We found significantly less effective cerebrovascular autoregulation in older compared with younger patients undergoing elective surgery under sevoflurane-based anaesthesia. We also found lower values for cerebral oxygenation measured by NIRS in the older group of patients. However, this difference was not due to age but rather FVm and MAP.
The most important question is whether the difference in autoregulation we found is clinically relevant. While our protocol was not designed to answer this question, some inferences from volunteer data may be made. In healthy volunteers, the difference in Mx between the left and the right hemispheres was 0.07 (0.07).20
In our patients, we found similar differences of Mx between the two hemispheres: 0.01 (0.08) in the younger and 0.01 (0.09) in the older patients. As all these data were collected in patients without known intracerebral or cerebrovascular pathology, this could also imply that an interindividual difference of Mx in the range of 2 sd
s of the interhemispherical differences cited above, that is, 0.18 is normal. This would suggest that despite statistical significance, the difference in Mx we found between younger and older patients (0.09) is clinically not relevant. In contrast, the Mx values we found intraoperatively are considerably higher in the younger [Mx: 0.41 (0.18) at 4.8 kPa of
] and older patients [Mx: 0.50 (0.16) at 4.6 kPa of
] than in awake healthy volunteers [Mx: 0.21 (0.16) at 5.8 kPa of
This suggests that under sevoflurane-based anaesthesia, cerebral perfusion in the older and in the younger patients may be more vulnerable to hypotension than in awake volunteers. Ideally, we would have collected data on Mx in all our patients before induction of anaesthesia. However, such a measurement would have to be made before induction of anaesthesia and requires ~1 h, which is unfortunately not compatible with the surgical scheduling at our institutions. Alternatively, measurements could have been repeated several days or perhaps even weeks after surgery to avoid effects of analgesic and other drugs. In both instances, the data would be difficult to interpret as it is unlikely that the same arterial pressure, and particularly the same
, is present during measurements performed intraoperatively and before or after operation. Autoregulation is strongly influenced by vascular tone.21
The arterial partial pressure of CO2
affects vascular tone in the segments of the cerebral vascular bed that are responsible for autoregulation. Increases in
not only narrow the plateau of the autoregulatory curve,21
but also the rate at which the cerebral resistance vessels react to changes in MAP is decreased,22
and Mx is increased,18
suggesting less efficient autoregulation. The opposite effects occur with decreases in
. To address the problem of the interaction between
and autoregulation, we again decided to rely on data obtained from healthy volunteers by the Cambridge group.18
The Mx values we measured were higher than those of healthy normocapnic volunteers,18
suggesting less efficient autoregulation both in the younger and older patients in comparison with awake volunteers.18
Moreover, in our data,
was lower (4.6 kPa) than in the volunteer study cited above (5.8 kPa).18
, the difference between volunteers and our patients would be even larger for the reasons outlined above. One possible explanation for the difference in Mx between volunteers and patients is an effect of sevoflurane. Mx is an index of dynamic autoregulation, and while static autoregulation seems to be quite robust even with higher sevoflurane concentrations than we used,23
it has been previously shown that dynamic autoregulation is impaired by sevoflurane at lower concentrations and also in the range of concentrations present in our patients.24
Apart from sevoflurane, hypertension could shift the autoregulatory curve to the right and have an impact on Mx. Pre-existing hypertension was not associated with higher values of Mx [mean difference between no hypertension and hypertension: −0.04 (95% CI −0.11; 0.03; P
=0.31)]. While there are sufficient data to make an effect of a pre-existing hypertension on our results unlikely, only five patients (5%, all belonging to the older age category) were diabetics and an analysis of the effect of this condition, which has been shown earlier to interfere with autoregulation,25
is not possible with our data. However, there are many factors, our protocol did not control for, that could have an impact on autoregulation such as concomitant medication.
