE S E A RC H Low-Dose Fentanyl, Propofol, Midazolam, Ketamine and Lidocaine Combination vs. Regular Dose Propofol and Fentanyl Combination for Deep Sedation Induction; a Randomized Clinical Trial Afshin Amini1, Ali Arhami Dolatabadi1, Hamid Kariman1, Hamidreza Hatamabadi1, Elham Memary2, Sohrab Salimi2, Shahram Shokrzadeh3∗ 1. Emergency Department, Imam Hossein Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 2. Anesthesiology Department, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 3. Emergency Department, Shahid Rajaee Hospital, Tonekabon, Iran. Received: August 2018; Accepted: September 2018; Published online: 2 October 2018 Abstract: Introduction: Need for procedural sedation and analgesia (PSA) is felt in emergency department (ED) more and more each day. This study aimed to compare the effectiveness of low-dose fentanyl, propofol, midazolam, ketamine and lidocaine combination with regular dose of propofol and fentanyl combination for induction of deep sedation. Methods: In this single-blind clinical trial, candidate patients for sedation and analgesia aged more than 15 and less than 60 years old, with pain score ≥6 were allocated to one of the groups using block randomization and were compared regarding onset of action, recovery time, and probable side effects. Results: 125 patients with the mean age of 37.8 ± 14.3 years were randomly allocated to each group. 100% of the patients in group 1 (5 drugs) and 56.5% of the patients in group 2 (2 drugs) were deeply sedated in the 3rd minute after injection. The 2 groups were significantly different regarding onset of action (p = 0.440), recovery time (p = 0.018), and treatment failure (p < 0.001). Conclusion: Low-dose fentanyl, propofol, midazolam, ketamine and lidocaine combination was more successful in induction of deep sedation compared to regular dose of propofol and fentanyl combination. Recovery time was a little longer in this group and both groups were similar regarding drug side effects and effect on vital signs. Keywords: Clinical trial; deep sedation; emergency service, hospital; ketamine; propofol; analgesia © Copyright (2018) Shahid Beheshti University of Medical Sciences Cite this article as: Amini A, Arhami Dolatabadi A, Kariman H, Hatamabadi H, Memary E, Salimi S, Shokrzadeh Sh. Low-Dose Fentanyl, Propofol, Midazolam, Ketamine and Lidocaine Combination vs. Regular Dose Propofol and Fentanyl Combination for Deep Sedation Induc- tion; a Randomized Clinical Trial. Emergency. 2018; 6(1): e57. 1. Introduction Pain and excessive agitation are usually big obstacles for pro- viding medical services (1, 2). Therefore, need for procedural sedation and analgesia (PSA) is felt in emergency department (ED) more and more each day. It is estimated that 10% of ED patients need some kind of sedative (3-5). PSA is a technique used to induce a level of anesthesia and analgesia for pa- ∗Corresponding Author: Shahram Shokrzadeh; Emergency Department, Shahid Rajaee Hospital, Imam Khomeini Street, Tonekabon, Iran. Tel: 00989111954119 Email: shahram.shokrzadeh@gmail.com tients in order to undergo unpleasant and painful procedures without changes in cardiopulmonary function. Drugs used for sedation induction can be classified in 2 general groups of sedatives such as propofol, ketamine, etomidate, and mi- dazolam and analgesics such as fentanyl, remifentanil, mor- phine, and ketamine (6). These drugs have the potential for causing dangerous side effects such as respiratory, cardiac and vascular depression, especially in higher doses (7). Find- ing new compounds that have few side effects in addition to effective and deep PSA with rapid recovery of patients from PSA is of great interest. Numerous studies have evaluated and compared drug compounds. Both propofol-ketamine and propofol-fentanyl have provided sufficient sedation and This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: www.jemerg.com A. Amini et al. 2 analgesia during