Ketofol simulations for dosing in pediatric anesthesia

Abstract

Background: Propofol mixed with racemic ketamine (or 'ketofol') is popular for short procedural sedation and analgesia. Use is creeping into anesthesia, yet neither the optimal combination nor infusion rate is known. The EC(50) of propofol's antiemetic effect is reported to be 0.343 mg·l(-1), while ketamine analgesia is thought to persist with concentrations above 0.2 mg·l(-1). We aimed to determine a ketofol dosing regimen for anesthesia 30-min and 1.5-h duration in a healthy child that did not unduly compromise recovery.

Methods: Pharmacokinetic-pharmacodynamic parameters were used to simulate drug concentration and effect profiles over time for different ratios of propofol to ketamine ratios (1 : 1 to 10 : 1) and rates. The target effect was the 95% probability of loss of response to a 5-s transcutaneous tetanus (P05). Combined effects were additive, with a propofol EC(50) of 3.1 mg·l(-1), ketamine EC(50) of 0.64 mg·l(-1), and slope of 5.4. The time to predicted 50% probability of return of this response after ceasing infusion (P(50)) was determined for a 5-year-old 20-kg healthy child.

Results: The addition of ketamine to propofol infused using a manual infusion regimen (loading dose 3 mg·kg(-1), then 15 mg·kg(-1) ·h(-1) for 15 min, 13 mg·kg(-1) ·h(-1) for 15 min, 11 mg·kg(-1) ·h(-1) for 30 min, and 10 mg·kg(-1) ·h(-1) for 1-2 h) caused prolonged postoperative sedation. The P(50) after a 1.5-h infusion using a 1 : 1 mixture was 4.5 h, 2 : 1 mixture was 3.25 h, 5 : 1 mixture was 1.6 h, and 10 : 1 mixture was 40 min. These P(50) estimates could be reduced by slowing administration infusion rates to 20%, 33%, 50%, 67%, 80%, and 90% for mixtures 1 : 1, 2 : 1, 3 : 1, 5 : 1, 6.7 : 1, and 10 : 1, respectively. These rates achieve a P(50) of approximately 20 min for 30-min duration anesthesia and 60 min for 1.5-h duration anesthesia.

Conclusions: The addition of ketamine to propofol infusion will prolong recovery unless infusion rates are decreased. We suggest an optimal ratio of racemic ketamine to propofol of 1 : 5 for 30-min anesthesia and 1 : 6.7 for 90-min anesthesia. Delivery of these ratios achieves propofol concentrations above an antiemetic threshold for longer than the ketamine concentration above the analgesic threshold during, potentially reducing postoperative nausea incidence.

Keywords: anesthesia; ketamine; pediatric; pharmacodynamics; pharmacokinetics; propofol; sedation; target concentration.