1 Université Claude Bernard Lyon 1, Faculté de Pharmacie, Département de Pharmacie, Clinique de Pharmacocinétique et dEvaluation du Médicament, 8 Avenue Rockefeller, F-69373 Lyon, Cedex 08, France. 2 Laboratoire de Pharmacocinétique Clinique and 3 Service de Soins Intensifs Post-opératoires, Hôpital Neuro-Cardiologique, 59 Boulevard Pinel, F-69394 Lyon, Cedex 03, France
Corresponding author. E-mail: roselyne.boulieu@chu-lyon.fr
Accepted for publication: September 25, 2002
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Abstract |
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Methods. We determined the pharmacokinetics of ketamine and its active metabolites, norketamine and dehydronorketamine, in 12 intensive care patients with brain or spinal cord injury. The effect of ketamine on haemodynamic variables was also investigated.
Results. The total clearance of ketamine, mean (SD), was 36.0 (13.3) ml min1 kg1, the volume of distribution (Vß) was 16.0 (8.6) litre kg1, and the elimination half-life was 4.9 (1.6) h. Ketamine did not alter any haemodynamic variables in the patients studied.
Conclusions. Pharmacokinetic variables of ketamine in intensive care patients are greater than in healthy volunteers and in surgical patients. The increase in the volume of distribution is greater than the increase in clearance, resulting in a longer estimated half-life of ketamine in this patient group.
Br J Anaesth 2003; 90: 15560
Keywords: brain, injury; intensive care; pharmacokinetics, ketamine
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Introduction |
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Haemodynamic stability is essential in neurotraumatized or neurosurgical patients in the intensive care unit. A change in arterial blood pressure, especially hypotension, may aggravate neuronal damage in patients with brain trauma.11 Circulatory responses to ketamine have been studied in surgical patients.9 10 However, no data are available in intensive care patients. It has also been reported that ketamine increases intracranial pressure and cerebral blood flow in man.12 However, Schwedler and colleagues13 have shown that intracranial pressure and cerebral blood flow were unchanged during ketamine anaesthesia. In addition, when ketamine was administered, either in animals or in humans, during controlled ventilation, no increase in intracranial pressure was observed.14 15 Because of the potential benefits of ketamine in intensive care patients, and the lack of data about its effect on intracranial pressure, we have studied the pharmacokinetics of ketamine and its metabolites in these patients with brain or spinal cord trauma undergoing controlled ventilation. The effects of ketamine on systemic haemodynamics were also studied.
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Methods |
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Measurements of haemodynamics
Systolic arterial pressure (SAP), diastolic arterial pressure (DAP), and heart rate (HR) were continuously measured using an intra-arterial catheter (Seldicath® 4F387613) purchased from Plastimed (Saint-Lieu-La-Foret, France). The haemodynamic values were recorded each time the blood samples were obtained.
Chemicals
Ketamine, norketamine, dehydronorketamine and nortilidine (internal standard) were supplied by Pfizer Laboratories (Paris, France). Solvents (Uvasol grade), and reagents were purchased from Elvetec (Lyon, France). Human serum Lyotrol® was purchased from Biomérieux (Lyon, France).
Drug assay
Ketamine, norketamine and dehydronorketamine were analysed according to the chromatographic method described by Bolze and Boulieu.16 The chromatographic system consisted of a Hewlett Packard 1050 series HPLC coupled with an HP Vectra 846/33M computer using HPChem software. The column used was a reversed-phase silica gel end-capped Purospher® RP-18e (5 µm) 125x4 mm purchased from Merck. Briefly, 1 ml of each sample was alkalinized with boric acid (pH 13) and extracted twice with a mixture of dichloromethane:ethyl acetate (80:20, v/v) followed by back-extraction with 2 M HCl. After evaporation of the acid layer and reconstitution of the residue with the mobile phase, 60 µl was injected into the HPLC column. The quantification limit of the assay method was 5 ng ml1 for ketamine and norketamine, and 10 ng ml1 for dehydronorketamine. The intra-assay precision (%CV) was <5%, and the inter-assay precision (%CV) <7% for ketamine and its metabolites in the range of 10 to 5000 ng ml1.
