Response to Letter by Prakash
In his/her letter regarding our article in Stroke,1 Dr Prakash suggests that our report of impaired cerebral autoregulation (CA) during hypotension was a result of the perfusion pressure falling below the lower limits of CA, rather than our experimental strategy of using an α-adrenergic blockade of cerebral vessels with Prazosin. However, based on previous literature, the idea of a perfusion pressure–related impairment of CA is untenable for the following reasons:
(1) No study has demonstrated the presence of a defined lower limit of CA in humans. Lassen2 established the CA range of mean arterial pressure (MAP) in humans to be an average from 60 to 150 mm Hg. However, this value was based on the data presented in 2 previous publications. First, Finnerty et al3 reported an impaired CA (a decreased cerebral blood flow) in young normotensive human subjects during acute hypotension. The average MAP during hypotension which identified an impaired CA (decreased cerebral blood flow) was 35 (26 to 44) mm Hg. Second, McCall4 demonstrated no change in cerebral blood flow during a pharmacologically induced mild hypotension of 57 mm Hg. Thus, the lower limit of CA of humans may range between 44 and 57 mm Hg not the 65 mm Hg claimed by Dr Prakash.
(2) The response of cerebral blood flow to hypotension around the lower limit of CA remains unclear in healthy humans because it is impossible—and unethical—to experimentally manipulate cerebral perfusion pressure to its clinically critical pressure. In dogs, Harper et al5 and Rapela et al6 demonstrated the response of cerebral blood flow to manipulated changes in arterial pressure. Even in dogs, the break point of the lower limit of CA was not clear. It seems that the lower limit of the CA curve occurs at the beginning of an exponential reduction in cerebral blood flow (not a straight line) without a marked change in cerebral blood flow. From these data, it is highly unlikely that the 5 to 10 mm Hg reduction in pressure resulting from Prazosin blockade of the α-receptors reported in our article explained the differences in the response of cerebral blood flow.
(3) Perhaps the most important concept to understand is that dynamic CA is not equal to static CA. Dr Prakash’s concerns regarding our interpretation of our data are based on the concept of static CA. In humans, the calculated transfer function gain (TFg) between cerebral blood flow and arterial pressure is well-validated index of CA. In the very low frequency range (0.02 to 0.07 Hz) the TFg is lower than that in the low frequency range (0.07 to 0.2 Hz).7,8 This reduction in TFg indicates that there is a discrepancy between gain of the static CA at 0 Hz and the gain of the dynamic CA in the high frequency range. A more simple explanation is that during orthostatic stress dynamic CA is preserved (P=0.36) despite a reduction in cerebral blood flow (P<0.0001), which when interpreted from a concept of static CA would indicate an impairment of CA.9 Hence, in response to Dr Prakash the results of investigations into dynamic CA cannot be explained using the concepts of static CA.
(4) Dr Prakash appears to consider that Prazosin affects cerebral vessels the same as peripheral vessels. However, it is difficult to identify the effect of adrenergic blockade on cerebral vessels by changes in cerebral blood flow because of changes in blood pressure. In addition, it is not correct to think that the cerebral vasculature is regulated to the same degree as the peripheral vasculature. The cerebral vascular bed is very small and strongly influenced by CO2, CA and, from our point of view, sympathetic nerve activity. Moreover, the distribution of sympathetic nerve activity on cerebral vessels is different from that in other vasculatures. For example, Zhang et al10 reported an impaired dynamic CA after ganglion blockade despite a decrease in cerebral blood flow (P=0.02). It is possible that the ganglion blockade caused cerebral vasodilatation; however, in this case, cerebral blood flow was not increased. The evidence in our publication1 supporting the idea that the impaired CA was independent of the reduction in cerebral perfusion pressure includes the following:
(5) The minimum MAP observed with Prazosin was lower than control (57±4 versus 64±4 mm Hg) but was not significant (P=0.125). Hence, using a static CA mechanism of interpretation there was no difference in the minimum MAP achieved between the control and the Prazosin conditions, indicating that the differences in the rate of regulation (RoR, an index of dynamic CA) were not affected by the reduction in MAP. In addition, although the minimum MAP in 2 subjects during the Prazosin condition was >65 mm Hg (66 and 68 mm Hg), the RoR clearly decreased from the control condition (−80% and −38%). In contrast, the RoR in 3 subjects who had a minimum MAP below 65 mm Hg (51, 59, 61 mm Hg) during the control condition was higher than that with Prazosin.
(6) In our study,1 the RoR response was not dependent on the minimum MAP. The average of RoR in the subjects who had a minimum MAP below or above 65 mm Hg was 0.151±0.05 (n=7) or 0.149±0.05 (n=5), respectively. There is no significant difference between these 2 values (P=0.982).
Collectively, it is clearly evident that an impaired CA was independent of the lower limit of CA in our study.1 However, although technically and ethically challenging, we do agree that further research is needed to identify the lower limit of CA in humans.
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