We retrieved 50 potentially relevant studies from the search of the electronic databases. After excluding duplicate results and those that did not meet the 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 (Figure 1).
We included 11 trials with a total of 1274 patients. All trials were single-centre studies. Four trials included 121 to 351 patients 13,15,17,18, while seven trials included 46 to 92 patients 14,16,19-23. The age of the patients ranged from one month to 16 years old. The trials involved three orthopaedic 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 summarises the characteristics of included trials.
Of the 11 trials, five trials compared with a single-agent 13,15,17,18,23 and six trials compared with a combination of agents 14,16,19-22. In all the trials, PSA was administered by experienced practitioners. Among the studies involving single-agent comparison, three trials compared with propofol 13,15,23 and three trials compared with ketamine 17,18,23. Among the other six studies, two trials compared with ketamine-dexmedetomidine 19,20, two trials compared with propofol-dexmedetomidine 21,22, and two trials compared with propofol-fentanyl 14,16. Five trials involved bolus sedation without maintenance infusion 13,16-19, while six trials involved bolus sedation with maintenance infusion 14,15,20-23.
Regarding the ratios of ketamine and propofol, six trials used a 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 the risk of bias is shown in Figures 2 and 3. Figure 2 shows the proportion of studies with 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 the trials described the method of randomisation used. For randomisation of participants, five trials used the closed envelope method 14,16,20,22,23; four trials used the computer-generated method 13,17,18,21; one trial used the coin toss method 19; one trial used the 1:1 block randomisation with different strata based on the age and type of magnetic resonance imaging (MRI) 15. Blinding of participants and personnel was not described in four trials 13,19,22,23. Six trials analysed all the samples without any withdrawal 16,19-23. Five trials carried the intention to treat an analysis in which the participants were analysed according to the group that they were initially assigned 13-15,17,18. All trials reported the outcomes as specified in their respective Methods sections. We detected no other potential source of bias.
Table 1: Characteristics 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
- 1 mg/kg propofol followed by 1 mg/kg ketamine
- Additional 1 mg/kg propofol, if needed
|
- 2 mL ketamine (50 mg/mL) + 8 mL NS
- 0.5 mL dexmedetomidine (50 μg) + 9.5 mL NS
- 0.5 µg/kg dexmedetomidine followed by 1 mg/kg ketamine
- Additional 0.5 μg/kg dexmedetomidine, if needed
|
60
|
8 months to 5 years
|
Burn injury dressing
|
- Surgeon satisfaction
- Adverse effects
- Hemodynamic parameters
|
Chiaretti 2011
|
Ketofol vs. propofol
|
- 0.5 mg/kg ketamine before propofol injection
- 2 mg/kg propofol over 2 min
- 0.5-1 mg/kg additional dose, if required
|
- 2 mg/kg bolus 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
|
- Adverse effects
- Hemodynamic parameters
|
Joshi 2017
|
Ketofol vs. dexmedetomidine-ketamine
|
- 1 mg/kg propofol, 1 mg/kg ketamine
- Maintenance IV infusion of 100 μg/kg/min of propofol and 1 mg/kg/h of ketamine
- Additional 0.5 mg/kg ketamine, if needed
|
- 1 μg/kg dexmedetomidine IV infusion over 1 min + 1 mg/kg ketamine IV bolus
- Maintenance IV infusion of 0.5 µg/kg/h of dexmedetomidine and 1 mg/kg/h of ketamine
- Additional 0.5 mg/kg ketamine, if needed
|
60
|
1 month to 6 years
|
Cardiac catheterisation procedure
|
- Recovery time
- Hemodynamic parameters
|
Khutia 2012
|
Ketofol vs. propofol-fentanyl
|
- Ratio 1:2 mixing 1 mL ketamine (50 mg/mL) with 10 mL of 1% propofol (10 mg/mL)
- Each mL contains 9 mg propofol: 4.5 mg ketamine
