The CO2 stimulus for cerebrovascular reactivity: Fixing inspired concentrations vs. targeting end-tidal partial pressures

Abstract

Cerebrovascular reactivity (CVR) studies have elucidated the physiology and pathophysiology of cerebral blood flow regulation. A non-invasive, high spatial resolution approach uses carbon dioxide (CO2) as the vasoactive stimulus and magnetic resonance techniques to estimate the cerebral blood flow response. CVR is assessed as the ratio response change to stimulus change. Precise control of the stimulus is sought to minimize CVR variability between tests, and show functional differences. Computerized methods targeting end-tidal CO2 partial pressures are precise, but expensive. Simpler, improvised methods that fix the inspired CO2 concentrations have been recommended as less expensive, and so more widely accessible. However, these methods have drawbacks that have not been previously presented by those that advocate their use, or those that employ them in their studies. As one of the developers of a computerized method, I provide my perspective on the trade-offs between these two methods. The main concern is that declaring the precision of fixed inspired concentration of CO2 is misleading: it does not, as implied, translate to precise control of the actual vasoactive stimulus - the arterial partial pressure of CO2 The inherent test-to-test, and therefore subject-to-subject variability, precludes clinical application of findings. Moreover, improvised methods imply widespread duplication of development, assembly time and costs, yet lack uniformity and quality control. A tabular comparison between approaches is provided.

Keywords: Cerebrovascular reactivity; carbogen; carbon dioxide; cerebral blood flow; end-tidal forcing; end-tidal targeting.

© The Author(s) 2016.

Figures

Figure 1.

Two examples of circuits that apply a fixed inspired CO2 concentration. Circuit (a) uses a large reservoir of 5% CO2, 21% O2, balance N2, attached to a three-way valve. The position of the valve determines whether inspired gas is room air or the 5% CO2 mix. Circuit (b) applies a fixed CO2 concentration (0–5% CO2 in air or O2) at constant flow as gas input. During exhalation, the input gas fills an open-ended tube. This tube acts as a gas reservoir to make input gas available for inhalation when inspiratory flow exceeds gas input flow. This figure illustrates circuits similar to those used in Lu et al.+ and Tancredi et al.

Figure 2.

The range of PetCO2 and PaCO2 in subjects breathing carbogen (5% CO2 in O2) from a circuit functionally identical to that shown in 1(A). Note the range of PetCO2 and PaCO2 with this constant inspired PCO2. Also note that when asked to hyperventilate (HV), the PetCO2 decreases to almost that of breathing ambient air, despite continuing to inspire 5% CO2. Data in blue from Prisman et al. in healthy subjects. Data in red from Baddeley et al. in patients administered carbogen intended as an adjuvant for effectiveness of radiotherapy for cancer.

Figure 3.

The dynamic end-tidal forcing system adapted from Wise et al. O2, CO2, and N2 are blended breath-by-breath to provide the respective inspired gas concentrations. Inspired gas concentrations are calculated from the respective exhaled gas concentrations of the preceding breath and the target gas concentrations. High inspiratory flows are required to meet peak inspiratory flows. Gases are dry and require efficient humidification.

Figure 4.

The prospective targeting system (RespirAct™). The system consists of a gas blender and a breathing circuit. Gas A is a blend of O2 and N2. Gas B is a blend of O2, and CO2 with balance N2. Gas C is O2. All gases contain O2 as a safety measure. A computer pre-calculates the breath-by-breath inspired gas concentrations and flow to attain end-tidal gas concentration targets and controls the gas blender delivery to a breathing circuit. The breathing circuit provides sequential gas delivery as follows. The subject exhales to the expiratory reservoir. During exhalation, the inspiratory reservoir fills with blended gas. On inspiration, the inspiratory reservoir is emptied and any additional gas is inhaled from the expiratory reservoir. Gas inhaled from the expiratory reservoir has already equilibrated with the blood and does not affect gas exchange, so that the gas inspired from the blender constitutes entirely of Va (see text). Thus, considering the alveolar gas equation (FetCO2 = FiCO2 + VCO2/Va), VCO2 is a user input function, and Va is imposed by the gas blender; control of these variables enables the targeting of FetCO2 and FetO2 independent of minute ventilation and breathing pattern. For further details see literatures.,,

Figure 5.

Screen capture of sinusoidal changes in PetCO2 and PetO2 produced using the RespirAct™. (a) compressed time course; (b) expanded time course. Note the precise breath-to-breath changes and lack of breath-to-breath variability during the steady segments. Note also that changes in PetCO2 and PetO2 are independent of each other. Red tracing is tidal PCO2; blue dots are end-tidal values. Green tracing is tidal PO2; red dots are end-tidal values.

Figure 6.

Screen capture of end-tidal targeting using RespirAct™. Simultaneous tracing from a step algorithm targeting sharp step changes in PCO2 and PO2. Typically (but not always) PCO2 transitions occur within 1–3 breaths. Red tracing is tidal PCO2; blue dots are end-tidal values. Green tracing is tidal PO2; red dots are end-tidal values.