We retrieved 33 potentially relevant records from the search of the electronic databases. After eliminating duplicate records and those that did not meet eligibility criteria, we reviewed 12 full-text articles. One study was excluded due to non RCT 12. Finally, 11 RCTs met the review eligibility criteria 13–23 (Fig. 1).
We included 11 trials with total 1274 patients. All trials were single centre study. Four trials included 121 to 351 patients. 13,15,17,18, seven trials included 46 to 92 patients 14,16,19−23. The age ranged from one month to 16 years old. The trials involved three orthopedic and one surgical procedures 14,17−19, five invasive procedures 13,16,20−22, one elective imaging study 15 and one dental procedure 23. Table 1 summarizes the characteristic of included trials.
In 11 trials, five trials compared with single agent 13,15,17,18,23 and six trials compared with combination of agents. 14,16,19−22. For single agent comparison, three trials compared with propofol 13,15,23, three trials compare with ketamine 17,18,23. For combination agents, two trials compare with ketamine-dexmedetomidine 19,20, two trials compare with propofol-dexmedetomidine 21,22, two trials compare with propofol-fentanyl 14,16. Five trials gave bolus sedation without maintenance infusion 13,16−19, six trials gave bolus sedation with maintenance infusion 14,15,20−23.
Regarding the ratio between ketamine and propofol combination, 6 trials used 1:1 ratio 17–20, 22,23, two trials used 1:2 ratio 14,21, one trial used 2:1 ratio 15, one trial used 1:4 ratio 13, and one trial used 1:6 ratio 16.
The assessment of risk of bias is shown in Fig. 2 and Fig. 3. Figure 2 shows the proportion of studies as low, high or unclear risk of bias for each risk of bias domain. Figure 3 shows the risk of bias summary for individual studies. All trials described the method of randomization used. Five trials randomized the participants by closed envelope method 14,16,20,22,23; four trials randomized the participants by computer generated method 13,17,18,21; one trial used the coin toss method 19; one trials used 1:1 block randomization with different strata based on age and type of magnetic resonance imaging (MRI) 15. Blinding of participants and personnel were not described in four trials 13,19,22,23. Six trials analyzed all the samples without any withdrawal 16,19−23. Five trials carried intention to treat analysis in which the participants were analyzed according to the group that they were initially assigned 13–15, 17,18. All trials reported the outcomes as specified in their method section. We detected no other potential source of bias
Table 1
Characteristic of included trials
study | Intervention | Dose of ketofol | Dose of control | n | Age | Procedure | Outcome |
Canpolat 2012 | Ketofol vs Ketamine-dexmedetomidine | • 2 ml ketamine (50 mg/ml) + 8 ml NS • Propofol 1 mg/kg follow by ketamine 1 mg/kg • Additional propofol 1 mg/kg if needed | • 2 ml ketamine (50 mg/ml) + 8 ml NS • 0.5 ml dexmede-tomidine (50 µg) + 9.5 ml NS • Dexmedetomidine 0.5 µg/kg follow by ketamine 1 mg/kg • Additional dexmedetomidine 0.5 µg/kg if needed | 60 | 8 months to 5 years | Burn injury dressing | 1. Surgeon satisfaction 2. Adverse effect 3. Hemodynamic parameter |
Chiaretti 2011 | Ketofol vs propofol | • Ketamine 0.5 mg/kg before propofol injection • Propofol 2 mg/kg over 2 min • 0.5-1 mg/kg additional dose if required | • Bolus 2 mg/kg over 2 min • 0.5-1 mg/kg additional dose if needed | 121 | Ketofol: mean (SD): 6.9 (5.4) years Propofol: mean (SD):7.3 (5.2) years | Lumbar puncture or bone marrow aspiration | 1. Adverse effect 2. Hemodynamic parameter |
Joshi 2017 | Ketofol vs Dexmedetomidine-ketamine | • Propofol 1 mg/kg, ketamine 1 mg/kg • Maintenance IV infusion 100 µg/kg/min of propofol and 1 mg/kg/H of ketamine • Additional ketamine 0.5 mg/kg if needed | • Dexmedetomidine IV infusion 1 µg/kg over 1 min + ketamine 1 mg/kg IV bolus • Maintenance IV infusion of 0.5 µg/kg/h of dexmedetomidine and 1 mg/kg/h of ketamine • Additional ketamine 0.5 mg/kg if needed | 60 | 1 months to 6 years | Cardiac catheterization procedure | 1. Recovery time 2. Hemodynamic parameter |