The small significant difference in TOI between younger and older patients as indicated by univariate analysis was not confirmed by the multivariable analysis. However, there were significant associations with FVm and MAP. The significant association with FVm is not surprising. TOI is a surrogate marker of oxygen extraction, and in our patients, oxygen extraction will most likely depend exclusively on delivery, that is, cerebral blood flow (CBF) or its surrogate marker FVm. In our patients,
was adequate and cerebral metabolic rate of oxygen was reduced due to the volatile anaesthetic, making an increased demand or insufficient O2
transport highly unlikely. The association of TOI with MAP we found in our patients is interesting, as it supports an impairment of autoregulation as discussed above and, hence, vulnerability to hypotension; for younger and older patients alike. In our patients, boluses of ephedrine and phenylephrine and infusions of norepinephrine were used as deemed necessary by the anaesthesiologist in charge of clinical management. The effects of vasopressors on cerebral oxygenation are controversial. Earlier work failed to show an effect of norepinephrine26
on cerebral haemodynamics in awake healthy volunteers. Recently, it has been suggested that in awake healthy volunteers, norepinephrine may decrease FVm and cerebral oxygenation.28
However, the results of that study could also be explained by variations in
rather than norepinephrine alone.29
Phenylephrine but not ephedrine has also been shown to decrease cerebral oxygenation.30
Unfortunately, no CO2
data are reported in that publication. In all experiments investigating changes in CBF or FVm induced by drugs, MAP, or other interventions such as hypothermia, the control of
is crucial. With normal cerebrovascular CO2
reactivity in the range of 15–20% kPa−1
even small differences in
may lead to changes in CBF and FVm that are larger than the effects of the intervention in question. Since we averaged our data over the duration of the surgical procedure, it is not possible to analyse the effect of the vasopressors that were used on cerebral oxygenation. As with Mx, a comparison with an awake TOI value would have been interesting. However, our patients were premedicated with benzodiazepines, and due to organizational limitations, we were unable to obtain values before premedication. Intraoperative cerebral desaturations, that is, decreases in TOI, occurred in younger and older patients. The threshold at which desaturations become clinically relevant is controversial. One group showed that a change of −13% is relevant when EEG data are analysed;32
another group found a threshold of −20% to be associated with clinical changes.33
Both studies were performed in patients undergoing carotid endarterectomy. Interestingly, we could not identify clear causes for the desaturations in most of our patients. Only in three patients who had TOI desaturations >20%, this happened concomitantly with a hypotensive episode. One of these three patients was younger than 40 yr and had short-lived decreases in MAP to <50 mm Hg. More data are needed to explore the pathophysiology of intraoperative desaturations and to define their clinical relevance and relevant thresholds for patients undergoing general surgery.
Our study has several limitations. We decided not to use BIS monitoring for our study. This monitor is not part of standard monitoring at our institutions, and in many patients, it would have been impossible to correctly place the sensors for TCD, NIRS, and BIS monitoring due to the limited amount of space on the forehead. Had we used BIS monitoring, many patients would probably have received lower doses of sevoflurane. However, it is not clear, whether this would have influenced our results.
Our data were averaged over the complete duration of the procedure. This precludes any statement on short-term changes in autoregulation. However, the method we used is not suitable to investigate short-term changes in autoregulatory efficiency. It depends on a minimal duration of ~25 min over which measurements have to be averaged. A further drawback of our method is the inability to discriminate between worsening of autoregulation and intraoperative arousal of the patient. Such an event would be characterized by an increase in FVm and most likely an increase in MAP, which with our method would result in an increase in Mx. However, in view of the rather high sevoflurane concentrations that were used and the fact that we averaged our data over longer periods, we assume that the relatively high values we report are not due to intraoperative arousal but represent autoregulation.
All our patients were haemodynamically reasonably stable and the variability of
was limited as well. This precludes extrapolation of our results to patients with marked intraoperative instability. Finally, our results cannot be extrapolated to patients anaesthetized with other volatile agents or propofol.
In summary, despite the fact that our data show statistically significant differences in cerebral autoregulation between younger and older patients under sevoflurane-based anaesthesia, these differences are small and of questionable clinical significance. The cerebral TOI was not significantly influenced by age. These data suggest that there is no fundamental difference in intraoperative cerebral perfusion between younger and older patients that could explain the effect of age on the risk for perioperative cerebral complications.