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Karen C. Peebles

Bio: Karen C. Peebles is an academic researcher from University of Otago. The author has contributed to research in topics: Cerebral blood flow & Blood pressure. The author has an hindex of 19, co-authored 43 publications receiving 1198 citations. Previous affiliations of Karen C. Peebles include Macquarie University & University of Auckland.

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TL;DR: The hypercapnic and hypocapnic MCAv‐CO2 reactivity was higher (∼97% and ∼24%, respectively) when expressed with P jv,CO 2 than P’s ’a, CO’2 (P < 0.05), indicating that a reduced reactivity results in less central CO2 washout and greater ventilatory stimulus.
Abstract: Measurement of cerebrovascular reactivity to CO2 has been widely applied in clinical practice to evaluate cerebral vascular function – e.g. in patients with carotid artery stenosis (Widder et al. 1994), hypertension (Serrador et al. 2005), stroke (Wijnhoud et al. 2006) and heart failure (Xie et al. 2005), and a related impairment has been linked to cerebral ischaemic events (Cosentino & Volpe, 2005; Wijnhoud et al. 2006). The acute manipulation of Pa,CO2 through hyperventilation has been used as an intervention to rapidly reduce intracranial pressure or to adjust cerebral blood flow (CBF) to metabolic needs. Furthermore, changes in cerebrovascular CO2 reactivity affect stability of the ventilatory responsiveness to CO2 via alterations in the degree of washout in central chemoreceptor hydrogen [H+]; these changes have been documented in a range of physiological (Cummings et al. 2007) and pathophysiological (Xie et al. 2005; Ainslie et al. 2007) conditions. In most instances CBF reactivity is expressed as the percentage change in CBF per mmHg change in Pa,CO2, or end-tidal CO2(PET,CO2) obviating the more invasive Pa,CO2 measurement. The tight correlation between the percentage of change in middle cerebral artery blood flow velocity (MCAv) measured by transcranial Doppler ultrasonography during PET,CO2 variations (Markwalder et al. 1984; Ide et al. 2003) has encouraged the use of transcranial Doppler (TCD) ultrasonography to measure CO2 cerebrovascular reactivity. However, several considerations are important when using Pa,CO2 (or PET,CO2) to investigate cerebral blood flow reactivity. First, PET,CO2 has been shown to underestimate Pa,CO2 at rest (Robbins et al. 1990) and to overestimate Pa,CO2 during exercise (Jones et al. 1979; Robbins et al. 1990). Similarly, a positive PET,CO2–Pa,CO2 gradient is seen in animals exposed to increased CO2 (Jennings & Chen, 1975; Oliven et al. 1985; Tojima et al. 1988). Such alterations in the Pa,CO2–PET,CO2 relationship may have implications for the true representation and physiological interpretation of cerebrovascular reactivity to CO2. In humans, it is not known how the Pa,CO2–PET,CO2 relationship is altered throughout the hypercapnic and hypocapnic range. To address these inaccuracies, Jones et al. (1979) developed a regression equation using PET,CO2 and tidal volume to provide an estimate of Pa,CO2 (ePa,CO2) during exercise to compensate for the overestimation of Pa,CO2 by PET,CO2. Thus, we reasoned that since hypercapnia evokes an increase in ventilation (and tidal volume), this empirical equation could also be used to estimate Pa,CO2 during step changes in PET,CO2. Therefore, cerebrovascular CO2 reactivity during hypercapnia and hypocapnia could be expressed in three different ways (Pa,CO2, ePa,CO2 and PET,CO2) and compared accordingly. The second consideration when investigating CBF reactivity is whether cerebrovascular reactivity to CO2 might be even better expressed as a percentage of brain tissue PCO2. This idea evolves from a study by Shapiro and colleagues who showed that changes in CBF corelated more closely with jugular venous CO2 tension (Pjv,CO2) than Pa,CO2 (r= 0.83 versus r= 0.72, respectively), suggesting that Pa,CO2 is not the effective stimulus for cerebral vasodilatation (Shapiro et al. 1966). In contrast, Severinghaus & Lassen (1967) provided data to indicate that brain tissue PCO2 (based on Pjv,CO2) was not the ultimate determinant of CBF during a single step of hypocapnia, and that Pa,CO2– or arterial wall PCO2– may have an important role. Whether there is a differential control of CBF via brain tissue PCO2 or Pa,CO2 during hypercapnia and hypocapnia remains to be established. With respect to ventilation, however, it is clear that the central contribution to the ventilatory response to CO2 is determined not by Pa,CO2 but by changes in brain tissue PCO2 and [H+] (Ahmad & Loeschcke, 1982; Smith et al. 2006). Thus, the stimulus at the central chemoreceptor level might also be better represented by the PCO2 of the venous cerebral outflow (Fencl, 1986; Xie et al. 2006). Given the outlined literature, it would appear that potential difference in cerebrovascular reactivity when expressed against Pa,CO2 or Pjv,CO2, and the potential relationship to CO2 ventilatory drive, has not been fully described in humans. Therefore the aims of this study were (1) to compare the accuracy of PET,CO2 and ePa,CO2 for predicting Pa,CO2 during step hyper- and hypocapnia changes, and (2) to compare CBF and ventilatory sensitivities to Pa,CO2, Pjv,CO2, ePa,CO2 and PET,CO2. Based on the aforementioned studies, we tested two original hypotheses: first, that PET,CO2 but not ePa,CO2 would overestimate Pa,CO2 during step changes in PCO2, and therefore result in apparent lower cerebrovascular CO2 reactivity; and second that because the changes in cerebral vascular tone occurring with changes in CO2 tension serve to limit changes in brain tissue PCO2 and thus Pjv,CO2, both PET,CO2 and Pa,CO2 reactivities would be lower when compared with Pjv,CO2. We also reasoned that, if MCAv–Pjv,CO2 reactivity determines brain PCO2, in those individuals with a low MCAv–Pjv,CO2 reactivity there would theoretically be less CO2 washout at the level of the central chemoreceptors and therefore a greater ventilatory stimulus.

