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BJA Advance Access originally published online on January 16, 2006
British Journal of Anaesthesia 2006 96(3):330-334; doi:10.1093/bja/aei316
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© The Board of Management and Trustees of the British Journal of Anaesthesia 2006. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Pharmacokinetics of S(+) ketamine derived from target controlled infusion

M. White1,*, P. de Graaff1, B. Renshof1, E. van Kan2 and M. Dzoljic1

1 Department of Anaesthesiology and 2 Department of Clinical Pharmacy, Academic Medical Centre, University of Amsterdam, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands

* Corresponding author. E-mail: m.white{at}amc.uva.nl

Accepted for publication December 8, 2005.


   Abstract
Top
 Abstract
Introduction
 Methods
 Computer analysis
 Results
 Discussion
 References
 
Background. A computer controlled infusion device for S(+) ketamine was used in combination with a Diprifusor® device to provide anaesthesia for 20 ASA I or II patients undergoing elective colonoscopy. The aim of the study was to assess the performance of the pharmacokinetic model for S(+) ketamine used in the delivery algorithm of the device.

Results. It was observed that during the first 30 min of infusion there was systematic underprediction by the delivery system of the measured levels of S(+) ketamine. New pharmacokinetic constants were derived from the observed data which provided, on pharmacokinetic simulation, improved prediction of the measured values of S(+) ketamine. Prospective application of this modified model for S(+) ketamine in a further nine study patients was performed and the pharmacokinetic performance of the model was reassessed. The data from all 29 patients was subsequently used to calculate the population distribution of S(+) ketamine clearance. The distribution was found to be normal only in the logarithmic domain. In the normal domain the mode of S(+) ketamine clearance was found to be 35.8 ml kg–1 min–1 with 5 and 95% confidence limits of, respectively, 11.5 and 111.1 ml kg–1 min–1.

Conclusion. It was necessary to modify the original published pharmacokinetic parameters incorporated into the S(+) ketamine delivery system in order to simulate improved PK performance during short procedures (<1 h duration) where propofol was concurrently administered. This improved performance was confirmed in a further prospective study.

Keywords: anaesthetics i.v., ketamine; anaesthetics i.v., propofol; anaesthetics i.v., target controlled infusion; pharmacokinetics


   Introduction
Top
 Abstract
 Introduction
Methods
 Computer analysis
 Results
 Discussion
 References
 
The i.v. anaesthetic agent ketamine is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist and may be used to provide analgesia together with dissociative anaesthesia.1 The racemic form of the drug has been in clinical use for more than 30 yr and lacks the cardiorespiratory depression seen with most other general anaesthetic agents.2 3 Ketamine also possesses sympathomimetic properties which counteract the cardio-depressive properties of propofol.4 The sedative effects of ketamine and propofol are additive at the end-points of hypnosis and anaesthesia, implying that the combination produces a deeper level of sedation with less risk of respiratory depression5 while, at the same time, providing analgesia.

The principal disadvantage of the drug, however, is that its use is associated with undesireable psychomimetic effects during and after anaesthesia, so called ‘emergence reactions’.3 Early human studies of ketamine isomers6 appeared to demonstrate that the S(+) isomer of ketamine produced less psychic emergence reactions than either the R(–) form or the racemic mixture. Recently, the racemic form of ketamine has been withdrawn by the manufacturer from clinical use in mainland Europe and replaced with the optically pure enantiomer S(+) of ketamine [Ketanest® (Parke Davis, Hoofddorp, The Netherlands)]. The S(+) enantiomer is considered to be twice as potent as the racemic mixture producing more effective anaesthesia for a given drug load and more postoperative analgesia than either the racemate or the pure R(–) form, whereas the R(–) enantiomer is considered to be responsible for the psychotomimetic side-effects.6 Benzodiazepines are known to attenuate such psychomimetic reactions by virtue of their ability to activate the {gamma}-aminobutyric acidA (GABAA) receptor.7 Propofol is also known to activate the GABAA receptor8 whilst at the same time having some NMDA receptor inhibiting activity.9 Concurrent administration of propofol with ketamine should, on theoretical grounds,10 reduce the likelihood of emergence reactions.

