In the present study, we measured and compared different TCD-derived hemodynamic and complexity indices of cerebrovascular dynamics, in order to investigate their behavior during VS in patients after SAH, dichotomized by the presence of DCI.
For the whole group of patients, we observed that during VS, CBFV SWs were found to increase in relation to the pre VS measurements (paired temporal comparisons). Similar differences were found between ipsilateral vs contralateral side during VS (paired spatial comparisons). Moreover, our findings confirm that VS can cause a disturbance of autoregulation at the side of aneurysm [3-5]. We also confirm previous study by Kasprowicz and colleagues , who found that tau is significantly reduced during VS even before formal TCD signs of VS are observed, suggesting a potentially therapeutic window for escalation of treatment.
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 [15,19.
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 . Thus, pCO2 changes related oscillations in the cerebrovascular volume, was believed to be one major mechanism of origin . However, such theory does not seem to be universally advocated, since SWs have been also found in deeply sedated patients with stable pCO2 levels under mechanical ventilation .
According to Rosner , SWs are related to plateau waves of ICP waveforms, since they are generated by the same mechanism. Thus, an unstable ABP or faster and greater ABP decrements, induce vasodilatation when autoregulation is intact. Subsequently and through a vasodilatory cascade, the increase in cerebral blood volume and ICP promotes through a Cushing response an increase in ABP, terminating the pressure waves.
Others have suggested that SWs are derived from rhythmic cerebral vasoconstriction caused by an intrinsic brain stem rhythm, since their occurrence is independent from changes in pCO2 levels, ABP and respiration . In this respect, general anesthesia has been found to reduce amplitude of SWs of ICP .
Greitz and colleagues , have proposed a different mechanism of origin of SWs. They suggested that restricted arterial distensibility due to decreased intracranial compliance in cases of chronic hydrocephalus, is associated with increased capillary pulsations and subsequently, increased CBFV SWs.
Stefanovska and coworkers , analyzing fluctuations in human peripheral blood flow, recognized 5 distinct oscillations, with frequency intervals between 0.02-0.05 Hz reflecting smooth muscle autonomic innervation, where frequencies lower than 0.05 Hz were related to both local neurogenic and metabolic inputs. Particularly, endothelial activity reflected in the concentration of different molecules secreted from endothelial cells, with vasodilatory or vasoconstrictive properties, such as nitric oxide (NO) and endothelin respectively, contributed to oscillations of around 0.01 Hz. According to classic studies of Fry and Byrom [35.36], 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 NO. Such metabolic effects might be reflected in the amplitude of blood flow oscillations within a frequency range below 0.02 Hz.
Based on the previous discussion, we suggest that increased CBFV SWs during VS in both temporal and spatial assessments that was found in our study, correspond 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 might reflect acceleration of the volume transmission, which in association with increased flow rate might enhance wall shear stress in the capillary network distal to insonation site. In this respect, a negative correlation between tau and SWs during VS was found but at the limit of statistical significance. Consequently, and according to Stefanovska’s findings, such effects could increase amplitude of oscillations below 0.02 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 SWs might reflect their dissociation due to vessel lumen narrowing during VS, whereas ABP SWs did not differ significantly from pre VS values. Such findings further support our suggestion that increased magnitude of SWs during VS is mainly attributed to local mechanisms related to capillary stress. Finally, triple H therapy cannot account for our results, since ABP values did not differ significantly between pre VS and VS period of measurements.
Another finding of this study was the negative correlation between ΔSW and ΔMxa during VS. In this case, disturbed autoregulation during VS (even if it did not reach statistical significance) seems to be associated with modest increase in SWs. It seems that a highly decreased vasomotor tone or even vasoparalysis due to dysautoregulation, reflected in increased Mxa values, 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 reduced amplitude of low frequency oscillations. Nevertheless, and since a significant stiffening of the arterial bed is also needed to explain our results, we assume that shortening of tau during VS partially reflects a decreased vascular compliance, as has already been suggested by Kasprowicz and colleagues .