Khutia 2012 | Ketafol vs propofol-fentanyl | • Ratio 1:2 mixing 1 ml ketamine (50 mg/ml) with 10 ml propofol 1% (10 mg/ml) • Each ml contains 9 mg propofol:4.5 mg ketamine • Bolus: 1 mg/kg propofol: 0.5 mg/kg ketamine • Infusion 0.5 µg/kg/min | • 10 ml propofol 1% mixed with 1 ml NS (9 mg/ml) • Fentanyl 1.5 µg/kg diluted to 2 ml of NS • Bolus: propofol 1 mg/kg • Infusion: 50 µg/kg/min | 92 | 3–14 years | Reduction of fracture, I&D abscess, wound debridement | 1. Recovery time 2. Adverse effect 3. Hemodynamic parameter |
Shah 2011 | Ketofol vs ketamine | • Ketamine 0.5 mg/kg + propofol 0.5 mg/kg • Additional 0.5 mg/kg propofol if needed | • Ketamine 1 mg/kg + intralipid placebo • Additional 0.25 mg/kg ketamine if needed | 140 | Median(IQR): 11(7–14) years | Closed manual reduction | 1. Recovery time 2. Adverse event 3. Satisfaction 4. Hemodynamic parameter |
Schmitz 2018 | Ketofol vs propofol | • 1 mg/kg ketamine 5% + propofol 1% 0.5 mg/kg + 0.03 ml/kg NS • propofol infusion 5 mg/kg/h | • Propofol 1% bolus 1 mg/kg • Propofol infusion 10 mg/kg/h | 351 | 3 months to 10 years | Elective MRI | 1. Recovery time 2. Satisfaction 3. Adverse event 4. Hemodynamic parameter |
Tewari 2018 | Ketofol vs Dexmedetomidine-propofol | • Bolus ketamine 1 mg/kg + propofol 2 mg/kg over 10 min • Infusion ketamine 0.5 mg/kg/h and propofol infusion 4–6 mg/kg/h | • Bolus dexmedetomidine 1 µg/kg and propofol 2 mg/kg over 10 min • Infusion dexmedeto-midine 0.25–0.75 µg/kg/h and propofol 4–6 mg/kg/h | 56 | 7–16 years | Congenital acyanotic heart disease considered amenable for device closure | 1. Recovery time 2. Adverse effect |
Tosun 2007 | Ketofol vs propofol-fentanyl | • Ketamine 0.2 mg/kg + propofol 1.2 mg/kg • Additional propofol 0.5-1 mg/kg if needed | • Fentanyl 0.2 µg/kg + propofol 1.2 mg/kg • Additional propofol 0.5-1 mg/kg if needed | 90 | 1–16 years | Upper gastrointestinal endoscope | 1. Recovery time 2. Adverse effect 3. Hemodynamic parameter |
Ulgey 2014 | Ketofol vs demedetomidine- propofol | • Ketamine 1 mg/kg + propofol 1 mg/kg • Maintenance ketamine 1 mg/kg/h and propofol 100 µg/kg/min • Additional propofol 0.5 mg/kg if needed | • Dexmedetomidine 1 µg/kg for 5 min, propofol 1 mg/kg • Maintenance dexmede-tomidine 0.5 µg/kg/h and propofol 100 µg/kg/min • Additional propofol 0.5 mg/kg if needed | 46 | 3–14 years | Atrial septal defect for transcatheter closure | 1. Recovery time 2. Adverse effect 3. Hemodynamic parameter |
Weisz 2017 | Ketofol vs ketamine | • Ketamine 0.5 mg/kg and propofol 0.5 mg/kg • 3 maximum additional dose 0.25 mg/kg ketamine and 0.25 mg/kg propofol if needed | • Ketamine 1 mg/kg • 3 maximum additional dose of 0.5 mg/kg ketamine | 183 | Ketofol: mean(SD): 9.3(5) Ketamine: mean(SD): 8.3(6) | Fracture of dislocation reduction | 1. Recovery time 2. Satisfaction 3. Adverse effect |
Yalcin 2018 | Ketofol vs ketamine vs propofol | • Ratio 1:1, 200 mg propofol (20 ml) + 200 mg ketamine (4 ml) • 0.6 mg/kg bolus followed by 40–60 µg/kg/min | • Ketamine 4 ml dilute with NS to 20 ml, 1 mg/kg bolus followed by 50–60 µg/kg/min • Propofol 2 mg/kg bolus followed by 70–90 µg/kg/min | 75 | 6–12 years | Dental treatment | 1. Recovery time 2. Adverse effect 3. Hemodynamic parameters |
A total of 11 trials measured the primary outcome i.e. recovery time 13–23. One study defined recovery time as time in minutes required for the patient to be conscious and responding to verbal stimuli, airway recovery with return of gag reflex or cough and motor recovery as purposeful movement of limbs 21; another study defined recovery time as period needed by the patient to spontaneously return to baseline consciousness 13; four studies used Steward Recovery Score to define the recovery time but with different cut off point: two studies used score of 6 20,22 while another two studies used score of 7 16,19; one study defined time from discontinuation of infusion of study and achievement of Ramsey Sedation Score of 3 as recovery time 14; another study used Modified Vancouver Sedation Recovery Scale to determine the recovery time 23.
