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Propofol–fentanyl versus propofol–ketamine for procedural sedation and analgesia in patients with trauma
YAJEM-57288; No of Pages 5 American Journal of Emergency Medicine xxx (2018) xxx–xxx
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Comparison of the combination of propofol–fentanyl with combination of propofol– ketamine for procedural sedation and analgesia in patients with trauma Hamed Aminiahidashti a,⁎, Sajad Shafiee b, Seyed Mohammad Hosseininejad a, Abulfazl Firouzian c, Ayyub Barzegarnejad d, Alieh Zamani Kiasari c, Behzad Feizzadeh Kerigh d, Farzad Bozorgi b, Misagh Shafizad b, Ahmad Geraeeli e a
Department of Emergency Medicine, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran Orthopedic Research Center, Mazandaran University of Medical Sciences, Sari, Iran c Department of Anesthesiology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran d Department of Urology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran e Student Research Committee, Department of Emergency Medicine, Mazandaran University of Medical Sciences, Sari, Iran b
a r t i c l e
i n f o
Article history: Received 30 September 2017 Received in revised form 24 January 2018 Accepted 25 January 2018 Available online xxxx Keywords: Procedural sedation and analgesia Emergency department Propofol Fentanyl Ketamine
a b s t r a c t Objective: Many procedures performed in emergency department are stressful and painful, and creating proper and timely analgesia and early and effective assessment are the challenges in this department. This study has been conducted in order to compare the efficacy of propofol and fentanyl combination with propofol and ketamine combination for procedural sedation and analgesia (PSA) in trauma patients in the emergency department. Method: This is a randomized prospective double-blind clinical trial conducted in the emergency department of Imam Khomeini Hospital, a tertiary academic trauma center in northern Iran. Patients with trauma presenting to the emergency department who needed PSA were included in study. Patients were divided into two groups of propofol fentanyl (PF) and propofol ketamine (PK). Pain score and sedation depth were set as primary outcome measures and were recorded. Results: Out of about 379 patients with trauma, who needed PSA, 253 met the criteria to be included in the study, 117 of which were excluded. The remaining 136 patients were randomly allocated to either PF group (n = 70) or PK group (n = 66). Pain management after drug administration was significantly different between the groups and the analgesia caused by fentanyl was significantly higher than ketamine. The sedation score after 15 min of PSA in the group PF was significantly higher than the group PK. Conclusion: It seems that regarding PSA in the emergency department, PF caused better analgesia and deeper sedation and it is recommended to use PF for PSA in the emergency departments. © 2018 Elsevier Inc. All rights reserved.
1. Introduction Pain is one of the most prevalent clinical complaints for which patients refer to emergency departments and creating proper and timely analgesia and early and effective assessment are the challenges in this department [1]. Trauma is also one of the most common causes of patients' referral to the emergency departments, and many patients with fractures, dislocations and lacerations refer to emergency departments [2]. Many procedures performed in emergency departments are stressful and painful including restoration of fractures and dislocations, laceration repair, bone marrow aspiration, abscess drainage, central venous catheter insertion, etc. [2,3]. Procedural sedation and analgesia (PSA) is an important aspect of the skills of emergency medicine specialists [4]. PSA refers to using sedative drugs with or without analgesic drugs ⁎ Corresponding author. E-mail address: [email protected] (H. Aminiahidashti).
for doing a stressful and painful procedure while maintaining cardiovascular and respiratory functions [5]. Various medications such as propofol, benzodiazepines like midazolam, opiates like fentanyl and etomidate are used in the emergency department for PSA, each of which has its own advantages and disadvantages [6]. The guideline published by Difficult Airway Society (DAS) in 2015 suggested that using ketamine with midazolam or propofol is beneficial and effective in short procedures for trauma patients in ICU [7], but Emergency Medicine physicians most often use a combination of midazolam and fentanyl for PSA and do not usually use new medications like propofol and ketamine [8]. Since propofol has not been shown to have an analgesic effect, it was used in combination with fentanyl and to prevent induction of dyspareunia and hallucination by ketamine, it was used in conjunction with propofol. Therefore, this study has been conducted in order to compare the efficacy of propofol and fentanyl combination with propofol and ketamine combination for PSA in trauma patients referred to the emergency department.
https://doi.org/10.1016/j.ajem.2018.01.080 0735-6757/© 2018 Elsevier Inc. All rights reserved.
Please cite this article as: Aminiahidashti H, et al, Comparison of the combination of propofol–fentanyl with combination of propofol–ketamine for procedural sedation and analgesia..., American Journal of Emergency Medicine (2018), https://doi.org/10.1016/j.ajem.2018.01.080
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H. Aminiahidashti et al. / American Journal of Emergency Medicine xxx (2018) xxx–xxx
2. Methods and materials 2.1. Study design and centre This is a randomized prospective double-blind clinical trial conducted in the emergency department of Imam Khomeini Hospital, a tertiary academic trauma center in northern Iran, which sees about 90,000 patients annually in cooperation with Mazandaran Orthopedic Research Center. This research was conducted from June 2016 to April 2017. It was approved by the Ethics Committee of Mazandaran University of Medical Sciences under the code IR. MAZUMS. REC. 95. 1555. The research was started after registration in the Iranian registry of clinical trials under the code IRTC 2016112224606 N 2 and also written consent was obtained from all the patients. 2.2. Selection of the patients All trauma patients who referred to the emergency department and needed PSA were included in the study. Patients under 18 and over 60 years old, patients with American Society of Anesthesiologists physical status classification of 3 or above, intoxicated trauma patients, patients with head trauma, patients with addiction history, pregnant women, patients with blood pressure lower than 90 mm Hg, pulse oximetry lower than 90%, pulse rate lower than 60 and patients with allergies or contraindications for fentanyl, propofol and ketamine were excluded from this study. 2.3. The study protocol Patients were divided into two groups of propofol fentanyl (PF) and propofol ketamine (PK). PF group was given 1 μg/kg fentanyl in 10 ml normal saline and the group PK was given 1 mg/kg ketamine in 10 ml normal saline. Both
groups were given 0.5 mg/kg propofol. Randomization was performed using a computer assisted randomization table. Propofol was administered in both groups but ketamine and fentanyl were prepared in two separate syringes only labeled with a number, each patient was assigned a number by the emergency department pharmaceutic nurse based on randomization table and based on that number, a syringe was ordered by the resuscitation room nurse who was unaware of the type of the medication. The emergency medicine assistant who recorded their results, the physician who performed the procedure and all the patients were unaware of the medications. Only the study administrator had access to the unblended randomization codes, which were not used during the study. 2.4. Outcome assessment method After administrating the medications, the depth of sedation was divided into four levels based on the criteria of the joint commission (TJC). Level 1: minimal sedation during which the patients obey the orders, but their cognitive functions and physical coordination may be impaired. Level 2: moderate sedation during which patients respond purposefully to verbal commands and show withdrawal reflection to pain. Level 3: deep sedation during which patients cannot be easily aroused but respond purposefully following repeated or painful stimulation. They may need assistance in maintaining a patent airway. Level 4: general anesthesia during which patients are not arousable even by painful stimulation. The ability to independently maintain ventilatory function is often impaired. Cardiovascular function may be incurred, too. Pain severity is categorized from 0 to 10 based on visual analogue scale (VAS), blood pressure, heart rate, respiratory rate and O2 saturation were measured before starting PSA and 15, 30 and 120 min after the initiation of PSA. The time interval between drug injection and the time when the patient leaves the recovery room and does not require accurate and close monitoring any more has been measured and
Fig. 1. Flow diagram of patients selection.
