In the present study, we evaluated how a hemodynamic insult such as VS, might affect CBFV’s SWs and SampEn, as well as Mxa and tau values, in patients suffering from SAH, dichotomized by the presence of DCI. We also hypothesized that a particular combination of measured metrics might predict DCI, constituting a novel cluster of ‘physiomarkers’ for monitoring of cerebral autoregulation in the ICU setting. Such markers could also be promising tools for early therapeutic intervention in vulnerable patients, even before clinical or TCD-derived signs of VS appear .
Temporal differences for the whole group of patients
For the whole studying population, we found that during VS, ipsilateral CBFV SWs were significantly higher in relation to pre VS measurements. Despite lack of statistical significance of our findings, we also confirm previous study by Kasprowicz and colleagues , who found that tau was reduced during VS even before formal TCD signs of VS were observed.
CBFV SWs with an associated frequency range of 0.005 to 0.05 Hz, reflect dynamic oscillations in cerebral blood volume related to autoregulatory vasodilatation and vasoconstriction . Fluctuations of CBFV measured with TCD have been found to occur simultaneously with intracranial pressure (ICP) B-waves and occupy the same frequency [13,22].
The physiological and clinical significance of SWs remains debated since they do not only occur during pathologic conditions but have also been observed in healthy subjects . Different theories of origin have been developed, relating SWs with pCO2 changes-induced oscillations in the cerebrovascular volume , plateau waves of ICP waveforms , or rhythmic cerebral vasoconstriction caused by an intrinsic brain stem rhythm . In this respect, general anesthesia has been found to reduce amplitude of SWs of ICP . Moreover, Greitz and colleagues , have proposed that restricted arterial distensibility due to decreased intracranial compliance is associated with increased capillary pulsations and subsequently, higher CBFV SWs.
According to classic studies of Fry and Byrom [37, 38], when cerebral arteries are narrowed, like in cases of VS, flow pulsations and wall shear stress will be enhanced, tending to increase the power dissipation and thus, the pressure gradient along the vascular tree. In this case, all sequential branches of the capillary network try to dilate in order to avoid or decrease this augmented pressure drop, through production of local vasodilatory molecules, such as nitric oxide (NO). Such metabolic effects might be reflected in the amplitude of blood flow oscillations within a frequency range below 0.05 Hz, as has been shown by Stefanovska and colleagues in peripheral blood flow  and described in the frequency-dependent behavior of cerebral autoregulation .
Based on the previous discussion, we suggest that higher CBFV SWs during VS correspond to local mechanisms related to increased capillary stress. In this case, stiffening of large conduit arteries due to VS might induce increased and faster pressure and volume transmission into the brain capillaries. Although VS is mainly associated with vessel narrowing, where volume transmission is not necessarily increased, we suppose that shortened tau (even non-significantly) might reflect acceleration of the volume transmission, which in association with increased blood flow rate might enhance wall shear stress in the capillary network distal to insonation site. Consequently, such effects could increase amplitude of oscillations below 0.05 Hz due to enhanced production of different vasodilatory molecules, as an endothelial response to augmented shear stress. In addition, lack of significant correlation between ipsilateral mean CBFV and CBFV SWs might reflect their dissociation due to vessel lumen narrowing during VS. Finally, triple H therapy cannot account for our results, since ABP values did not differ significantly between pre VS and VS period of measurements.
Cerebral circulation can be considered as a complex system, since it involves both central and peripheral control mechanisms through multiple feedback loops [40,41]. Decreased complexity reflects either decreased information content or decreased disorder, related to the number of ‘microstates’ that are accessible to the system .
Soehle and colleagues , evaluated complexity of CBFV signals in patients suffering from SAH and found significantly reduced values during VS. On the contrary, Placek and coworkers , found that VS was associated with gradually increasing complexity of CBFV, attributed to a potential improvement in autoregulation and the number of regulatory mechanisms involved with its variability. Additionally, complexity of blood flow was significantly reduced ipsilateral to aneurysm rupture related to contralateral side before occurrence of VS, suggesting a potential therapeutic window.
In our investigation and similarly with Placek’s study , SampEn was also reduced ipsilateral compared to contralateral side, both before and during VS, but without reaching statistical significance. We suggest that differences between methods for assessing complexity could be responsible for inconsistency across different studies.
Temporal differences between and within DCI and non-DCI groups
Ipsilateral Mxa values were increased during VS in patients with DCI related to pre VS measurements, as well as in DCI compared to non-DCI group. Nevertheless, differences were not significant. Such findings are similar with previous work from different research groups [3-5].