Three trials measured satisfaction of clinician 17,19,23. Nine trials measured the secondary outcome i.e. adverse effects 13–19, 21,23.
The protocol intended to report hemodynamic parameters as a secondary outcome. There were not analyzed because there were either compared in different unit or non-comparable group. 13–15, 23. Four trials were not included in hemodynamic status data because they were demonstrated in graph. 16,19,20,22.
Comparison ketofol vs single agent control
Five trials with single agent of control group were analyzed 13,15,17,18,23. Five trials measured recovery time, but three trials reported the results in median and interquatile range (IQR) 15,17,18. Ketofol shows significant effect on recovery time compared to control (MD -9.88, 95% CI: -14.30 to -5.46; P = 0.0003; I2 = 92%; 2 trials, 171 participants; low certainty evidence) 13,23 (Fig. 4) (Table 2). However, ketofol shows no different on clinician satisfaction compared to control (RR 2.86, 95% CI: 0.64 to 12.69; P = 0.001; I2 = 90%; 2 trials, 125 participants; low certainty evidence) 17,23 (Fig. 5) (Table 2); airway obstruction compared to control (RR 0.72, 95% CI: 0.35 to 11.48; P = 0.81; I2 = 0%; 2 trials, 467 participants; high certainty evidence) 15,17 (Fig. 6) (Table 2); apnea compared to control (RR 0.9, 95% CI: 0.33 to 2.44; P = 0.88; I2 = 0%; 2 trials, 514 participants; high certainty evidence) 15,18 (Fig. 7) (Table 2); desaturation compared to control (RR 1.11, 95% CI: 0.64 to 1.94; P = 0.28; I2 = 21%; 4 trials, 771 participants; high certainty evidence) 13,15,17,18 (Fig. 8) (Table 2); nausea compared to control (RR 0.52, 95% CI: 0.91 to 1.41; P = 0.2; I2 = 38%; 3 trials, 642 participants; high certainty evidence) (Fig. 9) (Table 2); vomiting compared to control (RR 0.63, 95% CI: 0.25 to 1.61; P = 0.18; I2 = 42%; 3 trials, 642 participants; high certainty evidence) (Fig. 10) (Table 2)
Table 2
Summary of Finding for Comparison Between Ketofol and Single Agent
Ketofol compared to single agent for procedural sedation and analgesia |
Patient or population: Procedural sedation and analgesia Intervention: Ketofol Comparison: single agent |
Outcomes | Anticipated absolute effects* (95% CI) | Relative effect (95% CI) | № of participants (studies) | Certainty of the evidence (GRADE) |
Risk with single agent | Risk with Ketofol |
Recovery time | The mean recovery time was 0 | MD 9.88 lower (14.3 lower to 5.46 lower) | - | 171 (2 RCTs) | ⊕⊕⊝⊝ LOW 1 2 |
Satisfaction Clinician | Study population | RR 2.86 (0.64 to 12.69) | 186 (2 RCTs) | ⊕⊕⊝⊝ LOW 2 3 |
457 per 1,000 | 1000 per 1,000 (293 to 1,000) |
Airway Obstruction | Study population | RR 0.72 (0.35 to 1.48) | 467 (2 RCTs) | ⊕⊕⊕⊕ HIGH |
72 per 1,000 | 52 per 1,000 (25 to 107) |
Apnea | Study population | RR 0.90 (0.33 to 2.44) | 514 (2 RCTs) | ⊕⊕⊕⊕ HIGH |
30 per 1,000 | 27 per 1,000 (10 to 74) |
Desaturation | Study population | RR 1.11 (0.64 to 1.94) | 771 (4 RCTs) | ⊕⊕⊕⊕ HIGH |
94 per 1,000 | 104 per 1,000 (60 to 182) |
Nausea | Study population | RR 0.52 (0.19 to 1.41) | 642 (3 RCTs) | ⊕⊕⊕⊕ HIGH |
85 per 1,000 | 44 per 1,000 (16 to 120) |
Vomiting | Study population | RR 0.63 (0.25 to 1.61) | 642 (3 RCTs) | ⊕⊕⊕⊕ HIGH |
104 per 1,000 | 65 per 1,000 (26 to 167) |
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio; OR: Odds ratio; |
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect |
Footnote:
1 Duration of treatment varies following different procedures, thus required different dose of intervention
2 Small sample size
3 Subjective outcome with different type of population
Comparison Ketofol vs Combined Agent Control