Please cite this article as: Aminiahidashti H, et al, Comparison of the combination of propofol–fentanyl with combination of propofol–ketamine for procedural sedation and analgesia..., American Journal of Emergency Medicine (2018), https://doi.org/10.1016/j.ajem.2018.01.080
H. Aminiahidashti et al. / American Journal of Emergency Medicine xxx (2018) xxx–xxx
defined as the recovery time in minutes. The physician satisfaction score was divided into three groups of Good, Moderate and Poor. In case the patients suffered from low O2 saturation (b90%) during PSA, first jaw thrust maneuver and then bag mask ventilation (BMV) would be used and the incident would be recorded. 2.5. Outcomes measured Sedation depth and severity of pain were considered as the primary outcomes and unexpected side-effects like changes in blood pressure, heart rate, respiratory rate, O2 saturation, and requiring intervention to maintain respiratory status, recovery time and physician satisfaction with PSA method were measured as the secondary outcomes. 2.6. Collection of data and statistical analysis There were at least 66 patients in each group with 15% difference, 80% power and two-sided significance level of 0.05. In order to analyze the data, data were entered to Microsoft Excel Microsoft 2007, and SPSS 15.0 (SPSS Inc., Chicago, IL) and MedCal for Windows, version 9.3.0.0 (MedCal Software, Mariakerke, Belgium) were used. Data with normal distribution were shown via mean ± SD and data with abnormal distribution are shown by median and interquartile range (IQR). Categorical variables with abnormal distribution were compared using Χ2 test and continuous variables with abnormal distribution were compared by Mann Whitney U test. Statistical significance was p = 0.05 for all tests. 3. The results 3.1. Demographic data Out of about 379 patients with trauma who needed PSA, 253 met the criteria to be included in the study, out of which 117 patients were excluded. The study flowchart is shown in Fig. 1. The included 136 patients were randomly allocated to either PF group (n = 70) or PK group (n = 66). Demographic data of the patients are shown in Table 1. There was no significant difference between the 2 groups regarding demographic results. 3.2. The primary outcomes The rate of pain was compared between the 2 groups and investigated before and 120 min after drug administration, Table 2. Table 1 Demographic data. Characteristics
PF (n = 70)
PK (n = 66)
p
Age (y), average (SD) Male, n (%) Female, n (%) ASA 1, n (%) ASA 2, n (%) Diagnosis, n (%) Dislocation, n (%) Shoulder Elbow Hip knee Fracture (FX) Humerus Radius Ulna Radius and ulna Femur Tibia Laceration repair Open FX irrigation
33.77(9.22) 44(62.86) 26(37.14) 64(91.43) 6(8.57)
31.71(8.76) 44(66.67) 22(33.33) 57(86.36) 9(13.64)
0.191 0.469 0.469 0.15
27(38.57) 23(32.86) 3(4.29) 1(1.43) 0(0.00) 30(42.86) 3(4.29) 8(11.43) 3(4.29) 4(5.71) 2(2.86) 6(8.57) 13(18.57) 4(5.71)
30(45.45) 28(42.42) 2(3.03) 0(0.00) 0(0.00) 25(37.88) 2(3.03) 11(16.67) 1(1.51) 6(9.09) 0.00 5(7.58) 9(13.64) 2(3.03)
0.41 0.24 0.69 0.33 0 0.79 0.69 0.37 0.33 0.45 0.16 0.92 0.43 0.44
3
There was no significant difference regarding pain scores in the 2 groups before the initiation of PSA, while the pain score in the PF group was significantly lower after PSA. In repetitive analyses, the pattern of changes in pain score after drug administration was significantly different and the analgesia caused by fentanyl was significantly better than ketamine. The patients' sedation score was as shown in Table 3. All patients were conscious and alert both before beginning PSA and after 120 min of PSA. The sedation score 15 min after induction of PSA in PF group was significantly higher than PK group, but 5 and 30 min after sedation, there were no significant differences between the two groups. 3.3. The secondary outcomes The studied secondary outcomes are shown in Table 4. Blood pressure changes, heart rate, respiratory rate and pulse rate in each group varied significantly at different times. Systolic blood pressure was significantly different between the 2 groups before treatment and mean systolic blood pressure of the patients in PF group was high, but during the treatment process there were significant differences in systolic blood pressure changes in the 2 groups. In repetitive measurement analysis, systolic blood pressure was not significantly different in the 2 groups (p = 0.788). Mean heart rate in PF group was significantly higher than PK group before drug administration. However, after drug administration mean heart rate in PK group was significantly higher than PF group. In measurement analysis, heart rate was significantly different between the 2 groups and ketamine had caused a significant increase in heart rate (p = 0.006). Both drugs had caused a decrease in respiratory rate and there was no significant difference between the 2 drugs in this regard. However, at the end of the study and after 2 h patients in PF group returned to normal respiratory rate, while PK group patients still had low respiratory rate. In repeated measurement analysis, patterns of change in the respiratory rate of patients in the 2 groups were significantly different and patients in PF group returned to the normal mode and respiratory rate faster than those in PK group (p = 0.001). Before beginning PSA O2 saturation was the same in both groups, but after drug administration during the first minutes, O2 saturation in PF group was significantly lower than PK group. After 2 h there was no difference. In repeated measurement analysis, O2 saturation changes in the 2 groups were significantly different and PF group caused more reduction in O2 saturation after the first minutes of drug administration (p b 0.001). During PSA, 11 patients had bradypnea and O2 saturation depression, 8 of them recovered after performing jaw thrust maneuver, and the other 3 needed temporary mask ventilation, and all of them returned to normal without any permanent complications. There was no significant difference between the 2 groups in this regard. In this study, none of the patients suffered from ketamine induced emergence hallucinations or dysphoria. The mean recovery time after PSA was 64.56 min in PF group and 72.68 min in PK group. The rate of satisfaction with PSA was not significantly different between the groups. Two patients with femoral fracture and one patient with shoulder dislocation, all of which were in PF group, had procedures that were not successful and so they were transferred to the operation room. 3.4. Limitations of the study In the present study, different patients with different complaints were included and the personal differences were neglected. The study
Table 2 Comparison of pain in two groups.