Pharmacokinetic analysis
Pharmacokinetic analysis was done using PK-fit software.17 Compartmental analysis was used to obtain the following ketamine pharmacokinetic variables: volume of central compartment (V1), volume of distribution (Vß), total clearance (CLt), area under the concentrationtime curve (AUC), distribution half-life (T1/2), and elimination half-life (T1/2ß). Individual data were fitted independently and the quality of the fitted model was assessed by the presence of a random scatter of residuals, a minimal value for the Akaike and Schwartz criteria, and by the coefficient of variation of the estimated pharmacokinetic variables (CV% <20%). According to these criteria, a two compartmental model and a weighing factor of 1/Y2(predicted) was the most appropriate for all patients. For norketamine and dehydronorketamine, non-compartmental analysis was used to determine the maximum concentration (Cmax), time taken to reach Cmax (Tmax), AUC, and the half-life (T1/2). As no data are available about the fraction of ketamine metabolized into norketamine and dehydronorketamine in humans, the apparent clearance of these metabolites (CLm/fm) was calculated from the equation:
CLm/fm=CLtxAUC/AUCm
where fm is the fraction metabolized, CLt is the clearance of ketamine, and AUC and AUCm are the areas under the concentrationtime curve of ketamine and its metabolites respectively, calculated from zero to infinity.
Statistical analysis
The statistical analysis was done using Graphpad Instat software. The repeated measures analysis of variance (ANOVA) test was used for multiple comparison of the haemodynamic variables at different time intervals. A paired t-test was used to compare the maximal change in the haemodynamic variables during ketamine administration with the baseline values. The non-parametric Spearmans rank correlation test was used to study the correlation between pharmacokinetic variables (CLt, Vß, T1/2) and pathophysiological variables (age, body weight, creatinine clearance, and bilirubinaemia).
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Results |
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Haemodynamic results
The haemodynamic responses after ketamine were studied in only nine patients. At the beginning of the study, the main objective was to study the pharmacokinetics, and then after the inclusion of the third patient, the study protocol was modified to investigate the effect of ketamine on haemodynamics. Mean (SD) baseline values of SAP, DAP and HR were 131 (25) mm Hg, 71 (16) mm Hg, and 76 (20) beats min1 respectively (Fig. 3). There was no statistically significant differences in SAP, DAP, and HR before and after ketamine administration over 26 h (P>0.05, ANOVA). Two group comparison of these variables at 10 min (maximum increase), and 960 min (maximum decrease) to baseline values showed no statistically significant difference (P>0.05, paired t-test), indicating that ketamine does not alter systemic haemodynamics in neurotraumatized intensive care patients.
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Discussion |
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The half-lives of norketamine and dehydronorketamine were longer than that of ketamine. Norketamine was detected earlier, reached its peak level earlier and was eliminated faster than dehydronorketamine. Plasma concentrations and AUC of norketamine showed a large interindividual variability. This might be because of the interindividual variability in CYP3A4,27 the enzyme responsible for ketamine N-demethylation to norketamine.
Ketamine did not alter systemic haemodynamics in the patients studied. An alteration in haemodynamic variables has been observed with ketamine in surgical patients.9 10 In the previous studies, a temporary elevation in arterial pressure and heart rate was observed 510 min after administration of an i.v. bolus of ketamine, and then haemodynamic variables returned rapidly to baseline levels. The circulatory stimulant effect of ketamine is related to its catecholaminergic effects.1 However, in the present study, SAP and DAP, as well as heart rate, showed no significant change during ketamine anaesthesia. In most patients, ketamine was well tolerated.
In conclusion, this preliminary study demonstrates that the pharmacokinetic variables of ketamine in intensive care patients with brain or spinal cord injury are different from those in surgical patients and healthy volunteers. This study also suggests that haemodynamic variables are not altered during ketamine anaesthesia in these patients. In spite of the limited number of patients in this study, the results obtained are relatively homogeneous. There is a need to conduct further clinical investigations on a larger number of similar patients to explain the pathophysiological factors causing the alterations in the pharmacokinetics of ketamine.
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Acknowledgement |
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References |
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