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 EC₅₀ 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 EC₅₀ of 3.1 mg·l⁻¹, ketamine EC₅₀ 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 (P₅₀) 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 P₅₀ 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 P₅₀ 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 P₅₀ 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.

Introduction

Ketofol is a neologism coined to refer to the combination of ketamine and propofol mixed together in one syringe. These two drugs are pharmacologically compatible 1, 2, and this combination has been used since the early 1990s for surgical anesthesia. There has been increasing interest in this mixture for anesthesia in both children 3-8 and adults 9-11, subsequent to reports of fewer adverse events, less vomiting and earlier discharge times after procedural sedation and analgesia. The ideal propofol to ketamine ratio for anesthesia remains unknown although an optimal ratio of racemic propofol to ketamine of 1 : 3 for short procedures (10–20 min) has been suggested 12. The duration of effect for ketamine is context sensitive 13. Consequently, a ratio of 1 : 3 may not be optimal for anesthesia of duration longer than 20 min. There is increasing enthusiasm for total intravenous anesthesia in children 14, 15, and ketamine may find a niche in this role because it maintains respiration and lacks opioid-associated adverse effects (respiratory depression, postoperative nausea and vomiting, pruritus, chest muscle wall rigidity). Ketamine augmented with other drugs such as propofol, dexmedetomidine, or midazolam has been suggested as an alternative to inhalation agents in children with neuromuscular disorders because of concerns about rhabdomyolysis 16.

Debate continues as to whether the interaction between propofol and ketamine is synergistic, additive or infra-additive for sedation and anesthesia 17, 18. We have assumed additivity of effect between propofol and ketamine, based on information from the study by Hui et al. 17. We used pharmacokinetic–pharmacodynamic (PK–PD) models reported in the literature to simulate ketofol effects when used for surgical anesthesia in a 5-year-old 20-kg child. We aimed to determine the optimum mixture ratio, and the best dosing regimen.

Methods

This was a simulation study in which drug concentrations (plasma and effect site) and anesthesia probability profiles over time were estimated for racemic ketamine with propofol. We used reported pharmacodynamic parameter estimates for ketamine and propofol in adults to predict probability of anesthesia defined as loss of response to verbal command and loss of response to a 5-s transcutaneous tetanus 17. We simulated response for endpoints of probability of consciousness (defined by response to tetanic stimuli) after anesthesia and recovery times using different dose combination ratios in a 5-year-old 20-kg child.

Simulations

Simulations were performed in Excel 2010 using PK–PD Tools for Excel© 2009, version 1.31 (www.pkpdtools.com). Plasma and effect-site concentrations were estimated using pharmacokinetic parameter sets available in the literature. We assumed the pharmacokinetic parameter set described by Kataria et al. 19 adequately described propofol pharmacokinetics in children aged 3–11 years. Ketamine pharmacokinetics were described for children using the parameter set reported by Herd et al. 20. Allometric scaling 21 was used to correct for size.

Response was related to drug concentrations in a hypothetical effect compartment. The rate of drug transfer between this effect compartment and that of the plasma was described using an equilibration rate constant, keo. Herd et al. 22 estimated an equilibration half-time (t_1/2keo) for ketamine to be 11 s. This equates to a keo value of 3.78 min⁻¹, i.e.,

$urn:x-wiley:11555645:media:pan12386:pan12386-math-0001$ (1)

A keo of 0.89 min⁻¹ for propofol effects on the bispectral index (BIS) has been reported 23. This was used to estimate propofol effect-site concentrations in the child.

We assumed additivity exists between propofol and ketamine for anesthesia. A modified sigmoidal dose–response curve was used to describe combined effects 24, 25, i.e.,

$urn:x-wiley:11555645:media:pan12386:pan12386-math-0002$ (2)

where Ce is the concentration of ketamine (k) or propofol (p) in the effect site, EC₅₀ is the concentration required to produce anesthesia in 50% of patients (P₅₀), and γ is a slope parameter describing the shape of the dose–response curve. Hui et al. 17 provided ED₅₀ estimates for anesthesia using a propofol and ketamine combination (ED₅₀, 1.05 mg·kg⁻¹ propofol and 0.35 mg·kg⁻¹ ketamine). As previously described 12, we used simulation to estimate the corresponding concentrations in the effect-site compartment for these doses and at the time of assessment of anesthesia probability. This gave an estimated EC_50,p 3.1 mg·l⁻¹ for propofol and EC_50,k 0.64 mg·l⁻¹ for ketamine. A slope (γ) of 5.4 was used as this was estimated by Hendrickx et al. during their reanalysis of the data from Hui et al. 18. The EC₅₀ of propofol's antiemetic effect is reported to be 0.343 mg·l⁻¹ 26. Ketamine analgesia is thought to persist with concentrations above 0.2 mg·l⁻¹ 27, 28.

Simulations were then performed with the PK–PD model to investigate the best dosing regimens for both boluses and infusions.