Pain score before PSA, median (minimum − maximum / IQR) Pain score after 120 min of PSA, median (minimum − maximum / IQR)
PF (n = 70)
PK (n = 66)
p
8.50(5–10/1)
8.00(06–10/1)
0.27
4.00(1–7/2)
5.00(2–7/1)
0.00
Please cite this article as: Aminiahidashti H, et al, Comparison of the combination of propofol–fentanyl with combination of propofol–ketamine for procedural sedation and analgesia..., American Journal of Emergency Medicine (2018), https://doi.org/10.1016/j.ajem.2018.01.080
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H. Aminiahidashti et al. / American Journal of Emergency Medicine xxx (2018) xxx–xxx
Table 3 Comparison of sedation in two groups.
Sedation score after 5 min of PSA, n (%)
Sedation score after 15 min of PSA, n (%)
Sedation score after 30 min of PSA, n (%)
TJC score
PF (n = 70)
PK (n = 66)
p
Alert Stage 1 Stage 2 Stage 3 Stage 4 Alert Stage 1 Stage 2 Stage 3 Stage 4 Alert Stage 1 Stage 2 Stage 3 Stage 4
1(0.7) 36(26.5) 22(16.2) 3(2.2) 8(5.9) 0(0) 7(5.1) 54(39.7) 5(3.7) 4(2.9) 23(16.9) 39(28.7) 6(4.4) 2(1.5) 0(0)
0(0) 43(31.6) 16(11.8) 4(2.9) 3(2.2) 0(0) 18(13.2) 44(32.4) 3(2.2) 1(0.7) 23(16.9) 40(29.4) 2(1.5) 1(0.7) 0(0)
0.30
0.04
0.52
limitations also included factors like lack of separate rooms in the emergency department for PSA, 2-hour follow-ups of the patients in the crowded emergency department, lack of cooperation of other departments like orthopedics and surgery departments. In the other words, patients' final condition was unknown because they were transferred from the emergency department. 4. Discussion In this double blind clinical trial, PF had deeper sedation and better analgesic effects on the patients compared to PK. In this study, pain reduction was significantly more in PF group compared to PK group and sedation was also significantly better in PF group in comparison with PK group after 15 min. Although relatively more side effects such as reduced heart rate and low O2 saturation were detected in PF group, they were not clinically important and considerable. In many studies propofol was considered as the drug of choice in painful measurements due to appropriate sedation and rapid return to the primary state [9,10]. Of course, in a systematic review study, the combination of ketamine and propofol had synergistic effects on sedation and analgesia and
also unexpectedly caused reduced respiratory side effects [11]. In systematic review studies, propofol was not significantly different from other medication options for PSA in the emergency department [12]. The study by Khutia et al. suggested that in order to reach a deeper sedation in PK group, less propofol is needed compared to PF group while there was no difference between the 2 groups regarding side effects such as blood pressure and apnea [13]. In the study by Chiaretti et al. it was suggested that respiratory depression in PF group was higher than PK group [14], which was confirmed in our study, yet the respiratory depression was not clinically important in this study. In a study by Bahrami Gorji, sedation score was the same in both groups for patients undergoing retrograde cholangiography, but the pain in PF group after endoscopy was lower than PK group [15]. In this study also the pain in the PK group was lower than PF group after 2 h. Of course in other studies, PK combination was a safe combination that caused deep sedation [16]. The rate of apnea and respiratory depression in PF group was higher than PK group and it had caused more respiratory side effects [15,17]. In the present study, although respiratory depression and low O2 saturation were seen, they were not important in clinical interventions. Measuring blood pressure during the first 20 min of PSA showed that after 8 min, the blood pressure in PF group was significantly lower than PK group [15]. In this study, low blood pressure was seen 15 min after PSA. Combination of propofol and fentanyl reduced the required dose of propofol for sedation compared to when using just propofol, which would result in manifestation of undesirable side effects like low blood pressure [18]. In the present study, it was also shown that the 2 groups were not significantly different regarding recovery time, which was also the same in some other studies [19]. Yet, in some studies, it was shown that there was a longer recovery time in PK group due to ketamine causing more side effects like dizziness, blurred vision and nausea [20]. Physician's satisfaction after PSA was the same in both groups and in line with the results of different previous studies, which reported similar results [15,21]. 5. Conclusion It seems that for induction of PSA in the emergency department, PF caused better analgesia and deeper sedation and 15 min after inducing
Table 4 Comparison of secondary outcomes. Variable Blood pressure (BP)
Pulse rate (PR)
Respiratory rate (RR)
O2 saturation (O2 sat)
Respiratory intervention, n (%)
Patient satisfaction, n (%)
Recovery time (min), median (minimum − maximum / IQR)
Before PSA, mean(SD) After 5 min of PSA, mean(SD) After 15 min of PSA, mean(SD) After 30 min of PSA, mean(SD) After 120 min of PSA, mean(SD) Before PSA, mean(SD) After 5 min of PSA, mean(SD) After 15 min of PSA, mean(SD) After 30 min of PSA, mean(SD) After 120 min of PSA, mean(SD) Before PSA, mean(SD) After 5 min of PSA, mean(SD) After 15 min of PSA, mean(SD) After 30 min of PSA, mean(SD) After 120 min of PSA, mean(SD) Before PSA, mean(SD) After 5 min of PSA, mean(SD) After 15 min of PSA, mean(SD) After 30 min of PSA, mean(SD) After 120 min of PSA, mean(SD) Normal Jaw thrust BMV Good Moderate Poor
PF
PK
p
130.15(11.62) 124.92(11.91) 120.30(10.14) 124.03(9.85) 127.80(10.52) 90.91(14.50) 85.85(11.00) 81.21(9.06) 86.39(9.25) 90.02(11.74) 16.53(3.15) 14.83(2.81) 13.74(2.49) 15.11(2.34) 15.70(2.26) 99.77(0.52) 97.33(3.09) 95.24(2.97) 97.83(2.58) 99.47(0.88) 63(90) 5(7.14) 2(2.86) 63(90) 3(4.29) 4(5.71) 22(11–41/7.25)
