Regional differences in cerebrovascular reactivity in response to acute isocapnic hypoxia in healthy humans: Methodological considerations

https://doi.org/10.1016/j.resp.2021.103770Get rights and content

Highlights

  • Regional cerebrovascular responses (CVR) to hypoxia reported in the literature are equivocal.

  • Differential reports are likely due to analytical differences.

  • We assessed anterior vs. posterior CVR in awake humans during exposure to acute steady-state isocapnic hypoxia.

  • Absolute CVR was greater in the anterior compared to posterior cerebral circulation during exposure to hypoxia.

  • These regional differences in CVR were not apparent when expressed in relative terms.

Abstract

The cerebrovasculature responds to blood gas challenges. Regional differences (anterior vs. posterior) in cerebrovascular responses to increases in CO2 have been extensively studied. However, regional cerebrovascular reactivity (CVR) responses to low O2 (hypoxia) are equivocal, likely due to differences in analysis. We assessed the effects of acute isocapnic hypoxia on regional CVR comparing absolute and relative (%-change) responses in the middle cerebral artery (MCA) and posterior cerebral artery (PCA). We instrumented 14 healthy participants with a transcranial Doppler ultrasound (cerebral blood velocity), finometer (beat-by-beat blood pressure), dual gas analyzer (end-tidal CO2 and O2), and utilized a dynamic end-tidal forcing system to elicit a single 5-min bout of isocapnic hypoxia (∼45 Torr PETO2, ∼80 % SpO2). During exposure to acute hypoxia, absolute responses were larger in the anterior compared to posterior cerebral circulation (P < 0.001), but were not different when comparing relative responses (P = 0.45). Consistent reporting of CVR to hypoxia will aid understanding normative responses, particularly in assessing populations with impaired cerebrovascular function.

Introduction

The brain makes up ∼2% of total body mass, yet it accounts for ∼20 % of the body’s energy consumption (Willie et al., 2014). The brain has a limited ability to store metabolic substrates (Willie et al., 2014) and, therefore requires adequate perfusion under all conditions to maintain normal function. There are several cerebrovascular mechanism(s) to ensure perfusion is maintained, including local regulatory systems that rapidly alter cerebral blood flow (CBF) in response to variations in blood gases (Kety and Schmidt, 1948). Both CO2 and O2 can act as vasoactive humoral stimuli, whereby high CO2 (hypercapnia) and low O2 (hypoxia) result in cerebral vasodilation and the magnitude change of CBF for a given change in O2 or CO2 is referred to as cerebrovascular reactivity (CVR; Kety and Schmidt, 1948; Willie et al., 2012; Ogoh et al., 2013).

There is evidence for regional differences (e.g., anterior vs posterior) in CBF regulation during various CO2 gas challenges (Kety and Schmidt, 1948; Battisti-Charbonney et al., 2011; Sato et al., 2012; Willie et al., 2012; Skow et al., 2013), where by anterior cerebrovasculature is more responsive to increases in CO2 compared to posterior cerebrovasculature, at least in absolute terms. However, less is known about the isolated regional CVR response to acute hypoxia (i.e., to what extent hypoxia effects anterior vs. posterior brain regions). Many factors contribute to the lack of consensus on this topic. First, there are multiple techniques utilized to measure CBF including duplex ultrasound to measure volumetric flow in the extracranial arteries (Willie et al., 2012; Lewis et al., 2014; Thomas et al., 2015; Hoiland et al., 2017; Morris et al., 2017; Fernandes et al., 2018; Lafave et al., 2019), transcranial Doppler (TCD) to measure the blood velocity within intracranial arteries (Willie et al., 2012; Skow et al., 2013; Feddersen et al., 2015; Thomas et al., 2015; Hoiland et al., 2017), and magnetic resonance imaging (MRI) to measure the global CBF using radiopharmaceuticals (Kolbitsch et al., 2002; Kellawan et al., 2017; Lawley et al., 2017). Furthermore, when TCD is employed to evaluate CBF, often only the middle cerebral artery (MCA) is insonated (e.g., Xie et al., 2006). This is based on the long-held assumption that the MCA velocity is representative of the perfusion of all cerebral territories, as the MCA perfuses ∼70 % of the brain and the posterior cerebral artery (PCA) perfused the other 30 % (Willie et al., 2014). Furthermore, the variability between isocapnic and poikilocapnic studies, as well as chronic and acute hypoxic studies, makes direct comparisons within existing literature challenging. Finally, these measurements can be reported in absolute terms (e.g., Willie et al., 2012; Hoiland et al., 2017; Fernandes et al., 2018; Lafave et al., 2019) and/or relative percentage changes (e.g., Willie et al., 2012; Ogoh et al., 2013; Lewis et al., 2014; Subudhi et al., 2014; Feddersen et al., 2015; Kellawan et al., 2017; Morris et al., 2017), which further complicates direct comparisons between studies. Thus, all the above factors contribute to the lack of consensus regarding regional CBF responses to hypoxia.

Given this lack of consensus, the aim of this study was to examine the regional effects of acute normobaric isocapnic hypoxia on CBF using TCD to determine if there are anterior (MCA) vs. posterior (PCA) differences in response to acute hypoxic perturbations by comparing absolute and relative (i.e., %-changes) responses. We hypothesized that (a) absolute responses to acute hypoxia in MCA cerebral blood velocity (CBV) and cerebrovascular conductance (CVC) would be larger than the PCA, but (b) this regional difference would not be observed in terms of relative responses, due to differences in baseline flow and through these arteries. An additional aim was to compare our absolute and relative regional CBF responses to hypoxia to those in other published reports.

Section snippets

Ethical approval

This study received ethical approval from the University of British Columbia (UBC) Clinical Research Ethics Board (Protocol H13-01041) and abided by the Canadian Government Tri-Council Policy Statement (TCPS2) for integrity in research and the Declaration of Helsinki, except for registration in a database. All participants provided written and verbal informed consent to the study prior to their voluntary participation and beginning the protocol. All data were collected at UBC where the ethics

Results

A total of 14 individuals (4 females) were recruited and completed both protocols in one lab visit between 9 AM and 6 PM. Participants had a mean age of 26.7 ± 3.9 years and a BMI of 26.1 ± 2.7 kg/m2. All baseline cardiorespiratory measurements are reported in Table 1.

Discussion

We aimed to measure and analyze anterior/posterior regional CBF and CVC responses to acute isocapnic hypoxia using TCD continuous velocity measurement. The principal findings of our study were that in response to acute isocapnic hypoxia, absolute CBV and CVC increased to a greater degree in the MCA compared to the PCA, but the percent change in CBV and CVC were not different between vessels. An additional aim was to generate a meta-analysis of similar work that has been published. Below we

Conclusion

Although many studies have investigated CVR in response to hypoxia, their combined results regarding differential anterior vs. posterior responses are equivocal, likely due to differences in measurement tools, arteries studied, and analytical methods. We aimed to assess CVR to hypoxia in the MCA and the PCA, and to compare the differential responses in both absolute and relative terms. The principal findings of our study were that (a) during isocapnic hypoxia, CBV and CVC increased in both the

Funding

Government of Canada, Natural Sciences and Engineering Research Council of Canada Discovery Grant (RGPIN-2016-04915; to TAD).

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  • Cited by (0)

    1

    Denotes co-first authors who contributed equally to this work.

    2

    Denotes co-senior authors who contributed equally to this work.

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