Ipsilateral CBFV SWs before VS were significantly higher in the DCI compared to the non-DCI cohort. Moreover, non-DCI patients exhibited significantly higher SWs during VS related to pre spasm values (Figure 2). Since there are no similar studies in the literature, we can only guess about the potential pathophysiological mechanisms of such findings. Thus, we suggest that patients with DCI might experience an increased capillary stress even before the occurrence of VS. Since the two groups did not differ in terms of pre-VS values of Mxa, we suppose that the increased heterogeneity of flow during the first days after SAH that has been found in a few studies , might reflect focal impairment of autoregulation, which cannot be captured with TCD-derived indices. In this respect, a positive correlation was found between mean CBFV and SWs before VS in the DCI group, suggesting an association between SWs and fluctuations in CBF.
Furthermore, higher pre VS SWs in the DCI group could also be attributed to enhanced local neurogenic inputs originating in the brain stem, which are independent of the sympathetic nervous system . It has been suggested that in cases of highly focal disturbances of flow and autoregulation, inputs from the brain stem towards cerebral blood vessels are increased, in order to preserve CBF at the level of microcirculation . In such cases, magnitude of CBFV SWs will be augmented, since different local neurogenic mechanisms are also considered responsible for blood flow oscillations within a frequency range below 0.05 Hz [12, 39]. Thus, the association of pre VS SWs with occurrence of DCI that was found in the regression analysis might reflect the positive predictive value of regional dysautoregulation. In addition, lack of significant collinearity between input variables in the regression model due to absence of any significant correlation between them, increases precision of our findings. Nevertheless, these results need to be validated in a larger prospective study.
Finally, modest increase in CBFV SWs during VS in DCI patients related to non-DCI group, could be related to a state of vasoparalysis, since such condition may partially account for a reduction in blood vessels oscillatory capacity. It seems that a decreased vasomotor tone due to dysautoregulation, reflected in increased Mxa values (even non-significant), is associated with loss of pressure reactivity of cerebral blood vessels, limiting the ability of endothelial factors to induce oscillations in vessels’ wall, with subsequent attenuated increase in the amplitude of CBFV SWs. In this respect, different experimental studies have found that cortical arterioles after VS due to SAH demonstrate attenuated dilation to different endothelial-dependent dilators , reflecting microvascular endothelial dysfunction.
Strengths and limitations of the study
Some of the major limitations of this study is its retrospective nature, as well as the small sample size. Nevertheless, we included only conscious patients, in order to have clinically proven diagnosis of DCI, since its diagnosis in sedated subjects is more difficult and depends on different imaging techniques . Moreover, the mixture of both sedated and conscious patients might dilute findings in terms of SWs changes .
Mean CBFV did not differ between groups significantly, both before and during spasm. Thus, our patients seem to have similar severity of VS, limiting its potential impact on our findings.
Measurement of ABP rather than CPP for calculation of Mx might limit accuracy of our results. However, both Mx and Mxa have been shown to exhibit good correlation, particularly in cases of impaired autoregulation in TBI patients .
Another potential confounder in our study might be the arterial tension of pCO2, limiting accuracy of comparisons between patients . Nevertheless, none from our patients had a history of chronic obstructive pulmonary disease or any other pulmonary disease that might affect pCO2 levels, assuming that its potential impact upon our measurements might be insignificant.
Non-invasive ABP measurement for Mx calculation through Finapres system could constitute a further limitation in terms of accuracy of results. However, agreement between invasive and non-invasive assessment of Mx has been tested and a good correlation between the two methods was found .
Finally, lack of a normal control group constitutes another limitation of our study. Thus, lack of normative values of SWs does not permit us to define accurately their change between and within groups. Moreover, the inclusion of patients without VS might shed more light into potential pathophysiological mechanisms associated with the occurrence of DCI, in case of different or similar changes found between SAH patients with and without VS. Nevertheless, this can be the objective of a new prospective study.
In conclusion, we suggest that daily monitoring of CBFV SWs using online processing systems that support real-time processing of multiple high-rate physiological data streams, might have added value in the ICU, supporting clinical decisions at the bedside . Thus, longitudinal changes of SWs, even in the early days post ictus, could help identify patients who are more susceptible to development of DCI throughout their hospital course and prompt early treatment in a proactive rather than a reactive way. Consequently, such methods might determine the potential for early risk stratification and probably closer observation in the ICU for patients at high risk of DCI.