123.14(9.60) 124.59(9.43) 126.20(9.81) 126.67(9.94) 124.35(1028) 86.09(13.33) 90.89(10.28) 94.03(10.29) 94.56(10.89) 91.08(9.82) 14.29(1.85) 14.12(1.81) 13.74(1.48) 13.94(1.44) 13.76(1.80) 99.80(0.40) 99.08(1.12) 98.24(2.46) 99.08(1.88) 99.71(0.51) 62 3 1 59(89.39) 5(7.58) 2(3.03) 24(12–42/5)
˂0.001 0.85 0.001 0.12 0.59 0.49 0.007 ˂0.001 ˂0.001 0.575 ˂0.001 0.086 1.0 ˂0.001 ˂0.001 0.706 ˂0.001 ˂0.001 0.002 0.056 0.63
0.55
0.22
Please cite this article as: Aminiahidashti H, et al, Comparison of the combination of propofol–fentanyl with combination of propofol–ketamine for procedural sedation and analgesia..., American Journal of Emergency Medicine (2018), https://doi.org/10.1016/j.ajem.2018.01.080
H. Aminiahidashti et al. / American Journal of Emergency Medicine xxx (2018) xxx–xxx
PSA, this difference is more obvious. Although there were undesirable side-effects, they have not been clinically considerable and have no effect on satisfaction and recovery time, the pain is significantly reduced after PSA and it is recommended to use PF for inducing PSA in emergency departments. References [1] Todd KH, Ducharme J, Choiniere M, Crandall CS, Fosnocht DE, Homel P, et al. Pain in the emergency department: results of the Pain and Emergency Medicine Initiative (PEMI) Multicenter Study. J Pain 2007;8:460–6. [2] Migita Russell T, Klein Eileen J, Michelle M. Garrison, sedation and analgesia for pediatric fracture reduction in the emergency department. A systematic review. Arch Pediatr Adolesc Med 2006 Jan;160(1):46–51. [3] Barkan S, Breitbart R, Brenner-Zada G, et al. A double-blind, randomised, placebocontrolled trial of oral midazolam plus oral ketamine for sedation of children during laceration repaire. Emerg Med J 2014;31(8):649–53. [4] Godwin SA, Caro DA, Wolf SJ, et al. Clinical policy: procedural sedation and analgesia in the emergency department. Ann Emerg Med 2005;45(2):177–96. [5] Bordo D, Chan SB, Shin P. Patient satisfaction and return to daily activities using etomidate procedural sedation for orthopedic injuries. West J Emerg Med 2008; 9(2):86–90. [6] Bawden J, Villa-Roel C, Singh M, et al. Procedural sedation and analgesia in a Canadian ED: a time-in-motion study. Am J Emerg Med 2011;29:1083–8. [7] DAS-Taskforce 2015, Baron Ralf, Binder Andreas, Biniek Rolf, Braune Stephan, et al. Evidence and consensus based guideline for the management of delirium, analgesia, and sedation in intensive care medicine. Revision 2015 (DAS-Guideline 2015) — short version. Ger Med Sci 2015;13:Doc19. [8] Pinto RF, Bhimani M, Milne WK, Nicholson K. Procedural sedation and analgesia in rural and regional emergency departments. Can J Rural Med 2013 Fall;18(4):130–6. [9] Stolz D, Kurer G, Meyer A, Chhajed PN, Pflimlin E, Strobel W, et al. Propofol versus combined sedation in flexible bronchoscopy: a randomised non-inferiority trial. Eur Respir J 2009;34(5):1024–30. [10] Gaisl T, Bratton DJ, Heuss LT, Kohler M, Schlatzer C, Zalunardo MP, et al. Sedation during bronchoscopy: data from a nationwide sedation and monitoring survey. BMC Pulm Med 2016 Aug 5;16(1):113.
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[11] Yan JW, McLeod SL, Iansavitchene A. Ketamine-propofol versus propofol alone for procedural sedation in the emergency department: a systematic review and metaanalysis. Acad Emerg Med 2015 Sep;22(9):1003–13. [12] Wakai A,Blackburn C, Mccabe A, Reece E, O'Connor G, et al. The use of propofol for procedural sedation in emergency departments. Cochrane Database Syst Rev 2015, Issue 7. Art. No.: CD007399. [13] Khutia SK, Mandal MC, Das S, Basu SR. Intravenous infusion of ketamine-propofol can be an alternative to intravenous infusion of fentanyl-propofol for deep sedation and analgesia in paediatric patients undergoing emergency short surgical procedures. Indian J Anaesth 2012 Mar;56(2):145–50. [14] Chiaretti A, Ruggiero A, Barone G, Antonelli A, Lazzareschi I, Genovese O, et al. Propofol/alfentanil and propofol/ketamine procedural sedation in children with acute lymphoblastic leukaemia: safety, efficacy and their correlation with pain neuromediator expression. Eur J Cancer Care (Engl) 2010 Mar;19(2):212–20 May 21. [15] Bahrami Gorji F, Amri P, Shokri J, Alereza H, Bijani A. Sedative and analgesic effects of propofol-fentanyl versus propofol-ketamine during endoscopic retrograde cholangiopancreatography: a double-blind randomized clinical trial. Anesth Pain Med 2016 Aug 22;6(5):e39835 eCollection 2016 Oct. [16] 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. Paediatr Anaesth 2007;17(10):983–8. [17] Kb N, Cherian A, Balachander H, Kumar CY. Comparison of propofol and ketamine versus propofol and fentanyl for puerperal sterilization, a randomized clinical trial. J Clin Diagn Res 2014 May;8(5):GC01–4. [18] Haytural C, Aydınlı B, Demir B, Bozkurt E, Parlak E, Dişibeyaz S, et al. Comparison of propofol, propofol-remifentanil, and propofol-fentanyl administrations with each other used for the sedation of patients to undergo ERCP. Biomed Res Int 2015; 2015:465465. [19] Akin A, Guler G, Esmaoglu A, Bedirli N, Boyaci A. A comparison of fentanyl-propofol with a ketamine-propofol combination for sedation during endometrial biopsy. J Clin Anesth 2005;17:187–90. [20] Singh R, Ghazanwy M, Vajifdar H. A randomized controlled trial to compare fentanyl-propofol and ketamine-propofol combination for procedural sedation and analgesia in laparoscopic tubal ligation. Saudi J Anaesth 2013 Jan;7(1):24–8. [21] Cevik E, Bilgic S, Kilic E, Cinar O, Hasman H, Acar AY, et al. Comparison of ketaminelow-dose midozolam with midazolam-fentanyl for orthopedic emergencies: a double-blind randomized trial. Am J Emerg Med 2013 Jan;31(1):108–13.