dressing change for burn patients (8). Both compounds have also provided sufficient analgesia for do- ing endoscopy of the upper digestive system but propofol- ketamine compound has led to more stable hemodynamics and deeper analgesia (9). Using low-dose drugs can prevent manifestation of drug side effects. However, there is no accu- rate data regarding the effects of using low-dose sedative and analgesic drugs. Therefore, this study aimed to compare the effectiveness and safety of using low-dose sedative and anal- gesic drugs (including propofol, ketamine, midazolam, fen- tanyl, and lidocaine) with regular dose of propofol and fen- tanyl in patients in need of PSA presenting to ED. 2. Methods 2.1. Study design and setting The present study is a clinical trial carried out aiming to com- pare the effectiveness of low-dose 5 drug combination (fen- tanyl, propofol, midazolam, ketamine, and lidocaine) with regular dose of 2 drug combination (propofol-fentanyl) for induction of deep sedation in patients presenting to the ED of Imam Hossein Teaching Hospital, during 6 months in 2015. In line with the Declaration of Helsinki, the researchers adhered to ethical principles and kept patient data confiden- tial. Before entering the study, all participants were given explanations regarding the study protocol and then writ- ten informed consent was obtained from them. The pro- tocol of the study was registered on the Iranian registry of clinical trials under the number IRCT2015112525235N1 and was approved by the ethics committee of Shahid Beheshti University of Medical Sciences under the license number: sbmu.rec.13930717. 2.2. Participants In this study, candidate patients for PSA, according to the de- cision of a senior emergency medicine specialist, whose age was over 15 and under 60 years and had a pain score equal to or higher than 7 (based on numeric analog scale: NAS) were included. In cases of patients not wanting to partici- pate, previous allergy to drugs used in the study, allergy to protein products such as egg and soy, hemodynamic insta- bility, increased intracranial pressure and lactating and preg- nant women, they were excluded. 2.3. Intervention In this study, patients were randomly allocated to 2 groups via block randomization. Group 1 consisted of patients receiving a low-dose fentanyl (0.5 -1 µg/kg), propofol (0.5 mg/kg), midazolam (0.1–0.02 mg/kg), ketamine (0.2–0.25 mg/kg), and lidocaine (0.5 mg/kg) combination and group 2 included patients receiving regular dose of propofol (1 mg/kg) and fentanyl (1 mg/kg). Drug injection was done during 20 - 30 seconds using syringes with a similar volume and color. All the patients were under close cardiac, respi- ratory, blood pressure, and blood O2 saturation monitoring during the procedure. Time interval between receiving drug and deep PSA induction was considered as the drug’s onset of action. In addition, the time interval between deep PSA and complete recovery was considered as recovery time. For measuring pain severity, NAS was used and for measuring depth of PSA, Ramsay system was applied. Ramsey score of 6 was considered as deep PSA and score of 2 was considered as recovery. Pain score equal to or higher than 6 was considered severe pain. 2.4. Data gathering To gather data, a checklist consisting of demographic data (age, sex, weight); vital signs (blood pressure, respiratory rate, heart rate, O2 saturation) before and during procedure; rea- son for requiring PSA (upper/lower limb injury, soft tissue in- jury); and final studied outcome (onset of drug action, re- covery time, probable side effects, and patient and physi- cian’s satisfaction) was designed and used. Data gathering was done by a senior emergency medicine resident in charge of carrying out the study. Patients and data analyzer were blind to the administered drugs. 