An additional aim of this thesis was to challenge the other arm of cerebral autoregulation, the response to static, prolonged increases in MAP. The classic static autoregulatory curve purposed by Lassen (1959) was based on steady-state CBF flow during changes in MAP in a varied cohort that included patients with various pathologies and that were taking medications. More recently Lucas et al. (2010) revisited this concept and used transracial Doppler to assess MCAv during steady state pharmacologically induced perturbations in MAP. The results presented by Lucas et al. (2010) indicate that the brain is much more pressure passive than traditionally accepted. Although, an autoregulatory curve similar to
173 that presented by Lassen (1959) has been shown during oscillatory lower body negative pressure. Only at slow frequencies of 0.03 Hz was a plateau apparent, with the plateau only extending 5 mm Hg each side of baseline pressure with changes beyond this resulting in a pressure passive region (Tan 2012; Tan & Taylor 2014). This plateau may have gone undetected in the study by Lucas et al. (2010) due to the magnitude of the step changes of MAP. As these MAP oscillations increase in frequency autoregulatory gain increased such that these fluctuations were un-buffered and a pressure-passive relationship was apparent (Tan 2012). Whilst dynamic cerebral autoregulation takes ~5 s to compensate for changes in MAP (Zhang et al. 1998a), the variance of MCAv is dependent on the ΔMAP/Δtime (Tzeng et al. 2011). Therefore, to assess the effectiveness of static cerebral autoregulation perturbations in MAP outside the autoregulatory plateau (>5 mm Hg increase in MAP from baseline) were used, as purposed by Tan et al. (2012). Moreover, slow steady state prolonged (5 min) increases in MAP were used as this is where static cerebral autoregulation appears to be more effective (Zhang et al. 1998a).
There is evidence to indicate that phenylephrine may constrict the MCA resulting in an increase in MCAv but not CBF per se (Ogoh et al. 2011). Therefore, the results of Lucas et al. (2010) may have been confounded by the use of pharmaceuticals. Therefore, a non- pharmacological means of increasing MAP was utilised in this thesis in the form of LBPP, which increases MAP in a dose dependent manner (Nishiyasu et al. 2007). In Chapter Seven
it was demonstrated that LBPP induced static increases in MAP elevated MCAv, consistent with the results from Chapters Five and Six in that dynamic changes in MAP can induce similar changes in MCAv. Contrary to the stated hypotheses this phenomenon was only apparent at 20 mm Hg. At higher pressures (40 mm Hg) MCAv demonstrated a small
174 decrease from baseline although this was not statistically significant. It was speculated that this restraint of MCAv despite the elevated MAP at 40 mm Hg LBPP is due to sympathetic modulation of the cerebral circulation. Indeed, the brain was pressure passive but only at lower pressures.
Interestingly, this increase at 20 mm Hg of LBPP was not replicated in Chapter Eight
although the same slight decrease from baseline at +40 mm Hg was apparent. The difference in results between these two experiments may be explained by the difference in cohort recruited. As autoregulatory efficacy differs greatly between individuals (Zhang et al. 2000), physiological variance (i.e., sensitivities) between the cohorts may underpin these differences. Moreover, the efficacy of cerebral autoregulation is inversely related to baroreflex sensitivity, indicative of a compensatory mechanism between the systemic and cerebral circulations (Tzeng et al. 2010a). In these individuals with poor autoregulatory efficacy an un-compensable forced increase in MAP is possibly unable to be counteracted by the cerebral resistance vessels. Therefore differential regulation between the systemic and cerebral circulations in the two cohorts may explain this variation.
Hypercapnia has been shown to impair dynamic cerebral autoregulatory processes (Aaslid et al. 1989; Zhang et al. 1998a; Ainslie et al. 2005; Maggio et al. 2013), however whether this extends to static cerebral autoregulation is unclear. Previous work has demonstrated during dynamic rebreathing that a break point is achieved during hypercapnia in that chemoreceptor-mediated increases in MAP result in subsequent elevations in MCAv. In
Chapter Eight the efficacy of static cerebral autoregulation during concomitant hypercapnia
was tested using LBPP-mediated increases in MAP. At 40 mm Hg LBPP the brain became pressure passive; i.e., the control mechanisms that would otherwise defend against the
175 elevated arterial blood pressure are impaired by hypercapnia and confirms the notion that autoregulatory efficacy is reliant on resting vascular tone (Aaslid et al. 1989). The superimposed 40 mm Hg of LBPP during hypercapnia (5% CO2) increased MAP by 14 ± 7 mm
Hg from baseline versus an increase 5 ± 6 mm Hg due to hypercapnia alone. This increase during 5% CO2 + 40 mm Hg LBPP elevated MCAv by 31 ± 13 cm·s-1 with hypercapnia alone
increasing MCAv 25 ± 11 cm·s-1. Thus, a 9 mm Hg increase in MAP resulted in a 6 cm·s-1 increase in MCAv. Despite the relatively small increase in MAP a significant change in MCAv was observed. Ideally larger increases in MAP would be used to demonstrate this autoregulatory impairment. However, given the assessment of static rather than dynamic autoregulation producing large and prolonged non-pharmacological increases in MAP is difficult. In order to produce such changes in MAP, a pharmacological intervention would be required (i.e., phenylephrine infusion). Despite this method’s potential influence on the MCA, further exploration in this area would require such interventions. Regardless, Chapter
Eight demonstrates impairment of static autoregulatory processes during hypercapnia and
confirmed the hypothesis.