Dose regimen selection

We aimed to identify the optimum mixture ratio and dosing that provides effective anesthesia [i.e., 95% probability of loss of response (P₀₅)] with the shortest time to emergence, longest antiemetic effect of propofol, and the easiest practical drug mixing and dosing volumes [based on the formulations commonly available in Australasia: racemic ketamine (10%, 2 ml vial) and propofol (1%, 20 ml vial)]. Propofol to ketamine ratios from 1 : 1 to 1 : 10 were investigated as infusion for both 30 min and 90 min. We used the base infusion rate for propofol described by McFarlan et al. 29. A loading dose of 2.5 mg·kg⁻¹ followed by an infusion rate of 15 mg·kg⁻¹·h⁻¹ for the first 15 min, 13 mg·kg⁻¹·h⁻¹ from 15 to 30 min, 11 mg·kg⁻¹·h⁻¹ from 30 to 60 min, 10 mg·kg⁻¹·h⁻¹ from 1 to 2 h.

Results

Dosing regimens

Infusion regimens that maintained a probability of response <0.05 are shown in Table 1. The addition of ketamine to the base propofol regimen (suggested by McFarlan) resulted in extremely delayed awakening (P₅₀) of over 4 h when the propofol:ketamine 1 : 1 mixture was used. This decreased to a delay of 50 min when a 10 : 1 ratio was used. However, reduction in infusion rate to maintain a probability of anesthesia >95% resulted in times to P₅₀ of 16–24 min after 30-min exposure and 40–60 min after 90-min exposure in all scenarios (Table 2). Figures 1-3 show the probability of consciousness, propofol concentrations, and ketamine concentrations after infusion regimens using propofol:ketamine mixes of 1 : 1, 5 : 1, and 10 : 1 with infusion reduction schedules (Table 1). Figure 2 shows the impact of age on return to consciousness after a 90-min infusion; the P₅₀ was 40 min in a 2-year-old and 65 min for a 10-year-old child. The propofol:ketamine ratio of 5 : 1 achieved a balance where propofol concentrations were above 0.343 μg·ml⁻¹ and ketamine above 0.2 μg·ml⁻¹ for 83 min after a 30-min infusion (Table 3). A propofol:ketamine ratio of 6.7 : 1 revealed a longer duration of propofol concentrations (135 min) over ketamine (150 min). Clearance, expressed as l·h⁻¹·kg⁻¹, increased with decreasing age 21. Consequently, recovery is slower as age increases (Figure 2). Infusion rates and recovery rates shown in the tables are for a 5-year-old child.

Table 1. Dosing regimens for propofol (P) and ketamine (K) mixes of ketofol. The table shows the McFarlan regime (initial bolus dose followed by an infusion) and then reductions in the McFarlan regime thereafter. Simulated probability of response for various regimes is illustrated in Figures 1-3

			20%		33%		50%		67%		80%		90%
			Rate as a percentage of McFarlan regime
	Ratio P:K		1 : 1		2 : 1		3 : 1		5 : 1		6.7 : 1		10 : 1
	Propofol alone (McFarlan)	Ketamine alone	P	K	P	K	P	K	P	K	P	K	P	K
	Initial loading doses (mcg·kg⁻¹)
	3000	1000	800	800	1500	750	2000	666	2500	500	2750	410	3000	300
	Subsequent infusion rates (mcg·kg⁻¹·min⁻¹)
0–15 min	250	70	50	50	82.5	41.25	125	41.25	167.5	33.5	200	25.1	225	22.5
15–30 min	216.7	55	43	43	71.5	37.8	108.3	37.8	145.2	29.0	173.3	21.8	195	19.5
30–60 min	183.3	45	36.6	36.6	60.5	30.3	91.7	30.3	122.8	24.6	146.7	18.4	165	16.5
6–90 min	166.7	25	33.3	33.3	55	27.5	83.3	27.5	111.7	22	133.3	16.8	150	15

Table 2. The time to predicted 50% probability of consciousness (P₅₀) after stopping an infusion of ketofol lasting 30 or 90 min

	Propofol McFarlan	Ketamine	1 : 1	2 : 1	3 : 1	5 : 1	6.7 : 1	10 : 1
Infusion duration	Time to P₅₀
30 min infusion	5 min	27 min	17	17	24	22	20	16
30 min infusion without rate reduction			3 h	2 h	1 h 25 min	45 min	35 min	20 min
90 min infusion	8 min	70 min	63 min	50 min	60 min	50 min	47 min	40 min
90 min infusion without rate reduction			4 h 35 min	3 h 15 min	2 h 25 min	1 h 35 min	1 h 10 min	50 min

Table 3. Duration propofol and ketamine concentrations are maintained above either 0.343 mg·l⁻¹ (propofol) or 0.2 mg·l⁻¹ (ketamine) after stopping an infusions lasting 30 or 90 min

