Sevoflurane has became one of the most widely used inhalational agent in general anaesthesia due to its excellent physical, pharmacodynamic and pharmacokinetic properties . However, in neurosurgical anaesthesia there has been concern due to the known vasodilator effect of all inhalational agents. As cerebral vasodilatation may result in increased cerebral blood flow and blood volume, the use of an inhalational agent may contribute to a secondary increase of the intracranial pressure in patients with space-occupying lesions [2–4].
Different methods have been used to assess the cerebrovascular effects among them transcranial Doppler sonography (TCD), positron emission computed tomography and magnetic resonance angiography. Conflicting results have been reported including that sevoflurane does not affect cerebral blood flow velocity  and global cerebral blood flow , increased global or regional cerebral blood flow [2,7,8], along with a decreased or unchanged cerebral metabolic rate for oxygen [7,9] and decreased cerebral blood flow [10–12] or cerebral blood flow velocity [13,14]. The vasodilator effect is dose dependent, and is more pronounced with incremental clinical doses [4,15,16].
In the majority of the previous studies, different minimal alveolar concentrations of sevoflurane were used. However, only a few studies measured the effect of sevoflurane on cerebral circulation at a level of surgical anaesthesia as assessed by a depth of anaesthesia monitor [13,14,17]. As the main goal of the routine anaesthesia practice is maintaining the level of appropriate depth of anaesthesia and analgesia during surgical procedures, it seemed logical to assess the effect of anaesthesia on cerebral blood flow under such circumstances. Therefore, the aim of the present work was to test whether sevoflurane influences cerebral blood flow velocity and cerebrovascular resistance at the level of surgical anaesthesia as measured using bispectral monitoring.
Subjects were recruited from patients undergoing elective surgical procedures for lumbar disc herniation (lumbar discectomies). Further inclusion criteria were: ASA Grade I–II, no hypertension, diabetes and stroke in previous history. Before the procedure, the whole study was explained for patients in detail, and all subjects gave written informed consent. The study was approved by the Local Medical Ethics Committee of the University of Debrecen Health and Medical Science Centre.
All patients received 100 mg diclofenac and 7.5 mg midazolam (Dormicum; Egis, Budapest, Hungary) for premedication orally approximately 1.5–2 h prior to induction. Anaesthesia was induced with a bolus injection of 1–2.5 mg of propofol (Diprivan; AstraZeneca Pharmaceuticals, Wilmington, USA), depending on the clinical effect, followed by an intravenous administration of 4 μg kg−1 of fentanyl (Fentanyl; Richter Pharmaceuticals, Budapest, Hungary). Suxamethonium chloride (Midarine; GlaxoSmithKline, Switzerland) was used for intubation in the dose of 1 mg kg−1. Administration of sevoflurane was delayed until the bispectral index (BIS) returned to at least 45 indicating the decline of the propofol effect. After the target level of BIS was reached, sevoflurane (Sevorane; Abbott Pharmaceuticals) was introduced in a stepwise fashion to maintain the BIS level between 45 and 55. Patients were mechanically ventilated with 40% oxygen and the use of nitrous oxide was avoided.
ECG, pulse rate, non-invasive blood pressure, end-tidal CO2 and peripheral oxygen saturation were measured throughout the study. After inhalational anaesthesia was used, the expired sevoflurane was measured.
All Doppler measurements were performed by the same experienced neurosonologist (GS). The middle cerebral artery was insonated at 50–55 mm depth through the temporal window by the 2 MHz probe of the Multidop TCD device (DWL Elektronische Systeme GmbH, Sipplingen, Germany). A probe fixed with a Lam probe holder in order to avoid misplacement during turning of the patients from supine to prone position was placed at the right temporal window after induction of anaesthesia. In each case the most powerful signal of the middle cerebral artery was found and recorded for at least 10 cardiac cycles in order to get stable blood flow velocity parameters. Systolic, diastolic and mean blood flow velocities and pulsatility indices were recorded. The latter parameter was always controlled by an off-line calculation based on the Gosling-formula (PI = (peak systolic FV − diastolic FV)/mean FV).