2.5. Outcome Onset of action and recovery time were considered as pri- mary outcomes and drug side effects such as nausea and vomiting, apnea and hemodynamic instability in addition to patient and physician’s satisfaction were considered sec- ondary outcomes. 2.6. Statistical Analysis Considering 17 minutes standard deviation in recovery time, 5% error, 10% desired precision, and 90% power, the mini- mum sample size required for each group was estimated to be 61 cases (10). Data were analyzed using SPSS 20. Quali- tative variables were reported as frequency and percentage, and quantitative ones as mean ± standard deviation. Chi squared and Fisher’s exact tests were applied for analytical comparisons. Non-parametric test of chi-square for trend was used for evaluating the frequency of successful PSA cases and assessing recovery time. Significance level was consid- ered to be p < 0.05. 3. Results 3.1. Baseline characteristics 125 patients with the mean age of 37.8 ± 14.3 (15-60) years were studied (75.2% male). 63 (50.4%) patients were ran- domly allocated to group 1 and 62 (49.6%) to group 2. Table 1 compares the baseline characteristics of the studied patients. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: www.jemerg.com 3 Emergency. 2018; 6 (1): e57 Table 1: Baseline characteristics of the studied patients Variable Group 1 (n = 63) Group 2 (n = 62) P Sex Male 45 (71.4) 46 (74.2) 0.80 Female 18 (28.6) 16 (25.8) Age (year) Mean ± standard deviation 37.2 ± 13.2 38.2 ± 15.6 0.70 Weight (kg) Mean ± standard deviation 73.4 ± 12.4 70.1 ± 11.1 0.12 History of PSA* No 56 (91.8) 54 (87.1) 0.40 Yes 5 (8.2) 8 (12.9) Reason for requiring PSA* Upper limb injury 45 (71.4) 44 (71.0) Lower limb injury 15 (23.8) 16 (25.8) 0.99 Soft tissue injury 1 (1.6) 1 (1.6) Other 2 (3.2) 1 (1.6) History of underlying illness Yes 5 (8.2) 8 (12.9) 0.29 No 58 (92.1) 54 (87.1) Vital signs Heart rate (/minute) 84.5 ± 11.6 88.0 ± 11.2 0.09 Respiratory rate (/minute) 15.6 ± 1.8 16.1 ± 1.9 0.23 Systolic blood pressure (mmHg) 123.4 ± 12.0 124.8 ± 12.7 0.52 Diastolic blood pressure (mmHg) 79.9 ± 9.4 79.3 ± 19.6 0.73 Arterial O2 saturation (%) 97.3 ± 1.6 98.3 ± 13.3 0.63 PSA: procedural sedation and analgesia; Data are shown as mean ± standard deviation or frequency (%). Figure 1: Kaplan-Meier curve of recovery time (in minutes) for the 2 studied groups. The 2 groups were not significantly different regarding demo- graphic data. 3.2. Comparison of outcomes Table 2 compares the outcome of treatment in the 2 groups. The 2 groups were significantly different regarding onset of action (p = 0.440), recovery time (p = 0.018), treatment failure (p < 0.001), physician’s satisfaction (p < 0.001), and patient’s satisfaction (p < 0.001). Kaplan-Meier curve of recovery time for the 2 studied groups is shown in figure 1. 100% of the pa- tients in group 1 and 56.5% of the patients in group 2 were deeply sedated in the 3rd minute after injection. In total, 5 cases of side effect due to PSA were detected that included 3 (2.4%) vertigo and 2 (1.6%) vomiting cases. The cost of the treatment regimen for a 70-kg patient was 33750 Rials (1.7 US dollar) in group 2 (2 drug combination) and 37400 Rials (1.9 US Dollar) in group 1 (5 drug combination). 4. Discussion Based on the findings of the present study, low-dose propo- fol, ketamine, midazolam, fentanyl, and lidocaine combina- tion had a higher success rate in inducing deep sedation, and patient and physician’s satisfaction compared to fentanyl and propofol combination with regular dose. Recovery time in this group was slightly longer and the 2 groups did not differ significantly regarding drug side effects and influence on vital signs. As mentioned before, finding new drugs that have few side effects in addition to effective and deep PSA with rapid recovery is of great interest among physicians. In line with the current study, Ebrahimi et al. aimed to com- pare propofol-midazolam and propofol-fentanyl regimens in patients undergoing microlaryngeal surgery and showed that mean arterial O2 saturation