Cerebrospinal fluid and blood propofol concentration during total intravenous anaesthesia for neurosurgery

A. L. Dawidowicz*,1, A. Fijalkowska2, A. Nestorowicz2, R. Kalitynski1 and T. Trojanowski3

1 Department of Chemical Physics and Physicochemical Separation Methods, Faculty of Chemistry, Maria Curie-Sklodowska University, 20–031 Lublin, pl. Marii Curie-Sklodowskiej 3, Poland. 2 Department of Anaesthesiology and Intensive Therapy and 3 Department of Neurosurgery and Paediatric Neurosurgery, University School of Medicine, 20–090 Lublin, Jaczewskiego 8, Poland E-mail: dawid@hermes.umcs.lublin.pl

Accepted for publication: August 24, 2002


    Abstract
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 Abstract
 Introduction
 Methods and results
 Comment
 References
 
Background. The aim of this paper is to compare the propofol concentration in blood and cerebrospinal fluid (CSF) in patients scheduled for different neurosurgical procedures and anaesthetized using propofol as part of a total intravenous anaesthesia technique.

Methods. Thirty-nine patients (ASA I–III) scheduled for elective intracranial procedures, were studied. Propofol was infused initially at 12 mg kg–1 h–1 and then reduced in steps to 9 and 6 mg kg–1 h–1. During anaesthesia, bolus doses of fentanyl and cis-atracurium were administered as necessary. After tracheal intubation the lungs were ventilated to achieve normocapnia with an oxygen-air mixture (FIO2=0.33). Arterial blood and CSF samples for propofol examination were obtained simultaneously directly after intracranial drainage insertion and measured using high-performance liquid chromatography. The patients were divided into two groups depending on the type of neurosurgery. The Aneurysm group consisted of 13 patients who were surgically treated for ruptured intracranial aneurysm. The Tumour group was composed of 26 patients who were undergoing elective posterior fossa extra-axial tumour removal.

Results. Blood propofol concentrations in both groups did not differ significantly (P>0.05). The propofol concentration in CSF was 86.62 (SD 37.99) ng ml–1 in the Aneurysm group and 50.81 (26.10) ng ml–1 in the Tumour group (P<0.005).

Conclusions. Intracranial pathology may influence CSF propofol concentration. However, the observed discrepancies may also result from quantitative differences in CSF composition and from restricted diffusion of the drug in the CSF.

Br J Anaesth 2003; 90: 84–6

Keywords: anaesthetic techniques, i.v. total; anaesthetics i.v., propofol; cerebrospinal fluid


    Introduction
 Top
 Abstract
 Introduction
 Methods and results
 Comment
 References
 
The main site of action of propofol is the central nervous system (CNS). Measurement of the brain concentration of this drug in humans poses obvious practical problems, but it has been done in experimental animals.14 The propofol concentration in human cerebrospinal fluid (CSF) has been measured5 6 infrequently because of limited accessibility to the CSF. Moreover, these measurements have been made only when the blood–brain barrier was normal. As intracranial pathology influences the permeability of the blood–brain barrier, the aim of this paper is to compare the propofol concentration in blood and CSF in patients scheduled for different neurosurgery procedures and anaesthetized using propofol as part of a total intravenous anaesthesia technique.


    Methods and results
 Top
 Abstract
 Introduction
 Methods and results
 Comment
 References
 
After obtaining approval from the university ethics committee and consent from patients, samples were obtained from 39 patients (ASA grade I–III) undergoing elective intracranial procedures. The patients were divided into two groups—those being treated for a ruptured intracranial aneurysm (Aneurysm group) and those undergoing posterior fossa extra-axial tumour removal (Tumour group).

All patients received oral diazepam 10 mg 2 h before anaesthesia. After pretreatment with fentanyl 0.2 mg, anaesthesia was induced with propofol 2 mg kg–1 and then maintained with a continuous infusion of propofol at the following rates: 12 mg kg–1 h–1 for the first 15 min; 9 mg kg–1 h–1 for the next 30 min and then 6 mg kg–1 h–1 until the end of the procedure. Tracheal intubation was facilitated by cis-atracurium 0.15 mg kg–1. After tracheal intubation, the lungs were ventilated to achieve normocapnia with an oxygen-air mixture (FIO2=0.33). In addition to the constant infusion of propofol, anaesthesia was maintained with repeated doses of fentanyl and cis-atracurium as necessary.

After induction of anaesthesia, a cannula was placed in the radial artery for blood pressure monitoring and blood sampling. As part of the surgical procedure, an External Drainage System (Codman, Johnson and Johnson Medical Ltd, UK) for CSF drainage was inserted into the subarachnoid cisterns in patients in the Aneurysm group and into a lateral ventricle in the Tumour group.

Arterial blood and CSF samples for propofol examination (5 and 2.5 ml respectively) were obtained simultaneously at the moment of CSF drainage insertion. Only CSF samples free from red blood cells were saved for further analysis.

The concentration of propofol in the samples was measured by high-performance liquid chromatography with fluorescence detection, according to the procedure previously described.7 The detection limit of the assay was 1.1 ng ml–1.