- Bolus: 1 mg/kg propofol, 0.5 mg/kg ketamine
- Infusion of 50 µg/kg/min
|
- 10 mL of 1% propofol mixed with 1 mL NS (9 mg/mL)
- 1.5 µg/kg fentanyl diluted to 2 mL of NS
- Bolus: 1 mg/kg propofol, 1.5 µg/kg fentanyl
- Infusion of 50 µg/kg/min
|
92
|
3-14 years
|
Reduction of fracture, I&D abscess, wound debridement
|
- Recovery time
- Adverse effects
- Hemodynamic parameters
|
Shah 2011
|
Ketofol vs. ketamine
|
- 0.5mg/kg ketamine + 0.5mg/kg propofol
- Additional 0.5 mg/kg propofol, if needed
|
- 1 mg/kg ketamine + intralipid placebo
- Additional 0.25 mg/kg ketamine, if needed
|
140
|
Median (IQR): 11(7-14) years
|
Closed manual reduction
|
- Recovery time
- Adverse events
- Satisfaction
- Hemodynamic parameters
|
Schmitz 2018
|
Ketofol vs. propofol
|
- 1 mg/kg ketamine (5%) + 0.5 mg/kg propofol (1%) + 0.03 mL/kg NS
- 5 mg/kg/h propofol infusion
|
- 1 mg/kg propofol (1%) bolus
- 10 mg/kg/h propofol infusion
|
351
|
3 months to 10 years
|
Elective MRI
|
- Recovery time
- Satisfaction
- Adverse events
- Hemodynamic parameters
|
Tewari 2018
|
Ketofol vs. dexmedetomidine-propofol
|
- Bolus: 1 mg/kg ketamine + 2 mg/kg propofol over 10 min
- Infusion: 0.5 mg/kg/h ketamine and 4-6 mg/kg/h propofol
|
- Bolus: 1 µg/kg dexmedetomidine and 2 mg/kg propofol over 10 min
- Infusion: 0.25-0.75 µg/kg/h dexmedetomidine and 4-6 mg/kg/h propofol
|
56
|
7-16 years
|
Congenital acyanotic heart disease considered amenable for device closure
|
- Recovery time
- Adverse effects
|
Tosun 2007
|
Ketofol vs. propofol-fentanyl
|
- 0.2 mg/kg ketamine + 1.2 mg/kg propofol
- Additional 0.5-1 mg/kg propofol, if needed
|
- 0.2 µg/kg fentanyl + 1.2 µg/kg propofol
- Additional 0.5-1 mg/kg propofol, if needed
|
90
|
1-16 years
|
Upper gastrointestinal endoscope
|
- Recovery time
- Adverse effects
- Hemodynamic parameters
|
Ulgey 2014
|
Ketofol vs. dexmedetomidine- propofol
|
- 1mg/kg ketamine + 1 mg/kg propofol
- Maintenance: 1 mg/kg/h ketamine and 100 µg/kg/min propofol
- Additional 0.5 mg/kg propofol, if needed
|
- 1 µg/kg dexmedetomidine for 5 min, 1 mg/kg propofol
- Maintenance: 0.5 µg/kg/h dexmedetomidine and 100 µg/kg/min propofol
- Additional 0.5mg/kg propofol, if needed
|
46
|
3-14 years
|
Atrial septal defect for transcatheter closure
|
- Recovery time
- Adverse effects
- Hemodynamic parameters
|
Weisz 2017
|
Ketofol vs. ketamine
|
- 0.5 mg/kg ketamine and 0.5 mg/kg propofol
- 3 maximum additional doses of 0.25 mg/kg ketamine and 0.25 mg/kg propofol, if needed
|
- 1 mg/kg ketamine
- 3 maximum additional doses of 0.5 mg/kg ketamine
|
183
|
Ketofol: mean (SD): 9.3 (5)
Ketamine: mean (SD): 8.3 (6)
|
Fracture of dislocation reduction
|
- Recovery time
- Satisfaction
- Adverse effects
|
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 infusion
|
- 4 mL ketamine diluted with NS to 20 mL, 1 mg/kg bolus followed by 50-60 µg/kg/min
- 2 mg/kg propofol bolus followed by 70-90 µg/kg/min infusion
|
75
|
6-12 years
|
Dental treatment
|
- Recovery time
- Adverse effects
- 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 as the return of gag reflex or cough, and motor recovery as a purposeful movement of limbs 21; another study defined recovery time as the period needed by the patient to regain consciousness spontaneously 13; four studies used Steward Recovery Score to define the recovery time but with different cut off points, of which 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 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 the satisfaction of clinicians 17,19,23. Nine trials measured the secondary outcome, i.e., adverse effects 13-19,21,23. Our protocol intended to report hemodynamic parameters as a secondary outcome. These were not analysed because they either involved comparison in a different unit or a non-comparable group. 13-15,23. Four trials were not included in the hemodynamic status data because their data were demonstrated in the graph 16,19,20,22.