during laryngoscopy was further reduced in fentanyl group, while recovery time was This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: www.jemerg.com A. Amini et al. 4 Table 2: Comparison of treatment characteristics between low-dose multi-drug group (group 1) and propofol-fentanyl combination group (group 2) Variable Group 1 Group 2 P Onset of action (minute) Mean ± standard deviation 1.73 ± 0.62 1.36 ± 1.29 0.044 Treatment failure Number (%) 0 (0) 22 (37.1) < 0.001 Recovery time (minute) Mean ± standard deviation 6.48 ± 1.84 5.02 ± 4.47 0.03 Vital signs Heart rate (/minute) 78.2 ± 8.8 83.1 ± 9.8 0.006 Systolic blood pressure (mmHg) 119.0 ± 12.1 121.0 ± 11.6 0.36 Diastolic blood pressure (mmHg) 74.8 ± 9.0 76.25 ± 9.7 0.73 Arterial O2 saturation (%) 95.5 ± 3.1 91.9 ± 6.8 0.00003 Side effects None 61 (96.8) 59 (95.2) Vertigo 1 (1.6) 2 (3.2) 0.836 Vomiting 1 (1.6) 1 (1.6) Patient’s satisfaction Dissatisfied 1 (1.6) 1 (1.6) Partial 19 (30.2) 56 (90.3) < 0.001 Complete 43 (68.3) 5 (8.1) Physician’s satisfaction Dissatisfied 1 (1.6) 1 (1.6) Partial 19 (30.2) 53 (86.9) < 0.001 Complete 43 (68.3) 7 (11.5) Data are shown as mean ± standard deviation or frequency (%). shorter in midazolam group (11). Comparison of propofol- ketamine and propofol-fentanyl compounds for PSA induc- tion in pediatric burn patients during change of dressing showed that there is no significant difference between these combinations regarding heart rate, systolic blood pressure, arterial O2 saturation, respiratory rate, and sedation score during PSA (8). Erden et al. showed that adding a low dose of ketamine to propofol-fentanyl combination leads to decreased risk of drop in arterial O2 saturation and less need for additional propofol for induction of analgesia (12). Using propofol-ketamine combination results in more sta- ble hemodynamics and deeper analgesia in PSA induction for pediatrics during upper gastrointestinal tract endoscopy compared to propofol-fentanyl. However, it had more side effects (9). Akin et al. also revealed that propofol-fentanyl and propofol-ketamine groups had no significant difference regarding analgesia during endometrial biopsy (13). As can be seen, most studies expressed that combination of propo- fol and ketamine or propofol and midazolam are better reg- imens for PSA induction compared to propofol-fentanyl. Other observations emphasize that ketamine is a safe drug and a proper sedative for use in EDs (14). The advantage of the present study over other similar ones is using low doses of multiple sedatives for PSA induction. Most study proto- cols have been based on using 2 or at most 3 drugs, while this study designed a 5-drug protocol. Confirmation of the re- sults of the current study requires carrying out further studies with stronger methodologies and considering different racial characteristics. 5. Limitation The study being single-blind is among the most important limitations of this study. 6. Conclusion Based on the findings of the present study, low-dose fentanyl, propofol, midazolam, ketamine and lidocaine combination was more successful in induction of deep sedation compared to regular dose of propofol and fentanyl combination and was associated with higher satisfaction among both patients and physicians. Recovery time was a little longer in this group and the 2 groups were not significantly different regarding drug side effects and effect on vital signs. 7. Appendix 7.1. Acknowledgement The present article is derived from Dr. Shahram Shokrzadeh’s thesis, numbered 105, to achieve his specialist degree in emergency medicine from Shahid Beheshti University of Medical Sciences. Hereby, we sincerely thank all the staff of This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: www.jemerg.com 5 Emergency. 2018; 6 (1): e57 emergency department of Imam Hossein Hospital for assist- ing us in all stages of the study. 