Please cite this article as: Aminiahidashti H, et al, Comparison of the combination of propofol–fentanyl with combination of propofol–ketamine for procedural sedation and analgesia..., American Journal of Emergency Medicine (2018), https://doi.org/10.1016/j.ajem.2018.01.080
Contents lists available at ScienceDirect
American Journal of Emergency Medicine journal homepage: www.elsevier.com/locate/ajem
Comparison of the combination of propofol–fentanyl with combination of propofol– ketamine for procedural sedation and analgesia in patients with trauma Hamed Aminiahidashti a,⁎, Sajad Shafiee b, Seyed Mohammad Hosseininejad a, Abulfazl Firouzian c, Ayyub Barzegarnejad d, Alieh Zamani Kiasari c, Behzad Feizzadeh Kerigh d, Farzad Bozorgi b, Misagh Shafizad b, Ahmad Geraeeli e a
Department of Emergency Medicine, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran Orthopedic Research Center, Mazandaran University of Medical Sciences, Sari, Iran c Department of Anesthesiology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran d Department of Urology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran e Student Research Committee, Department of Emergency Medicine, Mazandaran University of Medical Sciences, Sari, Iran b
a r t i c l e
i n f o
Article history: Received 30 September 2017 Received in revised form 24 January 2018 Accepted 25 January 2018 Available online xxxx Keywords: Procedural sedation and analgesia Emergency department Propofol Fentanyl Ketamine
a b s t r a c t Objective: Many procedures performed in emergency department are stressful and painful, and creating proper and timely analgesia and early and effective assessment are the challenges in this department. This study has been conducted in order to compare the efficacy of propofol and fentanyl combination with propofol and ketamine combination for procedural sedation and analgesia (PSA) in trauma patients in the emergency department. Method: This is a randomized prospective double-blind clinical trial conducted in the emergency department of Imam Khomeini Hospital, a tertiary academic trauma center in northern Iran. Patients with trauma presenting to the emergency department who needed PSA were included in study. Patients were divided into two groups of propofol fentanyl (PF) and propofol ketamine (PK). Pain score and sedation depth were set as primary outcome measures and were recorded. Results: Out of about 379 patients with trauma, who needed PSA, 253 met the criteria to be included in the study, 117 of which were excluded. The remaining 136 patients were randomly allocated to either PF group (n = 70) or PK group (n = 66). Pain management after drug administration was significantly different between the groups and the analgesia caused by fentanyl was significantly higher than ketamine. The sedation score after 15 min of PSA in the group PF was significantly higher than the group PK. Conclusion: It seems that regarding PSA in the emergency department, PF caused better analgesia and deeper sedation and it is recommended to use PF for PSA in the emergency departments. © 2018 Elsevier Inc. All rights reserved.
1. Introduction Pain is one of the most prevalent clinical complaints for which patients refer to emergency departments and creating proper and timely analgesia and early and effective assessment are the challenges in this department [1]. Trauma is also one of the most common causes of patients' referral to the emergency departments, and many patients with fractures, dislocations and lacerations refer to emergency departments [2]. Many procedures performed in emergency departments are stressful and painful including restoration of fractures and dislocations, laceration repair, bone marrow aspiration, abscess drainage, central venous catheter insertion, etc. [2,3]. Procedural sedation and analgesia (PSA) is an important aspect of the skills of emergency medicine specialists [4]. PSA refers to using sedative drugs with or without analgesic drugs ⁎ Corresponding author. E-mail address: [email protected] (H. Aminiahidashti).
for doing a stressful and painful procedure while maintaining cardiovascular and respiratory functions [5]. Various medications such as propofol, benzodiazepines like midazolam, opiates like fentanyl and etomidate are used in the emergency department for PSA, each of which has its own advantages and disadvantages [6]. The guideline published by Difficult Airway Society (DAS) in 2015 suggested that using ketamine with midazolam or propofol is beneficial and effective in short procedures for trauma patients in ICU [7], but Emergency Medicine physicians most often use a combination of midazolam and fentanyl for PSA and do not usually use new medications like propofol and ketamine [8]. Since propofol has not been shown to have an analgesic effect, it was used in combination with fentanyl and to prevent induction of dyspareunia and hallucination by ketamine, it was used in conjunction with propofol. Therefore, this study has been conducted in order to compare the efficacy of propofol and fentanyl combination with propofol and ketamine combination for PSA in trauma patients referred to the emergency department.
https://doi.org/10.1016/j.ajem.2018.01.080 0735-6757/© 2018 Elsevier Inc. All rights reserved.
