Near-infrared spectroscopy (NIRS)-derived measurement of oxidized cytochrome c oxidase concentration ([oxCCO]) has been used as an assessment of the adequacy of cerebral oxygen delivery. We report a case in which a reduction in conscious level was associated with a reduction in [oxCCO]. Hypoxaemia was induced in a 31-year-old, healthy male subject as part of an ongoing clinical study. Midway through the hypoxaemic challenge, the subject experienced an unexpected vasovagal event with bradycardia, hypotension and reduced cerebral blood flow (middle cerebral artery blood flow velocity decrease from 70 to 30 cm s(-1)) that induced a brief reduction in conscious level. An associated decrease in [oxCCO] was observed at 35 mm (-1.6 μM) but only minimal change (-0.1 μM) at 20-mm source-detector separation. A change in optical scattering was observed, but path length remained unchanged. This unexpected physiological event provides an unusual example of a severe reduction in cerebral oxygen delivery and is the first report correlating change in clinical status with changes in [oxCCO]

A Duncan

C Chen-Scarabelli

C Kolyva

CE Cooper

Christina Kolyva

M Smith

MM Tisdall

SR Arridge

Y Kakihana

PubMed

Near-infrared spectroscopy (NIRS)-derived measurement of oxidized cytochrome c oxidase concentration ([oxCCO]) has been used as an assessment of the adequacy of cerebral oxygen delivery. We report a case in which a reduction in conscious level was associated with a reduction in [oxCCO]. Hypoxaemia was induced in a 31-year-old, healthy male subject as part of an ongoing clinical study. Midway through the hypoxaemic challenge, the subject experienced an unexpected vasovagal event with bradycardia, hypotension and reduced cerebral blood flow (middle cerebral artery blood flow velocity decrease from 70 to 30 cm s-1) that induced a brief reduction in conscious level. An associated decrease in [oxCCO] was observed at 35 mm (-1.6 μM) but only minimal change (-0.1 μM) at 20-mm source-detector separation. A change in optical scattering was observed, but path length remained unchanged. This unexpected physiological event provides an unusual example of a severe reduction in cerebral oxygen delivery and is the first report correlating change in clinical status with changes in [oxCCO]

Ghosh, Arnab

Kolyva, Christina

Tachtsidis, Ilias

Highton, David

Elwell, Clare E.

Smith, Martin

University of Queensland eSpace

Reduction of cytochrome c oxidase during vasovagal hypoxia-ischemia in human adult brain: A case study

Arnab Ghosh

Ilias Tachtsidis

David Highton

Clare E. Elwell

Martin Smith

Crossref

Reduction of Cytochrome c Oxidase During Vasovagal Hypoxia-Ischemia in Human Adult Brain: A Case Study