In view of the above considerations, we wished to develop a target controlled infusion (TCI) system for S(+) ketamine which could work in parallel with the Diprifusor, and produce predictable stable concentrations of drug in our study population. The aim of the present study was to evaluate, under these conditions, the pharmacokinetic performance of such a TCI device for S(+) ketamine which used the pharmacokinetic model described by Geisslinger and colleagues.11


   Methods
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 Abstract
 Introduction
 Methods
Computer analysis
 Results
 Discussion
 References
 
The protocol for the study was approved by the local hospital Ethics Committee, and written informed consent was obtained from each patient before inclusion. Initially, 20 ASA I or II patients, who presented for elective day case colonoscopy, were studied (Group I). In the second prospective part of the study, we studied a further nine ASA I or II patients (Group II). Premedication was not administered. Patient monitoring comprised ECG, pulse-oximetry, end-tidal capnography and non-invasive arterial pressure. Bispectral Index (BIS) monitoring (Aspect Medical Systems, Natick, MA, USA) was used to assess the depth of sedation/anaesthesia. An i.v. cannula was then inserted to administer the i.v. drugs. The patient's lungs were preoxygenated for 3 min and supplemental oxygen was delivered throughout the procedure by a facemask to ensure Formula >90%. Using a propofol TCI infusion system (Diprifusor®,AstraZeneca, Macclesfield, UK), a suitable target of propofol was selected to render the patient unconscious with a stable BIS measurement between 50 and 70. After placement of a second i.v. catheter to facilitate the removal of blood samples, a second TCI infusion system for S(+) ketamine was commenced, selecting a target of 250 ng ml–1. This system consisted of a Graseby 3500 anaesthesia pump (Graseby Medical Ltd, Watford, UK) controlled by an external laptop computer programmed with TCI software [written by one of the authors (M.W.) in GFABasic for Windows v37, GFA Data Media, UK Ltd] running in compiled form on an IBM Pentium PC under Windows 98 (Microsoft Corporation). The pharmacokinetic parameters for the three compartment model used for the delivery of S(+) ketamine were derived by Geisslinger and colleagues.12 The concentration of S(+) ketamine in the pump syringe was 5 mg ml–1. Blood samples for both S(+) ketamine and propofol analyses were withdrawn 5 min after commencing the ketamine infusion and at 5 min intervals thereafter, until the patient had recovered. Serum propofol and S(+) ketamine concentrations were both measured using validated high performance liquid chromatography techniques12 13 in the hospital's Department of Clinical Pharmacy. Both assays had detection limits well below the observed concentrations and coefficients of variation of <10%.

The obtained BIS data were correlated with the depth of the sedation assessed clinically and stored on a laptop computer using the Microsoft Windows 98 accessory programme ‘Hyperterminal’ and analysed off-line.


   Computer analysis
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 Abstract
 Introduction
 Methods
 Computer analysis
Results
 Discussion
 References
 
The percentage prediction error (PE%), calculated for each data point was defined as:

Formula
where Cm is the measured drug concentration and Cp is the predicted blood concentration.

Bias is defined as the median prediction error and is a measure of the tendency of the system to under or over estimate the measured blood concentration of S(+) ketamine.

Precision is defined as the median absolute performance error and is a measure of the inaccuracy of the system.

The individual clearance of S(+) ketamine for each patient was estimated using a computer program written by one of the authors (M.W.) in GFABasic for Windows (GFA Data Media UK Ltd) and runs in compiled form on an IBM Personal Computer running Windows 98 (Microsoft Corporation). For each patient data set of measured blood levels of S(+) ketamine, non-linear regression was used in order to minimize the extended least squares objective function [NONMEM objective function or –2 times log likelihood (–2LL)]. The NONMEM objective function is a measure of the goodness of fit14 15 of the observed data to the proposed model and incorporated rate parameters. Data input is highly automated and consists of the computerized record of each infusion profile generated by the TCI pump together with a preformatted file containing the measured blood S(+) ketamine data. For each measured value of blood S(+) ketamine, a prediction was calculated from the computerized record of volume of drug actually delivered rather than using the direct prediction from the system algorithm, so as to avoid errors which arise from a discrepancy between ideal and actual pump performance.