Please cite this article as: Aminiahidashti H, et al, Comparison of the combination of propofol–fentanyl with combination of propofol–ketamine for procedural sedation and analgesia..., American Journal of Emergency Medicine (2018), https://doi.org/10.1016/j.ajem.2018.01.080
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H. Aminiahidashti et al. / American Journal of Emergency Medicine xxx (2018) xxx–xxx
2. Methods and materials 2.1. Study design and centre This is a randomized prospective double-blind clinical trial conducted in the emergency department of Imam Khomeini Hospital, a tertiary academic trauma center in northern Iran, which sees about 90,000 patients annually in cooperation with Mazandaran Orthopedic Research Center. This research was conducted from June 2016 to April 2017. It was approved by the Ethics Committee of Mazandaran University of Medical Sciences under the code IR. MAZUMS. REC. 95. 1555. The research was started after registration in the Iranian registry of clinical trials under the code IRTC 2016112224606 N 2 and also written consent was obtained from all the patients. 2.2. Selection of the patients All trauma patients who referred to the emergency department and needed PSA were included in the study. Patients under 18 and over 60 years old, patients with American Society of Anesthesiologists physical status classification of 3 or above, intoxicated trauma patients, patients with head trauma, patients with addiction history, pregnant women, patients with blood pressure lower than 90 mm Hg, pulse oximetry lower than 90%, pulse rate lower than 60 and patients with allergies or contraindications for fentanyl, propofol and ketamine were excluded from this study. 2.3. The study protocol Patients were divided into two groups of propofol fentanyl (PF) and propofol ketamine (PK). PF group was given 1 μg/kg fentanyl in 10 ml normal saline and the group PK was given 1 mg/kg ketamine in 10 ml normal saline. Both
groups were given 0.5 mg/kg propofol. Randomization was performed using a computer assisted randomization table. Propofol was administered in both groups but ketamine and fentanyl were prepared in two separate syringes only labeled with a number, each patient was assigned a number by the emergency department pharmaceutic nurse based on randomization table and based on that number, a syringe was ordered by the resuscitation room nurse who was unaware of the type of the medication. The emergency medicine assistant who recorded their results, the physician who performed the procedure and all the patients were unaware of the medications. Only the study administrator had access to the unblended randomization codes, which were not used during the study. 2.4. Outcome assessment method After administrating the medications, the depth of sedation was divided into four levels based on the criteria of the joint commission (TJC). Level 1: minimal sedation during which the patients obey the orders, but their cognitive functions and physical coordination may be impaired. Level 2: moderate sedation during which patients respond purposefully to verbal commands and show withdrawal reflection to pain. Level 3: deep sedation during which patients cannot be easily aroused but respond purposefully following repeated or painful stimulation. They may need assistance in maintaining a patent airway. Level 4: general anesthesia during which patients are not arousable even by painful stimulation. The ability to independently maintain ventilatory function is often impaired. Cardiovascular function may be incurred, too. Pain severity is categorized from 0 to 10 based on visual analogue scale (VAS), blood pressure, heart rate, respiratory rate and O2 saturation were measured before starting PSA and 15, 30 and 120 min after the initiation of PSA. The time interval between drug injection and the time when the patient leaves the recovery room and does not require accurate and close monitoring any more has been measured and
Fig. 1. Flow diagram of patients selection.
Please cite this article as: Aminiahidashti H, et al, Comparison of the combination of propofol–fentanyl with combination of propofol–ketamine for procedural sedation and analgesia..., American Journal of Emergency Medicine (2018), https://doi.org/10.1016/j.ajem.2018.01.080
H. Aminiahidashti et al. / American Journal of Emergency Medicine xxx (2018) xxx–xxx
defined as the recovery time in minutes. The physician satisfaction score was divided into three groups of Good, Moderate and Poor. In case the patients suffered from low O2 saturation (b90%) during PSA, first jaw thrust maneuver and then bag mask ventilation (BMV) would be used and the incident would be recorded. 2.5. Outcomes measured Sedation depth and severity of pain were considered as the primary outcomes and unexpected side-effects like changes in blood pressure, heart rate, respiratory rate, O2 saturation, and requiring intervention to maintain respiratory status, recovery time and physician satisfaction with PSA method were measured as the secondary outcomes. 2.6. Collection of data and statistical analysis There were at least 66 patients in each group with 15% difference, 80% power and two-sided significance level of 0.05. In order to analyze the data, data were entered to Microsoft Excel Microsoft 2007, and SPSS 15.0 (SPSS Inc., Chicago, IL) and MedCal for Windows, version 9.3.0.0 (MedCal Software, Mariakerke, Belgium) were used. Data with normal distribution were shown via mean ± SD and data with abnormal distribution are shown by median and interquartile range (IQR). Categorical variables with abnormal distribution were compared using Χ2 test and continuous variables with abnormal distribution were compared by Mann Whitney U test. Statistical significance was p = 0.05 for all tests. 3. The results 3.1. Demographic data Out of about 379 patients with trauma who needed PSA, 253 met the criteria to be included in the study, out of which 117 patients were excluded. The study flowchart is shown in Fig. 1. The included 136 patients were randomly allocated to either PF group (n = 70) or PK group (n = 66). Demographic data of the patients are shown in Table 1. There was no significant difference between the 2 groups regarding demographic results. 3.2. The primary outcomes The rate of pain was compared between the 2 groups and investigated before and 120 min after drug administration, Table 2. Table 1 Demographic data. Characteristics
PF (n = 70)
PK (n = 66)
p
Age (y), average (SD) Male, n (%) Female, n (%) ASA 1, n (%) ASA 2, n (%) Diagnosis, n (%) Dislocation, n (%) Shoulder Elbow Hip knee Fracture (FX) Humerus Radius Ulna Radius and ulna Femur Tibia Laceration repair Open FX irrigation