149 citations

Journal ArticleDOI
TL;DR: It is suggested that only select CA metrics can be used interchangeably and that interpretation of these measures should be done cautiously.
Abstract: We assessed the convergent validity of commonly applied metrics of cerebral autoregulation (CA) to determine the extent to which the metrics can be used interchangeably. To examine between-subject ...

146 citations

Journal ArticleDOI
TL;DR: The early morning reduction in cerebral autoregulation may facilitate the onset of cerebrovascular accidents; this may be of particular relevance to at‐risk groups, especially upon resuming the upright position.
Abstract: The reduction in cerebrovascular reactivity to CO(2) and/or endothelial function that occurs in the early hours after waking are potential causes for the increased risk for cardiovascular events at this time point. It is unknown whether cerebral autoregulation is reduced in the morning. We tested the hypothesis that early morning reduction in endothelium-dependent vascular reactivity would be linked to changes in cerebrovascular reactivity to CO(2) and cerebral autoregulation (CA). Overnight changes in a dynamic cerebral autoregulation index (ARI) were determined from continuous recordings of blood flow velocity in the middle cerebral artery (MCAv) and arterial blood pressure (BP) during transiently induced hypotension in 20 individuals. Frontal cortical oxygenation (near infrared spectroscopy) and cerebral haemodynamics were also monitored during hypercapnia and before and during 3 min of active standing. Brachial artery flow-mediated endothelium-dependent vasodilatation (FMD) and endothelium-independent dilatation (NFMD) were also monitored. From evening to morning, there was a significant lowering in ARI (5.3 +/- 0.5 versus 4.7 +/- 0.6 a.u.; P < 0.05), cerebrovascular reactivity to CO(2) (5.3 +/- 0.6 versus 4.6 +/- 1.1% mmHg(-1); P < 0.05) and FMD (7.6 +/- 0.9 versus 6.0 +/- 1.4%; P < 0.05). The lowered FMD was related to the decrease in cerebrovascular reactivity to CO(2) (r = 0.76; P < 0.05). Transient reductions in morning MCAv and cortical oxyhaemoglobin concentrations were observed upon resuming a supine-to-upright position (P < 0.05 versus evening). The early morning reduction in cerebral autoregulation may facilitate the onset of cerebrovascular accidents; this may be of particular relevance to at-risk groups, especially upon resuming the upright position.

96 citations

Journal ArticleDOI
TL;DR: The results show that the balance of oxygen (O2) and carbon dioxide (CO2) pressures in arterial blood explains 40% of the change in brain blood flow upon arrival at high altitude (5050 m).
Abstract: Non-technical summary Brain blood flow increases during the first week of living at high altitude. We do not understand completely what causes the increase or how the factors that regulate brain blood flow are affected by the high-altitude environment. Our results show that the balance of oxygen (O2) and carbon dioxide (CO2) pressures in arterial blood explains 40% of the change in brain blood flow upon arrival at high altitude (5050 m). We also show that blood vessels in the brain respond to increases and decreases in CO2 differently at high altitude compared to sea level, and that this can affect breathing responses as well. These results help us to better understand the regulation of brain blood flow at high altitude and are also relevant to diseases that are accompanied by reductions in the pressure of oxygen in the blood.

91 citations

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TL;DR: Increased apnoea following nicotine exposure does not appear to reflect changes in basal activity of rhythm or pattern‐generating networks, but may result, in part, from reduced nicotinic modulation of XII motoneurons.
Abstract: We examined the effects of in utero nicotine exposure on postnatal development of breathing pattern and ventilatory responses to hypoxia (7.4 % O2) using whole-body plethysmography in mice at postnatal day 0 (P0), P3, P9, P19 and P42. Nicotine delayed early postnatal changes in breathing pattern. During normoxia, control and nicotine-exposed P0 mice exhibited a high frequency of apnoea (fA) which declined by P3 in control animals (from 6.7 ± 0.7 to 2.2 ± 0.7 min−1) but persisted in P3 nicotine-exposed animals (5.4 ± 1.3 min−1). Hypoxia induced a rapid and sustained reduction in fA except in P0 nicotine-exposed animals where it fell initially and then increased throughout the hypoxic period. During recovery, fA increased above control levels in both groups at P0. By P3 this increase was reduced in control but persisted in nicotine-exposed animals. To examine the origin of differences in respiratory behaviour, we compared the activity of hypoglossal (XII) nerves and motoneurons in medullary slice preparations. The frequency and variability of the respiratory rhythm and the envelope of inspiratory activity in XII nerves and motoneurons were indistinguishable between control and nicotine-exposed animals. Activation of postsynaptic nicotine receptors caused an inward current in XII motoneurons that potentiated XII nerve burst amplitude by 25 ± 5 % in control but only 14 ± 3 % in nicotine-exposed animals. Increased apnoea following nicotine exposure does not appear to reflect changes in basal activity of rhythm or pattern-generating networks, but may result, in part, from reduced nicotinic modulation of XII motoneurons.