   Results
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 Abstract
 Introduction
 Methods
 Computer analysis
 Results
Discussion
 References
 
Twenty patients were enrolled in Group I and nine patients in Group II (Table 1). An example of the course of a typical anaesthetic (56 kg patient, Fig. 1) shows induction with a Diprifusor® system by initially selecting a target of 6 µg ml–1. After insertion of a second cannula for i.v. sampling, the propofol target was lowered to 3 µg ml–1 and S(+) ketamine infusion was commenced by the second TCI system to a target level of 250 ng ml–1 and maintained at that level until the end of the procedure. The propofol target was modified during the procedure, as required according to either the anaesthetist's clinical assessment and/or the BIS trend. For the study group, the mean duration of the S(+) ketamine infusion was 29.6 min (range 18–64 min). The mean dose of S(+) ketamine received by each patient during the procedure was 905.4 µg kg–1 (SD=74 µg kg–1).


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  		Table 1. Patient characteristics. Data are mean (range) or mean (SD)

 

Figure 1
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  		Fig 1 TCI profiles of (A) propofol (10 mg ml–1) and (B) S(+) ketamine (5 mg ml–1) delivered to a 35-yr-old female patient (weight=56 kg) undergoing elective colonoscopy. The continuous line represents the calculated blood concentration of either (A) propofol or (B) S(+) ketamine and the vertical bars represent the pump rate. The small decrease in concentration of propofol in (A) at 38 min was caused by the necessity to replace the empty syringe.

 
For all samples (n=150) the median PE% was calculated to be 35%, the median precision 51%, and –2LL=19.1 (Fig. 2). Especially during the first 30 min, there was a systematic underprediction by the delivery system of the measured values of S(+) ketamine. Thereafter there was a good prediction of the measured value of the drug.


Figure 2
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  		Fig 2 Individual time course of % prediction error for the 20 patients of Group 1 when prediction is based on PK parameters of Geisslinger and colleagues.11

 
After adjusting the PK parameters of the delivery model to provide an optimized relationship between predicted and measured values of S(+) ketamine, using a computer program which minimized the NONMEM objective function, pharmacokinetic simulation using this optimized model produced a new estimate of PE% for each data point (Fig. 3). The overprediction of measured values observed in the first 30 min of the infusion was largely abolished. The median bias was calculated to be –0.03%, the median precision was 26.5% and the value of the objective function (–2LL) was –192.


Figure 3
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  		Fig 3 Individual time course of % prediction error for the 20 patients of Group 1 when prediction is based on revised PK parameters.

 
The revised model was tested prospectively in Group II and the measured concentrations of S(+) ketamine were compared with corresponding predicted values calculated by the delivery system algorithm. For 75 samples, the median bias was calculated to be 16.2% and the median precision 64.2% (Fig. 4).


Figure 4
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  		Fig 4 Individual time course of prediction error for the nine patients in Group II when prediction is based on revised PK parameters in the delivery system.

 
To determine the distribution of S(+) ketamine clearance in the study population, the individual S(+) ketamine clearance was determined for each of the 29 patients in the two study groups. For the whole population, the distribution of S(+) ketamine clearance was found to be normal only in the log domain and, after back transformation into the normal domain, the curve is skewed to the right (Fig. 5). The mode clearance was then found to be 35.8 ml kg–1 min–1 with 5 and 95% confidence limits of 11.5 and 111.3 ml kg–1 min–1, respectively.


Figure 5
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  		Fig 5 Back transformation of the logarithmic distribution of S(+) ketamine clearance for combined Groups I and II to the normal domain.

 
During our study, one patient in Group I (male, age 38 yr, weight 94 kg) developed a severe emergence reaction. He had no history of psychiatric or psychological disturbance or of substance abuse. During the course of the 67 min procedure, the patient received a cumulative dose of 867 mg of propofol (9.2 mg kg–1) and 102.5 mg of S(+) ketamine (1.05 mg kg–1). At the time of the episode, the measured concentration of propofol in the patient's blood was subsequently determined to be 3.41 µg ml–1 and that of S(+) ketamine to be 210 ng ml–1. Although the target for the S(+) ketamine TCI system had been maintained constant at 250 ng ml–1 throughout the procedure, the measured concentrations varied with time between 680 and 260 ng ml–1.