The patient characteristics and the propofol concentration results are listed in Table 1. Statistical analysis was performed by means of the Student’s t-test for independent samples. Differences were considered significant with a P-value of <0.05.


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Table 1 Patient characteristics, times of blood and CSF sampling, and the propofol concentration in blood and CSF. Data are mean (SD) [range]
 

    Comment
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 Abstract
 Introduction
 Methods and results
 Comment
 References
 
There are only two papers discussing the relationship between propofol concentration in blood and CSF in humans.5 6 The first5 shows that within 30 min of anaesthesia, an equilibrium in propofol concentration between the blood and CSF is reached and the propofol concentration in CSF is 50- to 100-fold lower than in blood. The second paper6 discusses the relationship between propofol concentrations in blood and CSF during long-lasting anaesthesia maintenance. It confirms the constant ratio of drug concentration between the blood and CSF. However, a significant reduction in propofol concentration in the CSF followed insertion of the CSF drain.

The results presented in Table 1 confirm the earlier data.5 6 The calculated propofol concentration in CSF from the pooled data of all our patients is 1.64% of the analogous average concentration of the drug in blood. Moreover, the division of the patients into two groups depending on the type of neurosurgical procedure shows significant differences in CSF propofol concentrations (P<0.005).

The difference in propofol concentrations in CSF between the Aneurysm and Tumour groups may be attributed to differences in intracranial pathology. In a variety of pathological conditions, including vascular brain diseases and tumours, abnormal permeability of the blood– brain barrier can be observed.8 It is well-known that the passage of drugs from the blood to the CSF is increased after rupture of an intracranial aneurysm. Conversely, an intracranial tumour modifies the blood–brain barrier permeability only when it grows up from the brain parenchyma, whereas an extra-axial location keeps the blood–brain barrier intact.

There are quantitative differences, however, in composition of CSF originating from different sampling sites.9 10 For example, CSF from the ventricles of the brain contains less protein and more glucose than that from the subarachnoid cisterns. Variation in protein binding within the CSF may lead to differences in propofol concentration. The same mechanisms that are responsible for the differences in concentrations of proteins and glucose in CSF (e.g. restricted diffusion in a slowly circulating medium) may also cause the formation of a propofol concentration gradient within the CSF space (a gradient between different intracranial regions). These factors may also contribute to the differences in CSF propofol concentration found between the Aneurysm and Tumour groups.

In conclusion, our data indicate that intracranial pathology may influence CSF propofol concentration. However, the observed discrepancies may also result from quantitative differences in CSF composition and from restricted diffusion of the drug in the CSF.


    Acknowledgement
 
The presented work was supported by the Polish KBN (State Committee for Scientific Research, Warsaw, Poland) Grant No. 4/P-05C 03118.


    References
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 Abstract
 Introduction
 Methods and results
 Comment
 References
 
1 Shyr MH, Tsai TH, Tan PPC, Chen CF, Chan SHH. Concentration and regional distribution of propofol in brain and spinal cord during propofol anesthesia in the rat. Neurosci Lett 1995; 184: 212–15[CrossRef][ISI][Medline]

2 De Riu PL, De Riu G, Testa C, et al. Disposition of propofol between red blood cells, plasma, brain and cerebrospinal fluid in rabbits. Eur J Anaesthesiol 2000; 17: 18–22[CrossRef][ISI][Medline]

3 Dutta S, Ebling WF. Formulation-dependent brain and lung distribution kinetics of propofol in rats. Anesthesiology 1998; 89: 678–85[CrossRef][ISI][Medline]

4 Dutta S, Matsumoto A, Muramatsu A, Matsumoto M, Fukuoka M, Ebling WF. Steady-state propofol brain:plasma and brain:blood partition coefficients and the effect-site equilibrium paradox. Br J Anaesth 1998; 81: 422–4[CrossRef][ISI][Medline]

5 Engdahl O, Abrahams M, Björnsson A, et al. Cerebrospinal fluid concentrations of propofol during anaesthesia in humans. Br J Anaesth 1998; 81: 957–9[Abstract/Free Full Text]

6 Dawidowicz AL, Nestorowicz A, Fijalkowska A, Kalitynski R. Propofol concentration in cerebrospinal fluid during TIVA. Minerva Anestesiol 2001; 67 (suppl 1): 244–5

7 Dawidowicz AL, Fornal E, Mardarowicz M, Fijalkowska A. The role of human lungs in the biotransformation of propofol. Anesthesiology 2000; 93: 992–7[CrossRef][ISI][Medline]

8 Gumerlock MK. Blood–brain barrier and cerebral oedema. In: Tindall GT, Cooper PR, Barrow DL, eds. The Practice of Neurosurgery. Baltimore: Williams & Wilkins 1996; 4–12

9 Pollay M. Cerebrospinal fluid. In: Tindall GT, Cooper PR, Barrow DL, eds. The Practice of Neurosurgery. Baltimore: Williams & Wilkins 1996; 35–44

10 Hoag G. Urinanalysis, clinical microscopy and fluids. In: Tilton RC, Balows A, Hohnadel DC, Reiss RF, eds. Clinical Laboratory Medicine. St Louis: Mosby Yearbook, 1992; 402–47





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