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Changes of Propofol Concentration in Cerebrospinal Fluid During Continuous Infusion

Dawidowicz, Andrzej L., PhD*,; Kalityński, Rafal, MSc*,; Nestorowicz, Andrzej, MD, PhD†,; Fijalkowska, Anna, MD, PhD

doi: 10.1097/00000539-200211000-00033

We studied the changes in the propofol concentration in the cerebrospinal fluid (CSF) in 14 patients, undergoing elective intracranial procedures, who were anesthetized with propofol administered by target-controlled infusion. During anesthesia, fentanyl and cisatracurium were administered as required. After intubation of the trachea, the lungs of the patients were ventilated to normocapnia with an oxygen-air mixture (Fio2 = 0.33). Arterial blood and CSF samples (from an intraventricular drain) were collected between 90–180 min after the induction of anesthesia. Blood propofol concentrations were stable, between 5.0 ± 1.89 and 4.5 ± 1.7 μg/mL (mean ± sd). There was a significant decrease in the CSF propofol concentration, from 52.2 ± 35.01 ng/mL at 90 min to 28.6 ± 21.9 ng/mL at 150 min (P < 0.05). The CSF propofol concentration at 180 min (21.4 ± 14.0 ng/mL) was not significantly different from the concentration at 150 min. Some possible reasons for this decrease after commencing continuous intraventricular drainage are discussed.

*Department of Chemical Physics and Physicochemical Separation Methods, Maria Curie-Sklodowska University; and †Department of Anesthesiology and Intensive Therapy, University School of Medicine, Lublin, Poland

Financial support was provided by Polish KBN (State Committee for Scientific Research, Warsaw, Poland) Grant 4/P-05C 03118.

July 9, 2002.

Address correspondence and reprint requests to Andrzej L. Dawidowicz, PhD, Department of Chemical Physics and Physicochemical Separation Methods, Faculty of Chemistry, Maria Curie-Sklodowska University, PL 20-031 Lublin, pl. Marii Curie-Sklodowskiej 3, Poland. Address e-mail to dawid@hermes.

The specific morphologic properties of the choroidal epithelium and the existence of a cerebrospinal fluid (CSF) pathway for drug distribution to the central nervous system (CNS) suggests that the choroid plexus-CSF route may be more significant than previously thought for drug delivery to the brain (1). There is limited information about the CSF pharmacokinetics of propofol in humans (2,3). The aim of the present study was to investigate the changes in propofol concentration in the CSF during propofol anesthesia in neurosurgical patients.

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Materials and Methods

After obtaining approval from the University Ethics Committee and informed consent from the patients, 14 patients without symptoms of increased intracranial pressure (ICP), scheduled for elective removal of posterior fossa tumors, were studied.

After preoxygenation and pretreatment with a bolus of fentanyl 0.2 mg, anesthesia was induced and maintained with a target-controlled infusion of propofol (Diprivan™) by using a Graseby 3500 pump incorporating Diprifusor™ software. The initial target propofol concentration of 4.5–5 μg/mL was maintained for 15 min and then reduced to 3.5–4 μg/mL for maintenance of anesthesia (4). Cisatracurium 0.15 mg/kg was given to facilitate intubation of the trachea. After intubation, the lungs of the patients were ventilated with an oxygen-air mixture (Fio2 = 0.33), and ventilation was adjusted to maintain normocapnia. When indicated, additional doses of fentanyl and cisatracurium were given. After preparation of the surgical area, an external drainage system (Codman; Johnson & Johnson, UK) was inserted into one of the lateral ventricles.

CSF (2.5 mL) and blood (5 mL) samples were taken at 90, 120, 150, and 180 min after the start of target-controlled infusion. The blood samples were taken from a radial artery into heparinized syringes. The presence of red blood cells in any CSF sample caused the rejection of all the samples from that patient. Therefore, samples from 14 patients were studied. The concentration of propofol was measured by using high-pressure liquid chromatography as described previously (5–7). The lower limit of detection was 1.1 ng/mL.

Data were expressed as mean ± sd. Statistical analysis was performed by using the Student’s t-test for dependent samples. Differences were considered significant at P < 0.05.

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Demographic characteristics of the patients are listed in Table 1. Arterial blood and CSF propofol concentrations are shown in Figure 1, left and right, respectively. The blood propofol concentrations from 90 to 180 min after the induction of anesthesia were stable, ranging from 4.99 ± 1.89 to 4.52 ± 1.74 μg/mL. The CSF propofol concentration at 90 min after induction was 52.2 ± 35.01 ng/mL, and decreased to 28.6 ± 21.9 ng/mL at 150 min (P < 0.005). The CSF concentration at 180 min was 21.4 ± 13.96 ng/mL, which was not significantly different from the value at 150 min.

Table 1

Table 1

Figure 1

Figure 1

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The results of the present study show that the concentration of propofol in the CSF, during relatively steady blood concentrations, is 100- to 200-fold smaller than the concentration in whole blood. Our results are in agreement with those of previous studies showing a relatively small propofol concentration in CSF during total IV anesthesia (2,3). They are also comparable with those from experiments using an animal model (8,9). Our first CSF sample, however, could only be obtained at 90 minutes after the induction of anesthesia, and at that time the CSF propofol concentration was decreasing, only reaching a steady concentration at 150 minutes. It is therefore likely that CSF concentrations before 90 minutes were larger than 52 ng/mL.

There are many determinants of propofol uptake into the CSF. They include the cerebral blood flow, the permeability of the blood-CSF barrier, and the physicochemical properties of the drug. It is believed that for lipid-soluble IV anesthetics, the rate of their uptake by the brain is determined primarily by blood perfusion (10). Cerebral blood flow, however, may be reduced by up to 50% during propofol anesthesia (11). We therefore maintained the hemodynamic variables and end-tidal CO2 of each patient stable during surgery to minimize disturbances in cerebral blood flow autoregulation.

The changes in the CSF propofol concentration in the present study are difficult to interpret. Engdahl et al. (2) studied five neurosurgical patients receiving propofol anesthesia who had intraventricular drains inserted before surgery. Anesthesia was induced with propofol 2 mg/kg followed by a two-step continuous IV infusion of propofol. The CSF propofol concentration increased slowly and then remained almost constant from 15 to 30 minutes after induction. Thus, it is difficult to explain the larger CSF propofol concentration at 90 minutes in our study (about two times larger than the subsequent plateau concentration). One possible explanation is that the intraventricular drainage was responsible for a compensatory increase of CSF production in response to the decrease of ICP. This mechanism is highly improbable because physiologically the CSF production rate is constant and not related to ICP (12).

Another possible explanation of the observed decrease of propofol concentration in CSF is a limited rate of propofol transfer from blood into CSF. Intraventricular drainage and/or surgery may disturb the equilibrium in propofol partitioning between blood, brain, and CSF. The loss of CSF causes a new equilibrium with a smaller propofol CSF concentration.

Propofol concentration differences between different CNS regions may also be responsible for the decrease of propofol concentration after the start of intraventricular drainage. There are quantitative differences in the composition of CSF originating from different regions of the CNS (13,14). Thus, replacement of CSF lost by drainage with the fluid from regions with a smaller propofol concentration could account for the observed decrease in propofol concentration.

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