Doppler measurements were performed before induction of anaesthesia as well as after induction of anaesthesia when a stable and appropriate stable level of depth of anaesthesia was reached. Beside measured Doppler parameters, additional values were derived from blood flow velocity values as well as systemic arterial pressures at different time points of the measurements. According to the method first described by Aaslid and colleagues  and used by others [19,20] we also calculated the following haemodynamic parameters off-line: estimated cerebral perfusion pressure (eCPP) = Vmean/[(Vmean − Vdiast) × (BPmean − BPdiast)], resistance area product (RAP) = BPmean/Vmean and cerebral blood flow index (CBFI) = eCPP/RAP. Vmean and Vdiast are the mean and diastolic blood flow velocities respectively in the middle cerebral artery. BPmean and BPdiast are the systemic mean and diastolic blood pressures respectively. The logical background of using these indices is the fact that TCD does not measure cerebral blood flow, only changes in mean blood flow velocities are proportional to changes in blood flow in the corresponding arterial territory. Furthermore, during TCD measurements blood flow velocities are usually evaluated without the knowledge of the eventual change of the systemic blood pressure, which may also influence cerebral blood flow. These calculations were performed because we wanted to take into account the mean arterial pressure changes between the two examinations. Both the CPP and the RAP are derived from the systemic blood pressure while the CBFI, which reflects cerebral blood flow in the MCA territory, depends on the CPP and RAP changes.
Depth of anaesthesia was measured by an A-1000 bispectral monitor (Aspect Medical Systems Inc., Natick, MA, USA). Electrodes were placed on the forehead and temple before induction of anaesthesia. An average level of consciousness was recorded in patients before induction of anaesthesia after asking them to keep their eyes closed. After a stabilizing period, during which all sudden and additional light and acoustic stimuli were avoided, the numeric value of the bispectral indices were recorded as baseline values. After induction of anaesthesia and stabilization of the BIS at the target level, patients were considered to reach the appropriate depth of anaesthesia and all previously mentioned parameters (blood pressure, pulse rate, end-tidal CO2, expired sevorane concentration and Doppler velocities) were recorded again.
Means and standard deviations are reported for all values. Parameters with normal distribution were compared with the appropriate t-tests. A P-value of <0.05 was considered to indicate statistically significant differences.
Twenty adults (12 males and 8 females) entered the study. The mean age of the patients was 42.3 ± 5.2 yr. Fourteen were ASA Grade I, and six were ASA Grade II. The most important parameters recorded before and after induction of anaesthesia are summarized in Table 1.
Induction of anaesthesia resulted in a significant decrease of the mean arterial pressure by approximately 10%, whereas pulse rate remained relatively stable during the procedure. End-tidal CO2 and oxygen saturation did not change compared to the initial values. The decrease in the BIS indicated that the proper depth of anaesthesia had been reached at the time of the Doppler measurements.
Absolute blood flow velocities within the middle cerebral artery significantly decreased along with reduction of the mean arterial pressure. The decrease in mean absolute blood flow velocities was approximately 20%, 16% for systolic and 22% for diastolic blood flow velocities respectively. A statistically significant increase in pulsatility index was observed after induction of anaesthesia.
When we took changes in systemic blood pressure levels into account during the procedure, a statistically significant decrease in cerebral perfusion pressure of 18.3% was found, which was somewhat higher than expected from the reduction of the systemic mean arterial pressure (Fig. 1). The calculated index of cerebral blood flow within the middle cerebral artery territory decreased from 38.8 ± 11.4 to 28.9 ± 14.3 indicating a significant reduction by 25.5% (Fig. 2). If one takes into consideration that the corresponding decrease in middle cerebral artery mean blood flow velocity (which is supposed to reflect changes in the blood flow within the corresponding arterial territory) was approximately 20%, despite the obvious differences, the values are still comparable. As shown in Figure 3, induction of anaesthesia resulted in a statistically significant, 15% increase of the RAP, indicating an elevation of the cerebrovascular resistance within the middle cerebral artery territory.
