Cytochrome c oxidase response to changes in cerebral oxygen delivery in the adult brain shows higher brain-specificity than haemoglobin

Abstract

The redox state of cerebral mitochondrial cytochrome c oxidase monitored with near-infrared spectroscopy (Δ[oxCCO]) is a signal with strong potential as a non-invasive, bedside biomarker of cerebral metabolic status. We hypothesised that the higher mitochondrial density of brain compared to skin and skull would lead to evidence of brain-specificity of the Δ[oxCCO] signal when measured with a multi-distance near-infrared spectroscopy (NIRS) system. Measurements of Δ[oxCCO] as well as of concentration changes in oxygenated (Δ[HbO2]) and deoxygenated haemoglobin (Δ[HHb]) were taken at multiple source-detector distances during systemic hypoxia and hypocapnia (decrease in cerebral oxygen delivery), and hyperoxia and hypercapnia (increase in cerebral oxygen delivery) from 15 adult healthy volunteers. Increasing source-detector spacing is associated with increasing light penetration depth and thus higher sensitivity to cerebral changes. An increase in Δ[oxCCO] was observed during the challenges that increased cerebral oxygen delivery and the opposite was observed when cerebral oxygen delivery decreased. A consistent pattern of statistically significant increasing amplitude of the Δ[oxCCO] response with increasing light penetration depth was observed in all four challenges, a behaviour that was distinctly different from that of the haemoglobin chromophores, which did not show this statistically significant depth gradient. This depth-dependence of the Δ[oxCCO] signal corroborates the notion of higher concentrations of CCO being present in cerebral tissue compared to extracranial components and highlights the value of NIRS-derived Δ[oxCCO] as a brain-specific signal of cerebral metabolism, superior in this aspect to haemoglobin.

Keywords: Cytochrome c oxidase; Hypercapnia; Hyperoxia; Hypocapnia; Hypoxia; Near-infrared spectroscopy.

Fig. 1

Examples of individual data illustrating the protocol for hypoxia (A), hyperoxia (B), hypocapnia (C) and hypercapnia (D), with the physiological signal most pertinent to the challenge plotted in each graph. The challenge period (denoted with two ‘x’ marks), is the interval during which the subject was not breathing room air (A, B, D) or was hyperventilating (C). Time interval 1 corresponds to baseline, intervals 2–9 cover the challenge period and intervals 10–17 comprise the period after the end of the challenge, with explanation on how these intervals were determined, provided in the text.

Fig. 2

Grand averages of the time courses of Δ[Hbdiff], Δ[HbT] and Δ[oxCCO] measured by the detector distal to the light source (source-detector separation of 3.5 cm), over the 15 volunteers that participated in the hypoxia (A), hyperoxia (B), hypocapnia (C) and hypercapnia (D) protocols. The corresponding traces of arterial oxygen saturation (SpO₂) (A), end-tidal O₂ partial pressure (B) and end-tidal partial CO₂ pressure (C and D) are also provided for reference. The small symbols on top of each plot indicate statistical significance with respect to time point 1 (P < 0.05) for the parameters plotted in matching symbols and the error bars represent the standard error of the mean. For reasons explained in the text, we performed the statistical tests only for time intervals 1–10 for hypoxia, 1–14 for hyperoxia, 1–11 for hypocapnia and 1–15 for hypercapnia.

Fig. 3

Group data of the time courses of Δ[oxCCO] measured by the detectors 2.0, 2.5, 3.0 and 3.5 cm away from the light source (denoted, respectively, as det_2.0, det_2.5, det_3.0, and det_3.5). The averages are based on the 15 volunteers that participated (A) in the hypoxia challenge, (B) in the hyperoxia challenge, (C) in the hypocapnia challenge and (D) in the hypercapnia challenge. The small symbols on top of each plot indicate statistical significance with respect to time point 1 (P < 0.05) for the parameters plotted in matching symbols, while the coloured circles indicate statistically significant differences (P < 0.05) between detectors (yellow: det_3.0 from det_3.5; blue: det_ 2.5 from det_3.0; red: det_2.0 from det_2.5).

Fig. 4

Group data of the time courses of Δ[HbT] measured by the detectors 2.0, 2.5, 3.0 and 3.5 cm away from the light source (denoted, respectively, as det_2.0, det_2.5, det_3.0, and det_3.5). The averages are based on the 15 volunteers that participated (A) in the hypoxia challenge, (B) in the hyperoxia challenge, (C) in the hypocapnia challenge and (D) in the hypercapnia challenge. The small symbols on top of each plot indicate statistical significance with respect to time point 1 (P < 0.05) for the parameters plotted in matching symbols, while the coloured circles indicate statistically significant differences (P < 0.05) between detectors (yellow: det_3.0 from det_3.5; blue: det_ 2.5 from det_3.0; red: det_2.0 from det_2.5).

Fig. 5

Group data of the time course of TOI, for hypoxia (A), hyperoxia (B), hypocapnia (C) and hypercapnia (D). The corresponding traces of SpO₂ (A), end-tidal partial O₂ pressure (B) and end-tidal partial CO₂ pressure (C and D) are also provided for reference. The small symbols on top of each plot indicate statistical significance with respect to time point 1 (P < 0.05) and the error bars represent the standard error of the mean.