How does ketofol (ketamine and propofol) compare to propofol alone for procedural sedation?

Ketofol vs Propofol for Procedural Sedation

Ketofol produces comparable sedation and has potentially fewer adverse events of minimal clinical significance compared to propofol alone. The most recent and highest quality evidence demonstrates that while ketofol reduces respiratory adverse events, the clinical significance of this reduction is modest, and both regimens are highly effective and safe for emergency department procedural sedation.

Primary Outcome: Respiratory Adverse Events

The combination of ketamine and propofol results in fewer respiratory adverse events compared to propofol alone, though the absolute difference is small. A 2015 systematic review and meta-analysis found that ketofol had a lower frequency of adverse respiratory events (29.0% vs. 35.4%; RR = 0.82; 95% CI = 0.68 to 0.99) 1. A 2019 systematic review confirmed these findings, demonstrating a lower incidence of respiratory adverse effects in the ketofol group 2.

However, the clinical significance of this difference is limited:

• The largest randomized trial (284 patients) found no significant difference in adverse respiratory events between ketofol and propofol (30% vs. 32%; difference 2%; 95% CI -9% to 13%; P=.80) 3
• A subsequent trial of 271 patients comparing propofol alone to 1:1 and 4:1 ketofol ratios found similar frequencies of airway or respiratory adverse events requiring intervention (29%, 19%, and 32%, respectively; P=.21) 4
• Most respiratory events in both groups are transient and self-limited, requiring only minor interventions 1, 3

Sedation Quality and Efficacy

Ketofol provides more consistent sedation depth compared to propofol alone, requiring fewer redosing episodes. The 2012 randomized trial demonstrated that 46% of ketofol patients required repeated dosing or progressed to inadequate sedation compared to 65% of propofol patients (difference 19%; 95% CI 8% to 31%; P=.001) 3. This translates to more stable procedural conditions with ketofol.

The American Society of Anesthesiologists guidelines note that propofol combined with ketamine produces deeper sedation than propofol alone 5. A 2010 study using bispectral index monitoring found that ketofol resulted in better sedation quality with a smaller decline in BIS scores (18.78 ± 10 vs. 34.64 ± 11) 6.

Hemodynamic Profile

Ketofol demonstrates superior hemodynamic stability compared to propofol alone. The 2010 randomized trial found that the propofol/ketamine group experienced a smaller decline in systolic blood pressure (1.6% vs. 12.5%) 6. This advantage stems from ketamine's sympathomimetic properties counteracting propofol's vasodilatory effects 7.

Procedure and Recovery Times

Procedure times and recovery times are comparable between ketofol and propofol. Multiple randomized trials found no significant differences in:

• Sedation time 1, 3
• Procedure duration 1, 3, 4
• Recovery time 3, 4

The American Society of Anesthesiologists guidelines report equivocal findings for recovery times when comparing propofol with ketamine combinations 5.

Adverse Event Profile Beyond Respiratory Events

Overall adverse event rates are similar between ketofol and propofol, with one notable exception: recovery agitation. The 2015 meta-analysis found no significant difference in overall adverse events (38.8% vs. 42.5%; RR = 0.88; 95% CI = 0.75 to 1.04) 1.

Recovery Agitation

The primary disadvantage of ketofol is increased recovery agitation:

• The 2012 trial reported 6 patients treated for recovery agitation in the ketofol group versus none in the propofol group 3
• The 2015 trial found greater recovery agitation with 1:1 ketofol (21%) compared to propofol (8%) or 4:1 ketofol (10%) 4
• This adverse event is typically mild and self-limited, though it may require brief intervention 3, 4

Serious Adverse Events

Serious adverse events are rare with both regimens. The 2012 trial reported only 3 ketofol patients and 1 propofol patient requiring bag-valve-mask ventilation 3. The 2015 trial reported no serious adverse events in any group 4.

Dosing Considerations

Ketofol allows for lower propofol doses while maintaining effective sedation. The 2010 study demonstrated a lower mean propofol dose with ketofol (92.5 ± 58 mg vs. 177.27 ± 11 mg) 6. The American Society of Anesthesiologists notes that combining medications allows for lower doses of each agent 5.

Common ketofol ratios used in emergency departments:

• 1:1 mixture (equal parts ketamine and propofol) 3, 4
• 4:1 propofol to ketamine ratio 4

Clinical Bottom Line

For emergency department procedural sedation, ketofol offers a modest reduction in respiratory adverse events and more consistent sedation depth compared to propofol alone, at the cost of slightly increased recovery agitation. The absolute differences in adverse events are small and of minimal clinical significance, as both regimens are highly effective and safe 2, 1, 3, 4.

When to Choose Ketofol Over Propofol Alone:

• Patients at higher risk for hypotension or hemodynamic instability 6
• Procedures requiring more consistent sedation depth to avoid repeated dosing 3
• Painful procedures where ketamine's analgesic properties provide additional benefit 7, 6

When to Choose Propofol Alone:

• Patients at risk for emergence reactions or with psychiatric contraindications to ketamine 7
• Brief procedures where rapid recovery without agitation is prioritized 3, 4
• Painless diagnostic procedures where ketamine's analgesic properties are unnecessary 5

Critical Monitoring Requirements:

Both regimens require identical monitoring standards. The American Society of Anesthesiologists emphasizes that propofol combined with ketamine increases the risk of respiratory depression and requires careful monitoring 5. All patients should have continuous pulse oximetry, capnography, and hemodynamic monitoring regardless of agent choice 5.