33.77(9.22) 44(62.86) 26(37.14) 64(91.43) 6(8.57)
31.71(8.76) 44(66.67) 22(33.33) 57(86.36) 9(13.64)
0.191 0.469 0.469 0.15
27(38.57) 23(32.86) 3(4.29) 1(1.43) 0(0.00) 30(42.86) 3(4.29) 8(11.43) 3(4.29) 4(5.71) 2(2.86) 6(8.57) 13(18.57) 4(5.71)
30(45.45) 28(42.42) 2(3.03) 0(0.00) 0(0.00) 25(37.88) 2(3.03) 11(16.67) 1(1.51) 6(9.09) 0.00 5(7.58) 9(13.64) 2(3.03)
0.41 0.24 0.69 0.33 0 0.79 0.69 0.37 0.33 0.45 0.16 0.92 0.43 0.44
3
There was no significant difference regarding pain scores in the 2 groups before the initiation of PSA, while the pain score in the PF group was significantly lower after PSA. In repetitive analyses, the pattern of changes in pain score after drug administration was significantly different and the analgesia caused by fentanyl was significantly better than ketamine. The patients' sedation score was as shown in Table 3. All patients were conscious and alert both before beginning PSA and after 120 min of PSA. The sedation score 15 min after induction of PSA in PF group was significantly higher than PK group, but 5 and 30 min after sedation, there were no significant differences between the two groups. 3.3. The secondary outcomes The studied secondary outcomes are shown in Table 4. Blood pressure changes, heart rate, respiratory rate and pulse rate in each group varied significantly at different times. Systolic blood pressure was significantly different between the 2 groups before treatment and mean systolic blood pressure of the patients in PF group was high, but during the treatment process there were significant differences in systolic blood pressure changes in the 2 groups. In repetitive measurement analysis, systolic blood pressure was not significantly different in the 2 groups (p = 0.788). Mean heart rate in PF group was significantly higher than PK group before drug administration. However, after drug administration mean heart rate in PK group was significantly higher than PF group. In measurement analysis, heart rate was significantly different between the 2 groups and ketamine had caused a significant increase in heart rate (p = 0.006). Both drugs had caused a decrease in respiratory rate and there was no significant difference between the 2 drugs in this regard. However, at the end of the study and after 2 h patients in PF group returned to normal respiratory rate, while PK group patients still had low respiratory rate. In repeated measurement analysis, patterns of change in the respiratory rate of patients in the 2 groups were significantly different and patients in PF group returned to the normal mode and respiratory rate faster than those in PK group (p = 0.001). Before beginning PSA O2 saturation was the same in both groups, but after drug administration during the first minutes, O2 saturation in PF group was significantly lower than PK group. After 2 h there was no difference. In repeated measurement analysis, O2 saturation changes in the 2 groups were significantly different and PF group caused more reduction in O2 saturation after the first minutes of drug administration (p b 0.001). During PSA, 11 patients had bradypnea and O2 saturation depression, 8 of them recovered after performing jaw thrust maneuver, and the other 3 needed temporary mask ventilation, and all of them returned to normal without any permanent complications. There was no significant difference between the 2 groups in this regard. In this study, none of the patients suffered from ketamine induced emergence hallucinations or dysphoria. The mean recovery time after PSA was 64.56 min in PF group and 72.68 min in PK group. The rate of satisfaction with PSA was not significantly different between the groups. Two patients with femoral fracture and one patient with shoulder dislocation, all of which were in PF group, had procedures that were not successful and so they were transferred to the operation room. 3.4. Limitations of the study In the present study, different patients with different complaints were included and the personal differences were neglected. The study
Table 2 Comparison of pain in two groups.
Pain score before PSA, median (minimum − maximum / IQR) Pain score after 120 min of PSA, median (minimum − maximum / IQR)
PF (n = 70)
PK (n = 66)
p
8.50(5–10/1)
8.00(06–10/1)
0.27
4.00(1–7/2)
5.00(2–7/1)
0.00
Please cite this article as: Aminiahidashti H, et al, Comparison of the combination of propofol–fentanyl with combination of propofol–ketamine for procedural sedation and analgesia..., American Journal of Emergency Medicine (2018), https://doi.org/10.1016/j.ajem.2018.01.080
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Table 3 Comparison of sedation in two groups.
Sedation score after 5 min of PSA, n (%)
Sedation score after 15 min of PSA, n (%)
Sedation score after 30 min of PSA, n (%)
TJC score
PF (n = 70)
PK (n = 66)
p
Alert Stage 1 Stage 2 Stage 3 Stage 4 Alert Stage 1 Stage 2 Stage 3 Stage 4 Alert Stage 1 Stage 2 Stage 3 Stage 4
1(0.7) 36(26.5) 22(16.2) 3(2.2) 8(5.9) 0(0) 7(5.1) 54(39.7) 5(3.7) 4(2.9) 23(16.9) 39(28.7) 6(4.4) 2(1.5) 0(0)
0(0) 43(31.6) 16(11.8) 4(2.9) 3(2.2) 0(0) 18(13.2) 44(32.4) 3(2.2) 1(0.7) 23(16.9) 40(29.4) 2(1.5) 1(0.7) 0(0)
0.30
0.04
0.52
limitations also included factors like lack of separate rooms in the emergency department for PSA, 2-hour follow-ups of the patients in the crowded emergency department, lack of cooperation of other departments like orthopedics and surgery departments. In the other words, patients' final condition was unknown because they were transferred from the emergency department. 4. Discussion In this double blind clinical trial, PF had deeper sedation and better analgesic effects on the patients compared to PK. In this study, pain reduction was significantly more in PF group compared to PK group and sedation was also significantly better in PF group in comparison with PK group after 15 min. Although relatively more side effects such as reduced heart rate and low O2 saturation were detected in PF group, they were not clinically important and considerable. In many studies propofol was considered as the drug of choice in painful measurements due to appropriate sedation and rapid return to the primary state [9,10]. Of course, in a systematic review study, the combination of ketamine and propofol had synergistic effects on sedation and analgesia and
