Static autoregulation in humans: a review and reanalysis
Introduction
Cerebral autoregulation (CA) is a theoretical construct characterized by the changes in cerebral blood flow (CBF) during changes in blood pressure (BP), in which physiological mechanisms attempt to maintain constancy of CBF. Although the physiological underpinnings remain obscure [1], CA is characterized on a continuum ranging from static (steady-state) to dynamic (transient) components. Static CA is typically described as operating over several minutes to hours and represents the steady-state relationship between mean arterial pressure (MAP) and CBF [2]. In contrast, dynamic CA commonly refers to the cerebral pressure–flow relationship as observed during transient changes in MAP (e.g., with changes in posture), taking place over a period of seconds [3], [4]. Although these two metrics act on a continuum, the cerebrovasculature appears to be better suited at buffering lower frequency fluctuations in BP (<0.20 Hz), than higher frequency fluctuations (>0.20 Hz) [5]. The current study focuses on the cerebral pressure–flow relationship that is associated with static CA.
Many studies have been performed to evaluate CA in healthy subjects and patients with perturbations of MAP while measuring concordant changes in CBF. The first key paper to address this topic was the published review by Lassen in 1959 describing the notion that CBF remains constant for MAP values between 60 and 150 mmHg [6]. This so-called ‘static’ CA curve was notably formulated from 7 different studies with 11 different subject groups. The subject groups’ CBF was measured at a single MAP value and were not observed throughout a range in MAP. Furthermore, these subjects either had a pathological condition and/or were taking pharmaceuticals. This classic report has been commonly (mis)-cited as depicting a mean curve for intra-subject CA relationships collected over a range of MAP values versus actually representing connected individual inter-subject data points. Indeed, fixing a line through several singular subject MAP/CBF relationships ignores the potential of chronic resetting, e.g., in the case with sustained hypertension [7]. Upon closer examination of the response for CBF (or a related index of CBF) to a change in MAP, recent studies have revealed that this relationship appears to be more pressure passive [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22] than previously described. However, the limitations to drawing inferences from the majority of recent studies are three-fold. First, transcranial Doppler ultrasound (TCD) has been widely used to evaluate CBF velocity (CBFV) [8], [9], [10], [11], [18], [20], [21], [22], which accurately represents CBF exclusively in the event that diameter of the insonated vessel remains constant. Whether this is the case with severe decreases or increases in MAP is unclear [23], [24]. Second, many of these studies have also investigated CA through the use of cardiovascular-active substances [10], [11], [14], [17], [20], [22], which may have had an influence on cerebrovascular tone. Finally, only one of the previously mentioned studies corrected for effects of the partial pressure of arterial carbon dioxide (PaCO2) [12] on CBF. This is critically important since PaCO2—via changes in alveolar ventilation—can be profoundly altered during changes in blood pressure. It is well established that CBF is highly sensitive to changes in PaCO2, yielding an approximate 4 and 2% change in flow per mmHg change in PaCO2 above and below eupneic PaCO2, respectively [25].
The aim of this study was to conduct a literature analysis to provide an up-to-date understanding of the static relationship between MAP and CBF. Specifically, we formulated a new comprehensive cerebral pressure–flow response curve based on results from an extensive review of studies in which MAP was decreased and/or increased within each subject group. Although the mechanisms are not entirely understood, there is evidence in both humans [26], [27], [28] and animals [29] that support the idea of hysteresis in the relationship between MAP and CBF. That is, the cerebrovasculature is better able to buffer against increases, as opposed to decreases in MAP. As such, we compared the separate CBF response to increases and decreases in MAP.
Section snippets
Methods
Pubmed and Scopus were searched (Oct.–Dec. 2012) for studies with the terms ‘cerebral blood flow’, ‘arterial pressure’, and ‘healthy subjects’, having been published between 1960 and 2012. Non-human experiments and non-English studies were excluded. The initial review resulted in a total of 459 studies. The selected population was healthy subjects between 18 and 65 years of age. Within studies that had both clinical patients and control subjects, the results of the control subjects were
Results
From all reviewed articles, 40 were included in this study. Multiple within study or single study experiments were divided into categories of decreasing MAP (n = 23) and increasing MAP (n = 26); individual study results are depicted in Table 1, Table 2. In the studies where MAP was decreased, the calculated slopes were between −0.39 and 3.46%ΔCBF/%ΔMAP. The average slope for decreased MAP was 0.82 ± 0.77%ΔCBF/%ΔMAP (Fig. 2; or 0.97 ± 0.91%ΔCBF/mmHg MAP). In the studies where MAP was increased, the
Discussion
The results of this review indicate that during static changes in MAP, without an applied correction factor for CO2, the cerebral vasculature possesses more efficient autoregulation during increases in MAP as opposed to decreases. This apparent hysteresis is lost following a global correction for PaCO2. The findings of this analysis are discussed, the potential limitations of experimental approaches are highlighted, and future directions are considered.