	Propofol McFarlan	Ketamine	1 : 1	2 : 1	3 : 1	5 : 1	6.7 : 1	10 : 1
Infusion duration	Propofol concentration > 0.343 mg·l⁻¹
30 min infusion	5 min	–	15 min	43 min	66 min	83 min	95 min	110 min
90 min infusion	8 min	–	22 min	50 min	90 min	135 min	175 min	210 min
	Ketamine concentration >0.2 mg·l⁻¹
30 min infusion	–	180	150 min	120 min	110 min	83 min	70 min	30 min
90 min infusion		210	200 min	180 min	170 min	150 min	130 min	90 min

Details are in the caption following the image — **Figure 1**
Open in figure viewer PowerPoint

The upper panel shows the probability of response during anesthesia using a propofol:ketamine ratio of 1 : 1. The loading dose for induction of anesthesia was 0.8 mg·kg⁻¹ propofol and 0.8 mg·kg⁻¹ of ketamine. Infusion rate was 20% that suggested by McFarlan (see Table 1 for infusion rates). The lower panel shows simulation results for a 90-min infusion.

Bispectral index values for anesthesia using ratios of 1 : 1. 5 : 1 and 10 : 1 are shown in Figure 4. Higher BIS scores are predicted as the proportion of ketamine is increased relative to propofol infused.

Discussion

Both ketamine and propofol are drugs with half-lives that are context sensitive. Consequently, single bolus dose ketofol use for procedural sedation and analgesia remains popular because drug proportions are not as important as during infusion. Simply adding ketamine to a propofol infusion and using the manual rates suggested by McFarlan 29 results in unacceptable recovery duration times if infusion duration is longer than 20 min. The context-sensitive half-life of ketamine is known to increase dramatically after 30 min 13. Infusion rates should be reduced as the proportion of ketamine is increased for these longer duration infusions. When infusion rate is reduced, then all mixes resulted in a P₅₀ after 90 min that ranged from 40 to 63 min, with quicker emergence for lower ratios. The ‘best’ ratio will depend both on clinical factors—analgesia requirement, anesthesia duration, and local postanesthesia care unit (PACU) practices—and on the results of further investigation into the incidence of respiratory compromise and postoperative nausea and vomiting with different ketamine to propofol ratios.

Predictions for infusion rates of ketamine alone are similar to those reported by Singh and colleagues 30 in spontaneous breathing children (age 1 day–14 years, n = 107) undergoing interventional cardiac procedures. The procedure duration was 68 (sd 11) min and children were kept in PACU for 65 (sd 5) min, consistent with our predictions. Ketofol simulations are based on the premise that the pharmacodynamic responses in a child (5 years) are similar to that in an adult 31. We suggest that a propofol:ketamine mix of 10 : 1 be used for cardiac catheterization where patient stimulation after cannulation is minimal. This will result in the lower P₅₀ of 40 min after a 90-min procedure. A number of other different infusions rates have been suggested, but these commonly require individual syringe pumps 5, 7. Burn dressing changes are more painful, and propofol : ketamine ratios of 2 : 1 and 1 : 1 have been used 8, 11. These ratios were associated with high incidence of psychotropic effects (10% unpleasant dreams) and ratios of 4 : 1 to 6.7 : 1 proved just as effective 32. We would suggest that ratios of 5 : 1 or 6.7 : 1 be used depending on treatment duration.

Nausea and vomiting following ketamine use occurs with an incidence of 7–8% in children and 5–15% in adults, peaking in early adolescence after IV administration 33, 34. Less nausea and vomiting are reported when propofol is employed with ketamine for sedation. Children receiving ketamine with propofol had less vomiting than those given ketamine alone (2% vs 12%) after orthopedic procedures 35. Propofol has an antiemetic effect with an EC₅₀ 0.343 mg·l⁻¹. The time that this ‘antiemetic threshold’ exceeds the analgesic threshold for ketamine (0.2 mg·l⁻¹) changes with both the dose ratio and duration of infusion. This rationale further supports that upper ratios of 5 : 1 or 6.7 : 1 be used depending on treatment duration. During infusion, concentrations of ketamine were above 0.6 mg·l⁻¹ and these concentrations are associated with satisfactory analgesia 36.

Anesthesia may require the use of neuromuscular blocking drugs. It may be advantageous to use a modified electroencephalographic signal monitor on these occasions. However, ketamine has minimal effect on bispectral index (BIS) 37. Consequently, BIS values are >80 when the ketofol 1 : 1 ratio is used. We suggest that a BIS of 60, rather than 50 is targeted when using ratios of 5 : 1 or 6.7 : 1 (Figure 4).

Disclosures

Ethical approval was not required for this simulation study. Brian Anderson is a Section Editor for the journal Pediatric Anesthesia. This research was funded by departmental sources. J Hannam was supported by a PhD scholarship from the Green Lane Research and Educational Fund Board, Auckland, New Zealand.

Funding

This research was carried out without funding.

Conflict of interest

No conflicts of interest declared.

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Citing Literature

Volume24, Issue8

August 2014

Pages 806-812

Ketofol simulations for dosing in pediatric anesthesia