In our study we demonstrated a decrease in systemic blood pressure after reaching the proper level of anaesthesia with sevoflurane, which resulted in a decrease in cerebral blood flow and an increase in cerebrovascular resistance. This is the first study which has assessed the impact of sevoflurane on cerebral blood flow velocity along with taking blood pressure changes into account by calculating eCPP, CBFI and cerebrovascular resistance index. The use of these indices became widespread in recent years especially in studies assessing changes in cerebral blood flow and cerebral perfusion pressure of preeclamptic patients and of those suffering from head injury [20–22]. A fairly good correlation was found between TCD-derived indices and changes in cerebral blood flow during autoregulatory tests in human beings .
There are only a few studies available in the literature which used BIS or AAI (alaris autoregressive index) guided induction and maintenance and measured cerebral blood flow or cerebral blood flow velocity during sevoflurane anaesthesia [13–15,17]. Similar to our results, these authors also found a decreased cerebral blood flow velocity at surgical level of anaesthesia. Using PET, Kaisti and colleagues demonstrated that cerebral blood flow during sevoflurane anaesthesia is dose dependent: the drug induces a decrease in cerebral blood flow in all regions of the brain at <1 minimal alveolar concentration (MAC), whereas CBF gradually increases in the frontal cortex at 1–1.5 MAC. In our study population MAC values were <1, ranging from 0.7 to 0.9. It has to be noted that other studies at commonly used sevoflurane concentrations have reported no change [5,6] or an increase [2,7,8] in cerebral blood flow or cerebral blood flow velocity. The reasons for these discrepancies may be methodological, different techniques used for measuring cerebral blood flow or cerebral blood flow velocity at different concentration of the anaesthetics, different induction regimens used, as well as individual variations of the drug effect on cerebral circulation at the same MAC level. At present, the most widely accepted explanation for the different effects of sevoflurane on cerebral blood flow is that at low concentrations sevoflurane possesses an indirect vasoactive action secondary to flow-metabolism coupling so that with the reduction in cerebral metabolism during anaesthesia CBF is also reduced. With higher concentrations the direct vasodilatory effects of sevoflurane are more important leading to increases in cerebral blood flow.
The most important methodological limitation of TCD sonography is the fact that it is unable to measure cerebral blood flow directly, only changes in cerebral blood flow velocity as measured in the vessel is proportional to the change of CBF in the corresponding vascular territory. The prerequisite of the measurements is to accept that blood flow changes during TCD measurements may only reflect changes in CBF when the diameter of the large vessels remains constant. Additionally, changes in systemic blood pressure may influence cerebral blood flow and thus cerebral blood flow velocities. To avoid these biases, we introducede CPP, cerebral blood flow and cerebral resistance indices, which also take changes in systemic blood pressure into account.