   Discussion
Top
 Abstract
 Introduction
 Methods
 Computer analysis
 Results
 Discussion
References
 
In addition to considerations concerning the reduction of cardiorespiratory depression and the avoidance of emergence phenomena, use of TCI to deliver these two drugs in combination offers a further theoretical advantage in that it should be possible to achieve predictable and stable drug concentrations in the blood and to avoid problems associated with over and underdosage. Gray and colleagues16 described the delivery of racemic ketamine by TCI in combination with manually controlled propofol infusion in general surgical patients who were allowed to breathe spontaneously. They found the technique to be clinically satisfactory. Whereas the pharmacokinetic performance of the Diprifusor has been studied extensively,17 18 no information is currently available on the pharmacokinetic performance of any model for S(+) ketamine, nor is there any information on its pharmacokinetic variability within the patient population. We have used the pharmacokinetic data (Table 2) derived by Geisslinger and colleagues11 to deliver S(+) ketamine by TCI techniques in combination with propofol and assessed its pharmacokinetic performance (Table 3). We found that, especially during the first 30 min of infusion, the delivery algorithm using this model systematically underpredicted the blood concentrations of drug (bias=35%, precision 51%). Using computer simulations, it was possible to modify the original pharmacokinetic parameters of Geisslinger and optimize the relationship between predicted and measured concentrations of S(+) ketamine (bias=–0.03%, precision 26.5%). Prospective use of this optimized set of parameters in a second group of nine patients resulted in a clinically acceptable bias (16.2%) but a poor precision (64.2%). This result reflects a common problem in pharmacokinetic modelling, namely that pharmacokinetic variability within the population is often considerable and that an optimized pharmacokinetic model can be developed to yield a reasonable bias for the population, but it is difficult to reduce the high value of precision. We have demonstrated that variability of individual S(+)ketamine clearance within our study population was considerable. Furthermore there was no strong correlation between S(+) ketamine clearance and age in the patients of the two study groups [clearance (ml kg–1 min–1) = 33.43 + 0.218 x age (yr); r2=0.012], implying that addition of age covariates to the clearance parameter would not have improved pharmacokinetic prediction.


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  		Table 2. Pharmacokinetic variables. The original variables were from Geisslinger and colleagues.11 Vc refers to the central compartment volume of a three compartment model and K10, K12 etc. refer to the various rate constants that apply to the model

 

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  		Table 3. Pharmacokinetic performance of original and revised delivery variables in the two study groups

 
We have developed a modified pharmacokinetic model for S(+) ketamine which appears to be more suitable for TCI of less than 1 h duration than the original model proposed by Geisslinger and colleagues.11 We are unable to say whether the pharmacokinetic handling of S(+) ketamine is altered during concurrent propofol administration and whether the observed poor performance of the initial model could be ascribed to this factor as ethical considerations precluded the use of S(+) ketamine in the absence of propofol in our study, particularly in view of the adverse psychomimetic reaction observed in one of our initial study group patients.

We have assessed the accuracy of the pump in the first part of the study at only one target concentration as it was not necessary to vary the pump settings during the colonoscopic procedure. Validation of the pump performance at other pump settings must await a further study.

The quantity of S(+) ketamine delivered by the revised model is less than that administered to a corresponding patient for a given target concentration by the original model of Geisslinger and colleagues. This may be important in the prevention of psychomimetic effects caused by S(+) ketamine as such phenomena induced by racemic ketamine are known to be more frequent when the patient has been exposed to high concentration of drug.19

It is uncertain if premedication with a benzodiazepine might have prevented the emergence reaction we observed in one of our patients, or if the high S(+) ketamine levels played a role. It is of interest that such a reaction occurred despite concomitant administration of propofol and in the presence of a high measured propofol concentration. Engelhardt20 has reviewed several studies, either in volunteers or clinical patients, in which recovery and psychic emergence reactions were compared after administration of either S(+) ketamine or the racemic mixture, administered in a ratio of 1:2, respectively, either after a bolus or a bolus followed by a continuous infusion. He concluded that the incidence of emergence reactions was lower after S(+) ketamine in only a single study out of a total of eight studies and concluded that S(+) ketamine should always be combined with a hypnotic or sedative drug in clinical anaesthesia. Our experience however is that the use of S(+) ketamine (as opposed to the racemic mixture) or the combination of propofol with S(+) ketamine does not guarantee the avoidance of an emergence reaction.