87 citations


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TL;DR: This study is the first to establish reference and normal values for PWV, combining a sizeable European population after standardizing results for different methods of PWV measurement.
Abstract: Aims Carotid–femoral pulse wave velocity (PWV), a direct measure of aortic stiffness, has become increasingly important for total cardiovascular (CV) risk estimation. Its application as a routine tool for clinical patient evaluation has been hampered by the absence of reference values. The aim of the present study is to establish reference and normal values for PWV based on a large European population. Methods and results We gathered data from 16 867 subjects and patients from 13 different centres across eight European countries, in which PWV and basic clinical parameters were measured. Of these, 11 092 individuals were free from overt CV disease, non-diabetic and untreated by either anti-hypertensive or lipid-lowering drugs and constituted the reference value population, of which the subset with optimal/normal blood pressures (BPs) (n = 1455) is the normal value population. Prior to data pooling, PWV values were converted to a common standard using established conversion formulae. Subjects were categorized by age decade and further subdivided according to BP categories. Pulse wave velocity increased with age and BP category; the increase with age being more pronounced for higher BP categories and the increase with BP being more important for older subjects. The distribution of PWV with age and BP category is described and reference values for PWV are established. Normal values are proposed based on the PWV values observed in the non-hypertensive subpopulation who had no additional CV risk factors. Conclusion The present study is the first to establish reference and normal values for PWV, combining a sizeable European population after standardizing results for different methods of PWV measurement.

1,371 citations

Journal ArticleDOI
TL;DR: Mechanisms regulating cerebral blood flow (CBF), with specific focus on humans, are reviewed and the following four key theses are corroborated: that cerebral autoregulation does not maintain constant perfusion through a mean arterial pressure range of 60–150 mmHg; that there is important stimulatory synergism and regulatory interdependence of arterial blood gases and blood pressure on CBF regulation.
Abstract: Herein, we review mechanisms regulating cerebral blood flow (CBF), with specific focus on humans We revisit important concepts from the older literature and describe the interaction of various mechanisms of cerebrovascular control We amalgamate this broad scope of information into a brief review, rather than detailing any one mechanism or area of research The relationship between regulatory mechanisms is emphasized, but the following three broad categories of control are explicated: (1) the effect of blood gases and neuronal metabolism on CBF; (2) buffering of CBF with changes in blood pressure, termed cerebral autoregulation; and (3) the role of the autonomic nervous system in CBF regulation With respect to these control mechanisms, we provide evidence against several canonized paradigms of CBF control Specifically, we corroborate the following four key theses: (1) that cerebral autoregulation does not maintain constant perfusion through a mean arterial pressure range of 60–150 mmHg; (2) that there is important stimulatory synergism and regulatory interdependence of arterial blood gases and blood pressure on CBF regulation; (3) that cerebral autoregulation and cerebrovascular sensitivity to changes in arterial blood gases are not modulated solely at the pial arterioles; and (4) that neurogenic control of the cerebral vasculature is an important player in autoregulatory function and, crucially, acts to buffer surges in perfusion pressure Finally, we summarize the state of our knowledge with respect to these areas, outline important gaps in the literature and suggest avenues for future research

649 citations

Journal ArticleDOI
TL;DR: Reductions in cerebrovascular responsiveness to CO(2) that provoke an increase in the gain of the chemoreflex control of breathing may underpin breathing instability during central sleep apnea in patients with congestive heart failure and on ascent to high altitude.
Abstract: Cerebral blood flow (CBF) and its distribution are highly sensitive to changes in the partial pressure of arterial CO2 (PaCO2). This physiological response, termed cerebrovascular CO2 reactivity, i...

482 citations

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TL;DR: TCD is an efficient tool to access blood velocities within the cerebral vessels, cerebral autoregulation, cerebrovascular reactivity to CO(2), and neurovascular coupling in both physiological states and in pathological conditions such as stroke and head trauma.

460 citations

Journal ArticleDOI
TL;DR: This finding indicates that, during heavy exercise, CBF decreases despite the cerebral metabolic demand, and this reduced CBF duringheavy exercise lowers cerebral oxygenation and therefore may act as an independent influence on central fatigue.
Abstract: The response of cerebral vasculature to exercise is different from other peripheral vasculature; it has a small vascular bed and is strongly regulated by cerebral autoregulation and the partial pre...

429 citations