Although information gathered from these indices (decreased CBFI, increased cerebrovascular resistance index) showed similar trends to absolute blood flow velocity parameters (decrease in mean blood flow velocity and increased pulsatility indices), they also provide additional information. The systemic mean arterial pressure decreased by approximately 10% in our study after reaching the surgical level of anaesthesia. Theoretically, a decrease in systemic blood pressure should evoke vasodilatation of the cerebral arterioles to keep cerebral blood flow constant if cerebral autoregulation is maintained and no additional vasoactive effect is present. Taking into consideration that at clinically used doses cerebral autoregulation is preserved during sevoflurane anaesthesia, the magnitude of decrease in the mean arterial pressure (10%) alone should have not evoked changes in CBFI or at least not of the magnitude we observed (25%). Theoretically, a decrease in cerebral blood flow velocity within the middle cerebral artery may be explained by two mechanisms: either vasodilatation of the large vessels (e.g. middle cerebral artery) or vasoconstriction of the small resistance arterioles. With the latter, pulsatility index and cerebrovascular resistance index should increase, which in fact was observed in our study. Although cerebrovascular resistance and pulsatility index both increased during administration of the agent, the observed decrease in cerebral blood flow velocity was larger in magnitude (25.5%), than could be expected from the magnitude of increase in cerebrovascular resistance (15%). An increase in cerebrovascular resistance is the consequence of the vasoconstriction of the resistance arterioles, which may be explained by the combination of the constrictor effect of the slight decrease in end-tidal CO2 and the constrictor effect of sevoflurane on the cerebral arterioles. In a recent study, Rozet and colleagues  reported on cerebral CO2 reactivity during sevoflurane anaesthesia and they found that 1 mmHg change in CO2 results in 1.7 cm s−1 change in the blood flow velocity. In our study, end-tidal CO2 decreased by 1.4 mmHg on average after induction of anaesthesia, which corresponds to a 2.38 cm s−1 change in the mean blood flow velocity. Thus, it is likely that beside changes in CO2 during induction, an additional vasoconstrictor effect was present at the level of the arterioles. However, the arteriolar vasoconstriction is responsible for only a 15% change in the cerebrovascular resistance, and the discrepancy between the magnitude of blood flow velocity decrease (25%) as well as the 15% increase in cerebrovascular resistance cannot be explained by arteriolar vasoconstriction only. Therefore a possible mild vasodilative effect of the inhalational agent on the large cerebral arteries cannot be excluded. The vasodilatative effect of sevoflurane was observed by previous authors in human studies [4,17]. From animal experiments we also know that this inhalational agent exerts its dilatative effect on both large and small cerebral vessels via ATP-sensitive potassium-channel activation . So far human beings observations proving the large vessel-dilatative effect of sevoflurane have not been published.
On the other hand MRI measurements of the middle cerebral artery showed that the diameters of the vessel do not change during CO2 induced vasodilatory and vasoconstrictor stimuli and changes in cerebral blood flow in these circumstances are mainly related to the small resistance arterioles . If this also applies to sevoflurane, another explanation for the present results might be that sevoflurane at low concentrations as used in the present study decreases cerebral metabolism (as reflected by BIS) and thereby leads to vasoconstriction of the resistance vessels.
In conclusion we found a decreased systemic blood pressure, cerebral blood flow velocity and an increase in cerebrovascular resistance at a surgical level of sevoflurane anaesthesia as assessed by BIS. Our results suggest a combined effect from large vessel dilatation and arteriolar constriction.
1. Delgado-Herrera L, Ostroff RD, Rogers SA. Sevoflurance: approaching the ideal inhalational anesthetic.A pharmacologic, pharmacoeconomic, and clinical review. CNS Drug Rev
2. Lorenz IH, Kolbitsch C, Hormann C et al
. Subanesthetic concentration of sevoflurane
