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Sevoflurane-induced reduction of bispectral index does not affect human cerebral microcirculation

Klein, Klaus U.; Schramm, Patrick; Werner, Christian; Engelhard, Kristin

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European Journal of Anaesthesiology: February 2016 - Volume 33 - Issue 2 - p 152-154
doi: 10.1097/EJA.0000000000000278
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Sevoflurane was introduced into clinical practice in 1990 and is commonly used for the maintenance of general anaesthesia. The favourable pharmacokinetic and pharmacodynamic characteristics of sevoflurane include a limited impact on cerebral macrocirculation, pressure autoregulation and carbon dioxide vasoreactivity. However, knowledge of the microcirculatory effects of sevoflurane on the human brain remains limited. It has been proposed that sevoflurane and other anaesthetics may affect the homeostasis of organ microcirculation, potentially influencing clinical outcome.1,2

The aim of this study was to investigate the effects of deeper sevoflurane anaesthesia, when monitored by increased end-tidal sevoflurane concentration (etSevo) and bispectral index (BIS), on the cerebral microcirculation in both 2 mm (grey matter) and 8 mm (white matter) brain tissue. The measurements were obtained using a novel probe combining white light spectrometry and laser Doppler flowmetry (O2C-device; Lea Medizintechnik GmbH, Giessen, Germany) that was applied directly to the brain surface during craniotomy. The following variables were measured: regional capillary venous cerebral blood flow (rvCBF); regional capillary venous cerebral oxygen saturation (srvO2); and regional capillary venous cerebral haemoglobin amount (rvHb). From these, arteriovenous difference in cerebral oxygen concentration (avDO2) and approximated cerebral metabolic rate of oxygen, (aCMRO2) were estimated as measures of cerebral metabolism.3,4 The effects of interest, analogous to the effects of sevoflurane on cerebral macrocirculation, were as follows:

  1. increases in rvCBF (increased cerebral vasodilatation) and srvO2 (elevated rvCBF);
  2. decreases in avDO2 (reduced oxygen extraction fraction) and aCMRO2 (suppression of cerebral metabolism).

Ethical approval for this study [Ref: 837.136.05 (4794)] was provided by the Ethical Committee of the State of Rhineland-Palatinate (Landesärztekammer Rheinland-Pfalz, Deutschhausplatz 3, 55131 Mainz, Germany) on 11 May 2005. The study was conducted from 3 January 2008 until 8 August 2010. After written informed consent on the day before neurosurgery, patients (n = 24) scheduled for routine craniotomy were included in the randomised crossover study. A BIS electrode was placed at the forehead contralateral to the site of craniotomy (A-2000; Aspect Medical, Norfolk, Massachusetts, USA). etSevo was adjusted so as to produce ‘adequate’ (etSevo 1.5 %vol/vol) or ‘deeper’ (etSevo 2.5 %vol/vol) sevoflurane anaesthesia. At steady-state cardiopulmonary conditions, the sterile O2C-probe was placed onto macroscopically healthy brain tissue. Measurements were performed during stable haemodynamic and respiratory conditions at target etSevo concentrations. Data were recorded as follows: srvO2 in %; rvHb; and rvCBF in arbitrary units (AU). Mixed linear models and paired Student's t-tests were performed to determine the effects of etSevo concentrations on rvCBF, srvO2, rvHb, avDO2, aCMRO2 and BIS. Data were analysed using the software R (R Foundation for Statistical Computing, Vienna, Austria) with P value less than 0.05 considered significant.

Measurements were successfully completed in 20 patients (sequence A: adequate followed by deeper sevoflurane anaesthesia n = 11; sequence B: deeper followed by adequate sevoflurane anaesthesia; n = 9). In four patients, no O2C data could be recorded because the size of the craniotomy was too small. There were no signs or symptoms of raised intracranial pressure. Cerebral measurements were performed at the frontal (n = 7), temporal (n = 6), parietal (n = 6) and occipital (n = 1) lobes depending on the location of craniotomy. Important physiological variables with an impact on cerebral circulation remained unchanged during measurements. No adverse effects attributable to the positioning of the O2C-probe (e.g. bleeding, infection, cerebral tissue damage or severe neurological dysfunction) occurred before the patients were discharged.

Results are presented as median with interquartile range (Fig. 1). O2C measurements were performed at etSevo concentrations of 1.5 (1.3 to 1.7) %vol/vol and 2.5 (2.2 to 2.8) %vol/vol (P < 0.001). BIS levels were 30 (27 to 38) at deeper and 42 (40 to 47) at adequate etSevo concentrations (P < 0.001). Eight of 20 patients showed an ‘insufficient’ BIS reduction (<15 BIS units) and four patients showed a ‘paradoxical’ BIS increase with higher sevoflurane concentrations. Paradoxical BIS increases have previously been reported when increasing sevoflurane MAC levels.5 rvCBF, rvHb, srvO2 and the calculated variables, avDO2 and aCMRO2, did not differ at etSevo 1.5 and 2.5 %vol/vol, nor at cerebral depths of 2 and 8 mm (Fig. 1). A previous study showed that srvO2 decreased during increasing propofol anaesthesia when BIS was altered from 40 to 21.3 Although this and our studies are observational, it may be that propofol and sevoflurane exhibit specific effects on human cerebral microcirculation and oxygenation, an assumption that needs to be investigated in detail with regard to organ homeostasis on a microregional scale.

Fig. 1
Fig. 1:
Regional capillary venous cerebral blood flow, regional capillary venous cerebral oxygen saturation and regional capillary venous cerebral haemoglobin amount in brain tissue depths of 2 mm (grey matter) and 8 mm (white matter) at end-tidal sevoflurane concentrations (etSevo) of 1.5 and 2.5 %vol/vol. Box-whisker plots show median, 25th and 75th percentiles (box) with 10th and 90th percentiles (whiskers).

Low srvO2 values (e.g. 45.9% in 2 mm cerebral depth during etSevo 1.5 %vol/vol) and high avDO2 values (e.g. 8.3 ml dl−1 in 2 mm cerebral depth during 2.5 %vol/vol) represent a high oxygen extraction of brain tissue during sevoflurane anaesthesia. These values seem reasonable, as pericapillary partial pressure for oxygen gradients for grey matter are steep due to the high metabolic activity in this area.6 Clinical studies using cortical photospectroscopy showed similar capillary venous haemoglobin oxygen saturations (40 to 70%) when measured directly at the cerebral cortex.3,4 In the present study, unaltered rvHb values at varying BIS levels suggest that the cerebral capillary blood filling and emptying remained stable and that a microcirculatory flow problem in the cerebral capillary bed was unlikely.

In conclusion, our findings suggest that the microcirculatory environment (rvCBF, srvO2, rvHb, avDO2, aCRMO2) remains unchanged at two different concentrations of sevoflurane anaesthesia (etSevo 1.5 and 2.5 %vol/vol) during routine craniotomy.

Acknowledgements relating to this article

Assistance with the study: none.

Financial support and sponsorship: the study was supported by a research grant from the German Society of Anaesthesiology and Intensive Care Medicine (DGAI e.V.).

Conflicts of interests: none.


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© 2016 European Society of Anaesthesiology