The influence of carbon dioxide on cerebral metabolism and oxygen consumption: combining multimodal monitoring with dynamic systems modelling

Figures

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  Fig. 1.. Basic Structure of BrainSignals Model. Figure adapted from (Banaji et al., 2008). Summary of the main inputs, variables and processes in the model. Circulatory and mitochondrial sub models are linked by the interactions of O2 concentration and cytochrome oxidase redox state. Four physiological inputs feed into the model MABP, pCO2 and SpO2 feed into the circulatory model via effects on CBF (MABP and pCO2) and O2 concentration (SpO2); functional activation feeds into both the circulatory sub model (via effects on CBF) and the mitochondrial sub model via modifying mitochondrial ATPase turnover (ADP/ATP ratio) and the supply of mitochondrial reducing equivalents. Outputs of particular interest in this study are highlighted in bold (CBF, TOI, CMRO2 and oxCCO).

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  Fig. 2.. Summary of key dependencies in modified BrainSignals model. Arterial pCO2 (PaCO2), mean arterial blood pressure (Pa) and arterial oxygen saturation (SaO2sup) serve as model inputs determining the state variables. [oxCCO] is determined from the simulated CCO CuA centre (a), Vmca from CBF, and TOI via oxygen extraction fraction, and the arterial (r) and venous volumes. The hypothesized CO2 metabolic effects are simulated via supps (substrate supply) and uf (metabolic demand) and their effect on NAD oxidation (NADNADHrat) and proton (H+) re-entry into the mitochondrial matrix (L) respectively. Vascular compartment: PaCO2, Arterial pCO2; Pa, mean arterial blood pressure; SaO2sup, arterial oxygen saturation; Vc, vascular effects of CO2; τ time constant filtering vascular effects of CO2; Vc2, metabolic effects of CO2; τ2, time constant filtering metabolic effects of CO2; Rautc, magnitude of CO2 reactivity on vasculature; r, typical blood vessel radius; Pan, normal arterial blood pressure; CBFn, normal cerebral blood flow; CBF, cerebral blood flow; O2c, capillary O2 concentration; tissue oxygenation (TOI); Vmca, blood velocity in the middle cerebral artery. Mitochondrial compartment:…

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  Fig. 3.. Systemic physiological and cerebral measurements in volunteers. Mean value is in bold (n=15). s.d. is denoted by the dotted line.

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  Fig. 4.. Unoptimized BrainSignals model outputs. The basic BrainSignals model was run using the physiological inputs from Fig. 3. Illustrated are the time courses of model outputs relating to cerebral physiology: CBF, CMRO2; biochemistry: Dp (mitochondrial Δp), NAD/NADH (mitochondrial NAD/NADH ratio): measured optical changes (TOI, oxCCO).

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  Fig. 5.. Effect of varying CO2 effects on substrate supply and metabolic demand. Selected outputs from modified BrainSignals model using measured inputs from Fig. 3 and varying the effects of CO2 on ATP demand (uf) or substrate supply (supps). Charts illustrate the effects on CMRO2 (in mmol l tissue−1 s−1), oxCCO (in µM) and the dominant parameter affected by substrate supply (mitochondrial NAD/NADH ratio) and ATP turnover (mitochondrial Dp or Δp in mV).

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  Fig. 6.. Demand optimization. Model simulation of a change in metabolic demand (parameter uf). In each row different monitoring variables are used to achieve the parameter optimization. It can be seen that no optimization fits the data well (large difference between measured and modelled data), and this produces predictions of both increased and decreased CMRO2. Full parameter values are displayed in Table 1. Dashed grey lines denote the standard error of the means of the measured data. For abbreviations see Fig. 5 legend.

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  Fig. 7.. Supply optimization. Model simulation of a change in substrate supply (parameter supps). In each row different monitoring variables are used to achieve the parameter optimization. It can be seen that there is generally a good fit of modelled and measured data and this produces predictions of a small decrease in CMRO2. Full parameter values are displayed in Table 2. Grey dashed lines denote the standard error of the means of the measured data. For abbreviations see Fig. 5 legend.