Comparison of ketofol vs. single-agent control
Five trials with single agent in the control group were analysed 13,15,17,18,23. All five trials measured recovery time; however, three trials reported the results in median and interquartile 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<0.001; I2 = 92%; 2 trials, 171 participants; low certainty evidence) 13,23 (Figure 4, Table 2). However, compared to the control group, the ketofol group showed no difference in terms of clinician satisfaction (RR 2.86, 95% CI: 0.64 to 12.69; P=0.001; I2 = 90%; 2 trials, 125 participants; low certainty evidence) 17,23 (Figure 5, Table 2); airway obstruction (RR 0.72, 95% CI: 0.35 to 11.48; P=0.810; I2 = 0%; 2 trials, 467 participants; high certainty evidence) 15,17 (Figure 6, Table 2); apnoea (RR 0.9, 95% CI: 0.33 to 2.44; P=0.880; I2 = 0%; 2 trials, 514 participants; high certainty evidence) 15,18 (Figure 7, Table 2); desaturation (RR 1.11, 95% CI: 0.64 to 1.94; P=0.280; I2 = 21%; 4 trials, 771 participants; high certainty evidence) 13,15,17,18 (Figure 8, Table 2); nausea (RR 0.52, 95% CI: 0.91 to 1.41; P=0.200; I2 = 38%; 3 trials, 642 participants; high certainty evidence) (Figure 9, Table 2); and vomiting (RR 0.63, 95% CI: 0.25 to 1.61; P=0.180; I2 = 42%; 3 trials, 642 participants; high certainty evidence) (Figure 10, Table 2).
Table 2: Summary of Findings for Comparison between Ketofol and Single-Agent
Ketofol compared to a 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)
|
No. 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 of 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.
|
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, and thus, required different doses of intervention
2 Small sample size
3 Subjective outcome with different types of population
Comparison of Ketofol vs. Combined Agent Control
Six trials with combined agent in the control group were analysed 14,16,19-22. Ketofol shows no significant 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 (Figure 11, Table 3). Different RCTs used different ratios of ketamine and propofol in combined agent. We included three studies that used 1:1 ratio 19,20,22 and two studies that used the ratio 1:2 14,21 in subgroup analysis. With dosage ratio of 1:1, ketofol showed 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) (Figure 11, Table 3). With dosage ratio of 1:2, ketofol also showed 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) (Figure 11, Table 3). With respect to adverse events, compared to control, ketofol showed no effect on desaturation (RR 1.9, 95% CI: 0.15 to 23.6; P=0.110; I2 = 61%; 2 trials, 150 participants; low certainty evidence) 16,19 (Figure 12, Table 3) and respiratory depression (RR 1.98, 95% CI: 0.18 to 21.94; P=0.120; I2 = 59%; 2 trials, 116 participants; low certainty evidence) (Figure 13, Table 3). However, ketofol showed significant effect on hypotension (RR 4.2, 95% CI: 0.2 to 0.85; P=0.760; I2 = 0%; 3 trials, 208 participants; moderate certainty evidence) 14,19,21 (Figure 14, Table 3) but no effect on 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 (Figure 15, Table 3).
Table 3: Summary of Findings for Comparison between Ketofol and Combined Agents
Ketofol compared to a 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)
|
No. 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; MD: Mean difference; RR: Risk 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 Results show large heterogeneity that can be due to the following: 1) different populations: some procedures required a longer duration of treatment, thus, larger doses are required. 2) different ratios of the mixture and dosages of the combination
2 Results show large heterogeneity that can be due to different populations and durations of procedures that determine the required dose of intervention
3 Small sample size