increases regional cerebral blood flow more, but regional cerebral blood volume less, than subanesthetic concentration of isoflurane in human volunteers. J Neurosurg Anesthesiol
3. Petersen KD, Landsfeldt U, Cold GE et al
. Intracranial pressure and cerebral hemodynamic in patients with cerebral tumors: a randomized prospective study of patients subjected to craniotomy in propofol-fentanyl, isoflurane-fentanyl, or sevoflurane
-fentanyl anesthesia. Anesthesiology
4. Matta BF, Heath KJ, Tipping K, Summors AC. Direct cerebral vasodilatory effects of sevoflurane
and isoflurane. Anesthesiology
5. Fairgrieve R, Rowney DA, Karsli C, Bissonnette B. The effect of sevoflurane
on cerebral blood flow velocity in children. Acta Anaesthesiol Scand
6. Schlunzen L, Vafaee MS, Cold GE, Rasmussen M, Nielsen JF, Gjedde A. Effects of subanaesthetic and anaesthetic doses of sevoflurane
on regional cerebral blood flow in healthy volunteers. A positron emission tomographic study. Acta Anaesthesiol Scand
7. Bundgaard H, von Oettingen G, Larsen KM et al
. Effects of sevoflurane
on intracranial pressure, cerebral blood flow and cerebral metabolism. A dose-response study in patients subjected to craniotomy for cerebral tumours. Acta Anaesthesiol Scand
8. Kolbitsch C, Lorenz IH, Hormann C et al
. A subanesthetic concentration of sevoflurane
increases regional cerebral blood flow and regional cerebral blood volume and decreases regional mean transit time and regional cerebrovascular resistance in volunteers. Anesth Analg
9. Oshima T, Karasawa F, Okazaki Y, Wada H, Satoh T. Effects of sevoflurane
on cerebral blood flow and cerebral metabolic rate of oxygen in human beings: a comparison with isoflurane. Eur J Anaesthesiol
10. Schwender D, End H, Daunderer M, Fiedermutz M, Peter K. Sevoflurane
and the nervous system. Anaesthesist
11. Mielck F, Stephan H, Weyland A, Sonntag H. Effects of one minimum alveolar anesthetic concentration sevoflurane
on cerebral metabolism, blood flow, and CO2
reactivity in cardiac patients. Anesth Analg
12. Kaisti KK, Langsjo JW, Aalto S et al
. Effects of sevoflurane
, propofol, and adjunct nitrous oxide on regional cerebral blood flow, oxygen consumption, and blood volume in humans. Anesthesiology
13. Holzer A, Greher M, Hetz H et al
. Influence of aortic blood flow velocity on changes of middle cerebral artery blood flow velocity during isoflurane and sevoflurane
anaesthesia. Eur J Anaesthesiol
14. Holzer A, Winter W, Greher M et al
. A comparison of propofol and sevoflurane
anaesthesia: effects on aortic blood flow velocity and middle cerebral artery blood flow velocity. Anaesthesia
15. Kaisti KK, Metsahonkala L, Teras M et al
. Effects of surgical levels of propofol and sevoflurane
anesthesia on cerebral blood flow in healthy subjects studied with positron emission tomography. Anesthesiology
16. Iida H, Ohata H, Iida M, Watanabe Y, Dohi S. Isoflurane and sevoflurane
induce vasodilation of cerebral vessels via ATP-sensitive K+ channel activation. Anesthesiology
17. Holmstrom A, Akeson J. Sevoflurane
induces less cerebral vasodilation than isoflurane at the same A-line autoregressive index level. Acta Anaesthesiol Scand
18. Aaslid R, Lundar T, Lindegaard KF, Nornes H. Estimation of cerebral perfusion pressure from arterial blood pressure and transcranial Doppler recordings. In: Miller T, Rowan JO, eds. Intracranial Pressure
. Berlin-Heidelberg: Springer, 1986: 226–229.
19. Giannina G, Belfort MA, Cruz AL, Herd JA. Changes in cerebral perfusion pressure in puerperal women with preeclampsia. Obstet Gynecol
20. Zatik J, Major T, Aranyosi J, Molnar C, Limburg M, Fülesdi B. Assessment of cerebral hemodynamics during roll over test in healthy pregnant women and those with pre-eclampsia. BJOG
21. Steiner LA, Johnston AJ, Czosnyka M et al
. Direct comparison of cerebrovascular effects of norepinephrine and dopamine in head-injured patients. Crit Care Med
22. Steiner LA, Coles JP, Johnston AJ et al
. Assessment of cerebrovascular autoregulation in head-injured patients: a validation study. Stroke
23. Rozet I, Vavilala MS, Lindley AM, Visco E, Treggiari M, Lam AM. Cerebral autoregulation and CO2
reactivity in anterior and posterior circulation during sevoflurane
anesthesia. Anesth Analg
24. Serrador JM, Picot PA, Rutt BK, Shoemaker JK, Bondar RL. MRI measures of middle cerebral artery diameter in conscious humans during simulated orthostasis. Stroke