7.2. Authors’ contribution All the authors meet the 4 criteria for authorship based on recommendations of the International Committee of Medical Journal Editors. Authors’ ORCIDs Ali Arhami Dolatabadi: 0000-0001-9492-9520 Hamidreza Hatamabadi: 0000-0002-9085-8806 Elham Memary: 0000-0002-4845-9342 Sohrab Salimi: 0000-0002-0331-1619 Shahram Shokrzadeh: 0000-0002-8170-7686 7.3. Funding/Support No financial support has been received for this project. 7.4. Conflict of interest Hereby, the authors declare that there is no conflict of interest regarding the present study. References 1. Karceski S, Morrell M, Carpenter D. The expert consensus guideline series: treatment of epilepsy. Epilepsy & Behav- ior. 2001;2(6):A1-A50. 2. Group TC. Rapid tranquillisation for agitated patients in emergency psychiatric rooms: a randomised trial of midazolam versus haloperidol plus promethazine. BMJ: British Medical Journal. 2003;327(7417):708-14. 3. Esmailian M, Moshiri R, Zamani M. Comparison of the Analgesic Effect of Intravenous Acetaminophen and Morphine Sulfate in Rib Fracture; a Randomized Clinical Trial. 2014. 2014;3(3):4. 4. Faridaalaee G, Rahmani SH, Mehryar H, Bina Shishavan S, Merghati SZ, Valizade Hasanloei MA, et al. Compari- son of Intravenous Metoclopramide and Acetaminophen in Primary Headaches: a Randomized Controlled Trial. 2014. 2014;3(2):5. 5. Alimohammadi H, Shojaee M, Samiei M, Abyari S, Vafaee A, Mirkheshti A. Nerve Stimulator Guided Axillary Block in Painless Reduction of Distal Radius Fractures; a Ran- domized Clinical Trial. 2013. 2013;1(1):4. 6. Hoffman GM, Nowakowski R, Troshynski TJ, Berens RJ, Weisman SJ. Risk reduction in pediatric procedural se- dation by application of an American Academy of Pe- diatrics/American Society of Anesthesiologists process model. Pediatrics. 2002;109(2):236-43. 7. Apfelbaum JL, Silverstein JH, Chung FF, Connis RT, Fill- more RB, Hunt SE, et al. Practice Guidelines for Postanes- thetic CareAn Updated Report by the American Society of Anesthesiologists Task Force on Postanesthetic Care. The Journal of the American Society of Anesthesiologists. 2013;118(2):291-307. 8. Tosun Z, Esmaoglu A, Coruh A. Propofol–ketamine vs propofol–fentanyl combinations for deep sedation and analgesia in pediatric patients undergoing burn dressing changesa. Pediatric Anesthesia. 2008;18(1):43-7. 9. Tosun Z, Aksu R, Guler G, Esmaoglu A, Akin A, Aslan D, et al. Propofol-ketamine vs propofol-fentanyl for sedation during pediatric upper gastrointestinal endoscopy. Pedi- atric Anesthesia. 2007;17(10):983-8. 10. Correia LM, Bonilha DQ, Gomes GF, Brito JR, Nakao FS, Lenz L, et al. Sedation during upper GI endoscopy in cir- rhotic outpatients: a randomized, controlled trial com- paring propofol and fentanyl with midazolam and fen- tanyl. Gastrointestinal endoscopy. 2011;73(1):45-51. e1. 11. Sajedi1 PAY, Ahmad%A Bigi2, Ali Akbar%A Rezaie3, Mahin%A Mehrabi Kooshki4, Ali. Comparative Evalua- tion of Vital Signs Stability, Sedation and Analgesia Scores with Two Methods of Sedation: Propofol+Fentanyl and Ketamine+Fentanyl during Perm Cath Insertion. Re- search in Medicine. 2010;34(1):13-9. 12. Aydin Erden I, Gulsun Pamuk A, Akinci SB, Koseoglu A, Aypar U. Comparison of propofol-fentanyl with propofol-fentanyl-ketamine combination in pediatric patients undergoing interventional radiology proce- dures. Pediatric Anesthesia. 2009;19(5):500-6. 13. Akin A, Guler G, Esmaoglu A, Bedirli N, Boyaci A. A com- parison of fentanyl-propofol with a ketamine-propofol combination for sedation during endometrial biopsy. Journal of clinical anesthesia. 2005;17(3):187-90. 14. Treston G, Bell A, Cardwell R, Fincher G, Chand D, Cash- ion G. What is the nature of the emergence phenomenon when using intravenous or intramuscular ketamine for paediatric procedural sedation? Emergency medicine Australasia : EMA. 2009;21(4):315-22. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: www.jemerg.com Introduction Methods Results Discussion Limitation Conclusion Appendix References