A direct measure of cerebral energy metabolism can be obtained by measuring changes in oxidation state of cytochrome c oxidase (CCO) – a key component in oxidative metabolism which is directly related to mitochondrial ATP production . CCO is the terminal electron acceptor in the electron transport chain (ETC): the final stage of oxidative metabolism. A unique copper dimer (Copper A) in the enzyme has an absorption peak around 835nm in its oxidised form (oxCCO), but not in its reduced state. A change in the redox state represents a change in oxidative cellular metabolism. To accurately resolve changes in oxCCO, many wavelengths (broadband) are required as the concentration of CCO is 10% of the in-vivo haemoglobin concentration. Broadband NIRS-measured oxCCO changes are associated with acute changes in metabolism following hypoxia-ischaemia; see paper Bale et al. 2016 for a detailed review.
Recently, we have demonstrated in a study combining broadband NIRS and 31P MRS in 22 piglets that following HI, the recovery of the oxidation state of CCO (or oxCCO) was correlated with the recovery of Nucleotide-Triphosphate (NTP)/epp (epp=total exchangeable phosphate pool) and 24h survivability [5, 8]. Our results suggested that if NTP/epp and oxCCO recovery is not above 70% following HI, unfavourable outcome is likely. In addition, we observed that the measurements of the changes in brain tissue haemoglobin difference (Δ[HbDiff]=Δ[HbO2]-Δ[HHb]), which is indicative of brain oxygenation, show a poor correlation with NTP/epp and outcome. This approach has demonstrated that we can measure with broadband NIRS, oxCCO independently to haemoglobin. Importantly, when the measurement of oxCCO is combined with knowledge of baseline, its recovery following HI is associated with histology and is indicative of outcome (see Presentation-Ilias). In 2013, a novel broadband NIRS instrument (8 channels, 770-906nm) was developed specifically for neonatal monitoring of brain tissue oxCCO called CYRIL (see Poster-OSA).
In October 2013 the instrument, called CYRIL, was installed in the UCLH NICU to assess the feasibility of continuous monitoring of infants with HIE (see Presentation-Gemma). Since then we have monitored more than 80 infants with HIE during the first week of life and have demonstrated (i) that relationship of brain oxygenation and oxCCO during spontaneous desaturation events can be indicative of the severity of the brain injury; (ii) the association between the brain tissue oxCCO and systemic physiology fluctuations is highly correlated in infants with severe HIE[10, 11]; and (iii) the relationship between brain oxygenation and oxCCO during rewarming after therapeutic hypothermia was dependent on the severity of injury. In addition, we have demonstrated that the continuous metabolic measurement of oxCCO provides unique information regarding brain health during neonatal stroke and neonatal seizures.
5. Bale, G., C.E. Elwell, and I. Tachtsidis, J Biomed Opt, 2016. 21(9): p. 091307.
6. Sakata, Y., et al., Biomed Opt Express, 2012. 3(8): p. 1933-46.
7. Matcher, S.J., M. Cope, and D.T. Delpy, Phys Med Biol, 1994. 39(1): p. 177-96.
8. Bainbridge, A., et al., Neuroimage, 2014. 102 Pt 1: p. 173-83.
9. Bale, G., et al., Biomed Opt Express, 2014. 5(10): p. 3450-66.
10. Bale, G., et al., Adv Exp Med Biol, 2016. 923: p. 181-6.