Six trials with combined agent of control group were analyzed 14,16,19−22. Ketofol shows no effect on recovery time compared to control (RR 0.75, 95% CI: -6.24 to 7.74; P < 0.001; I2 = 98%; 6 trials, 404 participants; moderate certainty evidence) 14,16,19−22 (Fig. 11) (Table 3). Different RCTs had different ratio of mixture between ketamine and propofol. Thus, we included three studies which had 1:1 ratio of mixture 19,20,22 and two studies which had ratio of mixture 1:2 14,21 in subgroup analysis. With dosage ratio of 1:1, Ketofol shows no effect on recovery time compared to control (RR -7.95, 95% CI: -21.86 to 5.96; P < 0.001; I2 = 97%; 3 trials, 166 participants; low certainty evidence) (Fig. 11) (Table 3). With dosage ratio of 1:2, Ketofol also shows no effect on recovery time compared to control (RR 14.62, 95% CI: -11.09 to 40.33; P < 0.001; I2 = 98%; 2 trials, 148 participants; low certainty evidence) (Fig. 11) (Table 3). For adverse event, ketofol shows no effect on desaturation compared to control (RR 1.9, 95% CI: 0.15 to 23.6; P = 0.11; I2 = 61%; 2 trials, 150 participants; low certainty evidence) 16,19 (Fig. 12) (Table 3); respiratory depression compared to control (RR 1.98, 95% CI: 0.18 to 21.94; P = 0.12; I2 = 59%; 2 trials, 116 participants; low certainty evidence) (Fig. 13) (Table 3). However, ketofol shows significant effect on hypotension compared to control (RR 4.2, 95% CI: 0.2 to 0.85; P = 0.76; I2 = 0%; 3 trials, 208 participants; moderate certainty evidence) 14,19,21 (Fig. 14) (Table 3) but no difference in bradycardia compared to control (RR 0.70, 95% CI: 0.14 to 03.63; P = 0.09; I2 = 53%; 4 trials, 298 participants; low certainty evidence) 14,16,19,21 (Fig. 15) (Table 3)
Table 3
Summary of Finding Table for Comparison between Ketofol and Combined Agents
Ketofol compared to combined agent for procedural sedation and analgesia |
Patient or population: Procedural Sedation and Analgesia Intervention: Ketofol Comparison: Combined agent |
Outcomes | Anticipated absolute effects* (95% CI) | Relative effect (95% CI) | № of participants (studies) | Certainty of the evidence (GRADE) |
Risk with combined agent | Risk with Ketofol |
Recovery time | The mean recovery time was 0 | MD 0.75 higher (6.24 lower to 7.74 higher) | - | 404 (6 RCTs) | ⊕⊕⊕⊝ MODERATE 1 |
Recovery time - Dosage ratio 1:1 | The mean recovery time - Dosage ratio 1:1 was 0 | MD 7.95 lower (21.86 lower to 5.96 higher) | - | 166 (3 RCTs) | ⊕⊕⊝⊝ LOW 2 3 |
Recovery time - Dosage ratio 1:2 | The mean recovery time - Dosage ratio 1:2 was 0 | MD 14.62 higher (11.09 lower to 40.33 higher) | - | 148 (2 RCTs) | ⊕⊕⊝⊝ LOW 2 3 |
Desaturation | Study population | RR 1.90 (0.15 to 23.60) | 150 (2 RCTs) | ⊕⊕⊝⊝ LOW 1 3 |
54 per 1,000 | 103 per 1,000 (8 to 1,000) |
Respiratory depression | Study population | RR 1.98 (0.18 to 21.94) | 116 (2 RCTs) | ⊕⊕⊝⊝ LOW 1 3 |
68 per 1,000 | 134 per 1,000 (12 to 1,000) |
Hypotension | Study population | RR 0.42 (0.20 to 0.85) | 208 (3 RCTs) | ⊕⊕⊕⊝ MODERATE 3 |
194 per 1,000 | 82 per 1,000 (39 to 165) |
Bradycardia | Study population | RR 0.70 (0.14 to 3.63) | 298 (4 RCTs) | ⊕⊕⊝⊝ LOW 1 3 |
109 per 1,000 | 76 per 1,000 (15 to 395) |
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio; OR: Odds ratio; |
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect |
Footnote:
1 Result show large heterogeneity can be due to the following: 1) different population: some procedure required longer duration of treatment, thus larger dose required. 2) different ratio of mixture and dose of combination
2 Results show large heterogeneity can be due to different population and duration of procedure determine the required dose of intervention
3 Small sample size