also unexpectedly caused reduced respiratory side effects [11]. In systematic review studies, propofol was not significantly different from other medication options for PSA in the emergency department [12]. The study by Khutia et al. suggested that in order to reach a deeper sedation in PK group, less propofol is needed compared to PF group while there was no difference between the 2 groups regarding side effects such as blood pressure and apnea [13]. In the study by Chiaretti et al. it was suggested that respiratory depression in PF group was higher than PK group [14], which was confirmed in our study, yet the respiratory depression was not clinically important in this study. In a study by Bahrami Gorji, sedation score was the same in both groups for patients undergoing retrograde cholangiography, but the pain in PF group after endoscopy was lower than PK group [15]. In this study also the pain in the PK group was lower than PF group after 2 h. Of course in other studies, PK combination was a safe combination that caused deep sedation [16]. The rate of apnea and respiratory depression in PF group was higher than PK group and it had caused more respiratory side effects [15,17]. In the present study, although respiratory depression and low O2 saturation were seen, they were not important in clinical interventions. Measuring blood pressure during the first 20 min of PSA showed that after 8 min, the blood pressure in PF group was significantly lower than PK group [15]. In this study, low blood pressure was seen 15 min after PSA. Combination of propofol and fentanyl reduced the required dose of propofol for sedation compared to when using just propofol, which would result in manifestation of undesirable side effects like low blood pressure [18]. In the present study, it was also shown that the 2 groups were not significantly different regarding recovery time, which was also the same in some other studies [19]. Yet, in some studies, it was shown that there was a longer recovery time in PK group due to ketamine causing more side effects like dizziness, blurred vision and nausea [20]. Physician's satisfaction after PSA was the same in both groups and in line with the results of different previous studies, which reported similar results [15,21]. 5. Conclusion It seems that for induction of PSA in the emergency department, PF caused better analgesia and deeper sedation and 15 min after inducing
Table 4 Comparison of secondary outcomes. Variable Blood pressure (BP)
Pulse rate (PR)
Respiratory rate (RR)
O2 saturation (O2 sat)
Respiratory intervention, n (%)
Patient satisfaction, n (%)
Recovery time (min), median (minimum − maximum / IQR)
Before PSA, mean(SD) After 5 min of PSA, mean(SD) After 15 min of PSA, mean(SD) After 30 min of PSA, mean(SD) After 120 min of PSA, mean(SD) Before PSA, mean(SD) After 5 min of PSA, mean(SD) After 15 min of PSA, mean(SD) After 30 min of PSA, mean(SD) After 120 min of PSA, mean(SD) Before PSA, mean(SD) After 5 min of PSA, mean(SD) After 15 min of PSA, mean(SD) After 30 min of PSA, mean(SD) After 120 min of PSA, mean(SD) Before PSA, mean(SD) After 5 min of PSA, mean(SD) After 15 min of PSA, mean(SD) After 30 min of PSA, mean(SD) After 120 min of PSA, mean(SD) Normal Jaw thrust BMV Good Moderate Poor
PF
PK
p
130.15(11.62) 124.92(11.91) 120.30(10.14) 124.03(9.85) 127.80(10.52) 90.91(14.50) 85.85(11.00) 81.21(9.06) 86.39(9.25) 90.02(11.74) 16.53(3.15) 14.83(2.81) 13.74(2.49) 15.11(2.34) 15.70(2.26) 99.77(0.52) 97.33(3.09) 95.24(2.97) 97.83(2.58) 99.47(0.88) 63(90) 5(7.14) 2(2.86) 63(90) 3(4.29) 4(5.71) 22(11–41/7.25)
123.14(9.60) 124.59(9.43) 126.20(9.81) 126.67(9.94) 124.35(1028) 86.09(13.33) 90.89(10.28) 94.03(10.29) 94.56(10.89) 91.08(9.82) 14.29(1.85) 14.12(1.81) 13.74(1.48) 13.94(1.44) 13.76(1.80) 99.80(0.40) 99.08(1.12) 98.24(2.46) 99.08(1.88) 99.71(0.51) 62 3 1 59(89.39) 5(7.58) 2(3.03) 24(12–42/5)
˂0.001 0.85 0.001 0.12 0.59 0.49 0.007 ˂0.001 ˂0.001 0.575 ˂0.001 0.086 1.0 ˂0.001 ˂0.001 0.706 ˂0.001 ˂0.001 0.002 0.056 0.63
0.55
0.22
Please cite this article as: Aminiahidashti H, et al, Comparison of the combination of propofol–fentanyl with combination of propofol–ketamine for procedural sedation and analgesia..., American Journal of Emergency Medicine (2018), https://doi.org/10.1016/j.ajem.2018.01.080
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PSA, this difference is more obvious. Although there were undesirable side-effects, they have not been clinically considerable and have no effect on satisfaction and recovery time, the pain is significantly reduced after PSA and it is recommended to use PF for inducing PSA in emergency departments. References [1] Todd KH, Ducharme J, Choiniere M, Crandall CS, Fosnocht DE, Homel P, et al. Pain in the emergency department: results of the Pain and Emergency Medicine Initiative (PEMI) Multicenter Study. J Pain 2007;8:460–6. [2] Migita Russell T, Klein Eileen J, Michelle M. Garrison, sedation and analgesia for pediatric fracture reduction in the emergency department. A systematic review. Arch Pediatr Adolesc Med 2006 Jan;160(1):46–51. [3] Barkan S, Breitbart R, Brenner-Zada G, et al. A double-blind, randomised, placebocontrolled trial of oral midazolam plus oral ketamine for sedation of children during laceration repaire. Emerg Med J 2014;31(8):649–53. [4] Godwin SA, Caro DA, Wolf SJ, et al. Clinical policy: procedural sedation and analgesia in the emergency department. Ann Emerg Med 2005;45(2):177–96. [5] Bordo D, Chan SB, Shin P. Patient satisfaction and return to daily activities using etomidate procedural sedation for orthopedic injuries. West J Emerg Med 2008; 9(2):86–90. [6] Bawden J, Villa-Roel C, Singh M, et al. Procedural sedation and analgesia in a Canadian ED: a time-in-motion study. Am J Emerg Med 2011;29:1083–8. [7] DAS-Taskforce 2015, Baron Ralf, Binder Andreas, Biniek Rolf, Braune Stephan, et al. Evidence and consensus based guideline for the management of delirium, analgesia, and sedation in intensive care medicine. Revision 2015 (DAS-Guideline 2015) — short version. Ger Med Sci 2015;13:Doc19. [8] Pinto RF, Bhimani M, Milne WK, Nicholson K. Procedural sedation and analgesia in rural and regional emergency departments. Can J Rural Med 2013 Fall;18(4):130–6. [9] Stolz D, Kurer G, Meyer A, Chhajed PN, Pflimlin E, Strobel W, et al. Propofol versus combined sedation in flexible bronchoscopy: a randomised non-inferiority trial. Eur Respir J 2009;34(5):1024–30. [10] Gaisl T, Bratton DJ, Heuss LT, Kohler M, Schlatzer C, Zalunardo MP, et al. Sedation during bronchoscopy: data from a nationwide sedation and monitoring survey. BMC Pulm Med 2016 Aug 5;16(1):113.
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Please cite this article as: Aminiahidashti H, et al, Comparison of the combination of propofol–fentanyl with combination of propofol–ketamine for procedural sedation and analgesia..., American Journal of Emergency Medicine (2018), https://doi.org/10.1016/j.ajem.2018.01.080