Cerebral circulation can be considered as a complex system, since it involves both central and peripheral control mechanisms through multiple feedback loops . Loss of complexity during illness might be attributed to altered coupling between system’s components . 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 variability and complexity of TCD-derived CBFV signals in patients suffering from SAH and found significantly reduced variability and complexity during VS, which was associated with unfavorable outcome. In addition, Placek and coworkers , using an index based on Renyi entropy, 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. In addition, complexity of blood flow was significantly reduced ipsilateral to aneurysm rupture related to contralateral side before occurrence of VS, suggesting, as in the case of tau, 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. Furthermore, ipsilateral SampEn during VS was non significantly increased in relation to pre VS measurements. We suggest that differences between methods for assessing complexity could be responsible for inconsistency across different studies.
Cerebral autoregulation estimated with Mxa was found to be significantly impaired during VS in patients who developed DCI related to pre VS measurements. Moreover, ipsilateral Mxa values during VS were significantly increased in DCI compared to non-DCI groups (temporal comparisons). Finally, patients with DCI exhibited a significant interhemispheric difference in autoregulation, since Mxa during VS was found to increase in the ipsilateral related to contralateral side of aneurysm rupture (spatial comparisons). Such findings are in keeping with previous studies [4,5], which showed that development of DCI was associated with a significant interhemispheric difference of autoregulation in the first 5 days after ictus.
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, although Mxa was not found to differ between patients with different outcome . In this respect, our findings agree with those of Calviere and coworkers , who showed that the combination of both large artery VS and impaired autoregulation estimated with Mxa during the first 7 days from ictus, was correlated to subsequent DCI. 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. In any case, our results agree with those from other studies where no arterial tension pCO2 measurements were performed [3-5].
Ipsilateral CBFV SWs before VS were significantly increased in the DCI compared to the non-DCI cohort, whereas high ΔSW during VS was present only in patients who did not develop DCI. 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; however, lack of differences between groups in terms of pre-VS values of Mxa or tau might signal different mechanisms of origin. Perhaps the increased heterogeneity of flow during the first days after SAH, which has been found in studies using direct perfusion methodology , suggest focal impairment of autoregulation that 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, reflecting an association between SWs and fluctuations in CBF.
Furthermore, increased pre VS SWs could also be attributed to enhanced local neurogenic inputs originating in the brain stem, which are independent of the sympathetic nervous system . Probably, 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 0.02 Hz . In this respect, no differences were found between ABP SWs before and during VS, either between or within groups. Finally, ABP mean values were not different between groups. Thus, the association of high pre VS SWs with occurrence of DCI might reflect the significant predictive value of regional dysautoregulation. Nevertheless, these results need to be validated in a larger prospective study.
Finally, attenuated 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. Moreover, microvascular endothelial dysfunction and spasm could also be associated with lack of change in SWs during VS. Thus, experimental studies have found that cortical arterioles after VS due to SAH demonstrate attenuated dilation to different endothelial-dependent dilators, such as NO and adenosine diphosphate .
Some of the major limitations of this study is its retrospective nature, as well as the small sample size that might account for some of the negative associations found. Nevertheless, we included only conscious patients, in order to increase homogeneity of studied population, as well as 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 . In addition, 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. Our results are in keeping with those from other investigators who evaluated relationships between different TCD-derived cerebrovascular parameters with outcome, in similar patients’ groups. Non-invasive ABP measurement for Mx calculation through Finapres system could constitute another 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 .
Since TCD has limited spatial resolution, it is conceivable that regional disturbance of autoregulation, particularly affecting the posterior circulation might have been missed. Moreover, TCD cannot detect microvascular spasm, a potential mechanism of modest ΔSW increase during VS in DCI group.
In conclusion, we suggest that CBFV SWs even in the early days post ictus might help identify patients who are more susceptible to development of DCI throughout their hospital course. Moreover, simultaneous analysis of ICP and CBFV could enhance accuracy of measurements through estimation of CPP instead for ABP, whereas parallel monitoring of arterial tension of pCO2 that affects thresholds of disturbed autoregulation might improve accuracy of comparisons between patients.