Relationship between MAP and CBF: The
Perspective
Our findings provide new insights into the steady-state cerebral pressure–flow response for healthy subjects, although it is important to further confirm this newly depicted relationship in future studies. A definitive, within-subjects assessment of global and regional CBF across a range of non-pharmacologically and pharmacologically perturbed BP with maintained PaCO2 has yet to be completed. Until this is done, we cannot define what constitutes ‘normal’ and ‘impaired’ static CA.
Conclusion
In conclusion, we interpret our findings to highlight that the cerebral vasculature may have more efficient autoregulatory ability in the face of increased MAP, versus that during decreases in MAP. The apparent loss of this relationship following our attempt at correcting for changes in PaCO2 highlights the need for future, unified, research. However, we hypothesize that future studies involving properly controlled PaCO2 values will display an autoregulatory hysteresis in agreement with our
Funding
None.
Ethical approval
Not required.
Conflict of interest
None declared.
References (79)
- et al.
Effects of aging on the cerebrovascular orthostatic response
Neurobiol Aging
(2011) - et al.
The effect of the cold pressor test on a visually evoked cerebral blood flow velocity response
Ultrasound Med Biol
(2012) - et al.
Basal cerebral blood flow is dependent on the nitric oxide pathway in elderly but not in young healthy men
Exp Gerontol
(2004) - et al.
Utility of transcranial Doppler ultrasound for the integrative assessment of cerebrovascular function
J Neurosci Methods
(2011) - et al.
Effects of target-controlled infusion of propofol on the transient hyperaemic response and carbon dioxide reactivity in the middle cerebral artery
Br J Anaesth
(1999) - et al.
Effect of generalised sympathetic activation by cold pressor test on cerebral haemodynamics in healthy humans
J Auton Nerv Syst
(1998) - et al.
Integrative physiologic and computational approaches to understand autonomic control of cerebral autoregulation
Exp Physiol
(2014) Assessment of cerebral pressure autoregulation in humans—a review of measurement methods
Physiol Meas
(1998)- et al.
Cerebral autoregulation dynamics in humans
Stroke
(1989) - et al.
Comparison of flow and velocity during dynamic autoregulation testing in humans
Stroke
(1994)
Blood pressure regulation IX: cerebral autoregulation under blood pressure challenges
Eur J Appl Physiol
Cerebral blood flow and oxygen consumption in man
Physiol Rev
Regional cerebral blood flow in chronic hypertension: a correlative study
Stroke
Differential blood flow responses to CO2 in human internal and external carotid and vertebral arteries
J Physiol (Lond)
The different effects of midazolam and propofol sedation on dynamic cerebral autoregulation
Anesth Analg
Dexmedetomidine weakens dynamic cerebral autoregulation as assessed by transfer function analysis and the thigh cuff method
Anesthesiology
Influence of changes in blood pressure on cerebral perfusion and oxygenation
Hypertension
Effect of generalized sympathetic activation by cold pressor test on cerebral hemodynamics in diabetics with autonomic dysfunction
Cerebrovasc Dis
The effect of hypocapnia on the autoregulation of cerebral blood flow during administration of isoflurane
Anesth Analg
The effect of age on cerebrovascular reactivity to cold pressor test and head-up tilt
Acta Neurol Scand
Dynamic regulation of middle cerebral artery blood flow velocity in aging and hypertension
Stroke
Characterization of angiotensin-II effects on cerebral and ocular circulation by noninvasive methods
Br J Clin Pharmacol
Cerebral autoregulation in the vertebral and middel cerebral arteries during combine head upright tilt and lower body negative pressure in healthy humans
IEEE
Dynamic cerebral autoregulation during passive heat stress in humans
Am J Physiol—Regul Integr Comp Physiol
The effect of sevoflurane on dynamic cerebral blood flow autoregulation assessed by spectral and transfer function analysis
Anesth Analg
Autonomic neural control of dynamic cerebral autoregulation in humans
Circulation
Segmental vascular responses to acute hypertension in cerebrum and brain stem
Am J Physiol
Role of large arteries in regulation of cerebral blood flow in dogs
J Clin Invest
Regional brain blood flow in man during acute changes in arterial blood gases
J Physiol
Cerebrovascular regulation during transient hypotension and hypertension in humans
Hypertension
Asymmetric dynamic cerebral autoregulatory response to cyclic stimuli
Stroke
Cerebral autoregulatory response depends on the direction of change in perfusion pressure
J Neurotrauma
Sympathetic withdrawal augments cerebral blood flow during acute hypercapnia in sleeping lambs
Sleep
Vasodilatory effect of adenosine triphosphate does not change cerebral blood flow: a PET study with (15)O-water
Ann Nucl Med
Autonomic neural control of the cerebral vasculature: acute hypotension
Stroke
Face cooling with mist water increases cerebral blood flow during exercise: effect of changes in facial skin blood flow
Front Physiol
Effects of losartan on cerebral and ocular circulation in healthy subjects
Br J Clin Pharmacol
Effects of morphine-nitrous oxide anesthesia on cerebral autoregulation
Anesthesiology
S-ketamine anesthesia increases cerebral blood flow in excess of the metabolic needs in humans
Anesthesiology
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