   References
Top
 Abstract
 Introduction
 Methods
 Computer analysis
 Results
 Discussion
 References
 
1 Idvall J. Ketamine—a review of clinical applications. Anaesth Pharm Rev 1995; 3: 82–9

2 Mortero RF, Clark LD, Tolan MM, Metz RJ, Tsueda K, Sheppard RA. The effects of small dose ketamine on propofol sedation, respiration, postoperative mood, perception cognition and pain. Anesth Analg 2001; 92: 1465–9[Abstract/Free Full Text]

3 White PF, Way WL, Trevor AJ. Ketamine: its pharmacology and therapeutic uses. Anesthesiology 1982; 56: 119–36[ISI][Medline]

4 Idvall J, Ahlgren I, Avonsen KF, Stenberg P. Ketamine infusions; pharmacokinetics and clinical effects. Br J Anaesth 1979; 51:1167–73[Abstract/Free Full Text]

5 Hui TW, Short TG, Hong W, Suen T, Gin T, Plummer J. Additive interactions between propofol and ketamine when used for anaesthesia induction in female patients. Anesthesiology 1995; 82: 641–8[CrossRef][ISI][Medline]

6 White PF, Ham J, Way WL, Trevor AJ. Pharmacology of ketamine isomers in surgical patients. Anesthesiology 1980; 52: 231–9[CrossRef][ISI][Medline]

7 Olney JW, Labruyere J, Price MT. Pathological changes induced in cerebrocortical neurones by phencyclidine and related drugs. Science 1989; 244: 1360–2[Abstract/Free Full Text]

8 Hara M, Kai Y, Ikemoto Y. Propofol activates GABAA receptor chloride ionophore complex in dissociated hippocampal pyramidal neurones of the rat. Anesthesiology 1993; 79: 781–8[ISI][Medline]

9 Orser BA, Bertlik M, Wang LY. Inhibition by propofol of the N-methyl D-aspartate subtype of glutamate receptor in cultured hippocampal neurones. Br J Pharmacol 1995; 116: 1761–8[ISI][Medline]

10 Nagata A, Nakao S, Miyamoto E, et al. Propofol inhibits ketamine induced C-fos expression in the rat posterior cingulate cortex Anesth Analg 1998; 87: 1416–20[Abstract/Free Full Text]

11 Geisslinger G, Hering W, Kamp HD, Vollmers KO. Pharmacokinetics of ketamine enantiomers. Br J Anaesth 1995; 75: 506–7[Free Full Text]

12 Geisslinger G, Menzel-Soglowek S. Stereoselective high performance liquid chromotography determination of the enantiomers of ketamine and norketamine in plasma. J Chromatogr 1991; 568: 165–76[ISI][Medline]

13 Plummer GF. Improved method for the detection of propofol in blood by high pressure liquid chromotography with fluorescence detection. J Chromatogr 1987; 421: 171–6[ISI][Medline]

14 Beal S, Sheiner LB. Nonmem User's Guide, Part 1. San Francisco: University of California, 1994

15 Gepts E, Shafer SL, Camu F, et al. Linearity of pharmacokinetics and model estimation of sufentanil. Anesthesiology 1995; 83:1194–204[CrossRef][ISI][Medline]

16 Gray C, Swinhoe CF, Myint Y, Mason D. Target controlled infusion of ketamine as analgesia for TIVA with propofol. Can J Anaesth 1999; 46: 957–61[Abstract/Free Full Text]

17 Swinhoe CF, Peacock JA, Glen JB, Reilly CS. Evaluation of the predictive performance of a Diprifusor TCI system. Anaesthesia 1998; 53 (Suppl): 61–7

18 Coetzee JF, Glen JB, Wium CA, Boshoff L. Pharmacokinetic model selection for target controlled infusions of propofol. Anesthesiology 1995; 82: 1328–45[CrossRef][ISI][Medline]

19 Badrinath S, Avramov MN, Shadrick M, Witt TR, Ivankovich AD. The use of a ketamine–propofol combination during monitored anaesthesia care. Anesth Analg 2000; 90: 858–62[Abstract/Free Full Text]

20 Engelhardt W. Aufwachverhalten und psychomimetische reaktionen nach S(+) ketamine. Anaesthesist 1997; 46 (Suppl 1): S38–4


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