Ghosh, A

Kolyva, C

Tachtsidis, I

Highton, D

Elwell, CE

Smith, M

UCL Discovery

21S. Van Huffel et al. (eds.), Oxygen Transport to Tissue XXXV, Advances in Experimental Medicine and Biology 789, DOI 10.1007/978-1-4614-7411-1_4,© Springer Science+Business Media New York 2013 Abstract  Near-infrared spectroscopy (NIRS)-derived measurement of oxidized cytochrome  c oxidase concentration ([oxCCO]) has been used as an assessment of the adequacy of cerebral oxygen delivery. We report a case in which a reduction in conscious level was associated with a reduction in [oxCCO]. Hypoxaemia was induced in a 31-year-old, healthy male subject as part of an ongoing clinical study. Midway through the hypoxaemic challenge, the subject experienced an unexpected vasovagal event with bradycardia, hypotension and reduced cerebral blood fl ow (middle cerebral artery blood fl ow velocity decrease from 70 to 30 cm s −1 ) that induced a brief reduction in conscious level. An associated decrease in [oxCCO] was observed at 35 mm (−1.6 μM) but only minimal change (−0.1 μM) at 20-mm source-detector separation. A change in optical scattering was observed, but path length remained unchanged. This unexpected physiological event provides an unusual example of a severe reduction in cerebral oxygen delivery and is the fi rst report correlating change in clinical status with changes in [oxCCO].  Chapter 4  Reduction of Cytochrome  c Oxidase During Vasovagal Hypoxia-Ischemia in Human Adult Brain: A Case Study  Arnab Ghosh ,  Christina Kolyva ,  Ilias Tachtsidis ,  David Highton ,  Clare E. Elwell , and  Martin Smith  A.  Ghosh () •  D.  Highton  Neurocritical Care Unit ,  University College Hospitals ,  WC1N 3BG  London ,  UK  e-mail: arnab.ghosh@ucl.ac.uk  C.  Kolyva •  I.  Tachtsidis •  C. E.  Elwell  Medical Physics & Bioengineering ,  University College London  WC1E 6BT  London ,  UK  M.  Smith  Neurocritical Care Unit ,  University College Hospitals ,  WC1N 3BG  London ,  UK  Medical Physics & Bioengineering ,  University College London ,  WC1E 6BT  London ,  UK 224.1  Introduction  Cytochrome  c oxidase is the fi nal electron acceptor in the mitochondrial electron transport chain, and its oxidation state, measured by NIRS as [oxCCO], has thus been proposed as a marker of the adequacy of cerebral oxygen delivery (DO 2 ) [ 1 ]. However, prior studies of moderate hypoxia achieved only modest reductions in DO 2 , leaving the relationship between DO 2 and Δ[oxCCO] unclear [ 2 ]. Furthermore, interpretation of [oxCCO] measurements is diffi cult as there are no adult human data regarding its total concentration or resting oxidation state.  We aimed to address some of these concerns with studies using a hybrid NIR spectrometer, the pHOS, to measure [oxCCO] and other optical parameters whilst modulating DO 2 in a cohort of healthy volunteers [ 3 ]. We report the case of a vaso-vagal event that occurred during one such study and explore the insights into cere-bral physiology gleaned from this unexpected event. 4.2  Methods  A single case was selected from a larger group study. This study was approved by the Institutional Research Ethics Committee, and written informed consent was pro-vided by the subject, a 31-year-old male who had been screened for pre-existing medical conditions, was selected as he suffered from vasovagal pre-syncope during a challenge that comprised induction of isocapnic hypoxia with a target arterial oxygen saturation (SpO 2 ) of 80 % [ 3 ].  The pHOS, described in more detail elsewhere [ 4 ], combines frequency domain (FD) and broadband (BB) components. Changes in chromophore concentration were estimated by using the changes in light attenuation as measured by the BB spectrom-eter, using the UCLn algorithm to resolve for three  chromophores – oxyhaemoglobin (HbO 2 ), deoxyhaemoglobin (HHb) and oxCCO – between 780 and 900 nm. A fi xed differential path length factor (DPF) of 6.26 [ 5 ] was used to enable comparison with previous studies. The FD component measured the absolute absorption and scatter-ing coeffi cients (μa and μs, respectively) at discrete wavelengths 690, 750, 790 and 850 nm, allowing the estimation of DPF at each of these wavelengths using the dif-fusion approximation [ 6 ]. The pHOS optode was placed over the FP1 point on the right side of the forehead.  Other monitoring included beat-to-beat SpO 2 , continuous non-invasive arterial blood pressure, and transcranial Doppler (TCD) ultrasonography was used to mea-sure middle cerebral artery fl ow velocity (Vmca), insonating through the right tem-poral window, ipsilateral to pHOS monitoring. Estimated relative cerebral oxygen delivery (ecDO 2 ) was calculated as the product of changes in SpO 2 and Vmca (rela-tive to their initial values) [ 2 ]. Synchronization between the pHOS and other A. Ghosh et al.23monitors was performed by means of a signal voltage output by the frequency domain spectrometer for the length of recording; all data were resampled to a sam-ple period of 3.2 s across the length of recording. Twenty-second data windows were selected for the reporting of summary data. Changes in hemoglobin species concentration are expressed as total hemoglobin (Δ[HbT] = Δ[HbO 2 ] + Δ[HHb]) and hemoglobin difference (Δ[HbDiff] = Δ[HbO 2 ] − Δ[HHb]). All analysis was carried out in Matlab® 2011b. 4.3  Results  Approximately 600 s after the commencement of recording, during the nadir of hypoxia, the subject suffered from sudden-onset bradycardia and hypotension (a typical vasovagal episode), resulting in a reduction in ecDO 2 to 41.5 % of base-line values (Table  4.1 and Fig.  4.1 ). During this time, the subject became briefl y unresponsive. When this occurred, he was laid fl at and the breathing circuit replaced with a Mapleson C circuit delivering high-fl ow oxygen. Hemoglobin species showed a consistent pattern of change with a decrease in both [HbT] and [HbDiff] seen at all source-detector separations (Fig.  4.2 ). By con-trast, [oxCCO] showed a source-detector separation-dependent decrease (Δ[oxCCO] −1.6 μM at 3.5 cm c.f. −0.1 μM at 2.0-cm source-detector separation), with larger decreases seen at further source-detector separations (Fig.  4.3 ). Comparison of Δ[oxCCO] (observed at the 3.5-cm detector) with ΔecDO 2 suggests a linear relationship (Fig.  4.4 ) between the two variables ( r 2 = 0.81,  p < 0.001). There appeared to be a roughly 10 % decrease in the μs observed at all four discrete wavelengths, but this did not translate into an apparent change in DPF (Fig.  4.5 ). Table 4.1  Mean values of systemic and cerebral physiological parameters observed during four observed phases  Baseline  Hypoxia  Hypoxia-ischemia  Recovery  ABP (mmHg)  85.4  88.9  32.1  83.5  HR  78.0  117  41.3  101  Vmca (cm s  −1  )  70.4  73.9  34.1  57.8  SpO  2   (%)  100  72.6  86.3  99.4  ecDO  2   (%)  99.8  75.8  41.5  81.2  Δ[oxCCO] (μM)  3.5 cm  0  −0.74  −1.56  −0.13  3.0 cm  0  −0.38  −0.62  0.008  2.5 cm  0  −0.30  −0.55  0.045  2.0 cm  0  −0.14  −0.16  0.23 4 Reduction of Cytochrome  c Oxidase During Vasovagal Hypoxia-Ischemia…24 Fig. 4.1  Changes in systemic and physiological parameters. Data averaging periods  A baseline,  B hypoxia,  C hypoxia-ischemia,  D recovery  Fig. 4.2  Changes in hemoglobin concentrations at four source-detector separations   A. Ghosh et al.25 Fig. 4.3  Changes in [oxCCO] at four source-detector separations  Fig. 4.4  Relationship between ecDO 2 and Δ[oxCCO] at 3.5 cm source-detector separation  Fig. 4.5  Changes in μs and DPF    4 Reduction of Cytochrome  c Oxidase During Vasovagal Hypoxia-Ischemia…264.4  Discussion  We report a reduction in cranial [oxCCO] measured with the pHOS during a  vasovagal pre-syncope in a healthy adult volunteer. This reduction was larger in further (3.5 cm) than closer (2.0 cm) source-detector separations. The pattern of [oxCCO] reduction has been related to neurological outcome following cardiopulmonary bypass [ 7 ], and asymptomatic reductions in [oxCCO] have been reported during moderate hypoxia [ 2 ], but this is the fi rst change in [oxCCO] to be correlated to changes in conscious level and the largest change to be reported in humans.  Whilst hypoxia is a recognized cause of syncope, the occurrence of bradycardia and hypotension indicates a vasovagal etiology [ 8 ], in this case, provoked by – as the subject reported – the shock of seeing his reduced SpO 2 reading. This vasovagal response resulted in a profound reduction in cerebral blood fl ow (observed by both NIRS and TCD), and this led to a signifi cant reduction in DO 2 .  Prior experiments have achieved only modest reductions in DO 2 , leaving ques-tions unanswered about the relationship between DO 2 and Δ[oxCCO] [ 2 ]. In par-ticular, it was unclear whether the relationship between DO 2 and Δ[oxCCO] was linear or whether there was a DO 2 threshold below which rapid CCO reduction occurs. However, our data (Fig.  4.4 ) suggest a linear relationship between Δ[oxCCO] and ΔecDO 2 ( r 2 = 0.81,  p < 0.001). From this, the extrapolated value of Δ[oxCCO] of −2.6 μM with zero cerebral oxygen delivery is suggestive of a resting oxidized CCO concentration of around 2.6 μM. Although no reduction of this size has been reported in humans – understandably as a reduction in DO 2 to nothing is impractical in humans – these values are consistent with animal anoxia models [ 9 ,  10 ].  Given the distance dependence of the [oxCCO] but not hemoglobin changes, we consider spectral crosstalk to be unlikely. Similarly, the modest μs changes that were observed appeared consistent in their spectral expression across 690–850 nm and thus are unlikely to account for the [oxCCO] changes seen. DPF showed no signifi cant qualitative change during the hypoxic or ischaemic phases of the study, although the absolute values were larger than those that were previously reported [ 5 ]; using the measured values of DPF rather than the fi xed value of 6.26 would thus change the magnitude, but not the qualitative profi le of our observed chromophore changes.  Whilst we are aware of the limitations of extrapolating from a single case report, these data, especially when considered in conjunction with the results of the larger cohort of (uncomplicated!) hypoxia and hypercapnia studies [ 3 ], further underline confi dence in the ability to use NIRS to measure [oxCCO] as a marker of cellular energy status.  Acknowledgments This work was undertaken at University College London Hospitals and par-tially funded by the Department of Health’s National Institute for Health Research Centers funding scheme, the Medical Research Council and Wellcome Trust. A. Ghosh et al.27 References   1.  Smith M, Elwell C (2009) Near-infrared spectroscopy: shedding light on the injured brain. Anesth Analg 108(4):1055–1057   2.  Tisdall MM, Tachtsidis I, Leung TS, Elwell CE, Smith M (2007) Near-infrared spectroscopic quantifi cation of changes in the concentration of oxidized cytochrome c oxidase in the healthy human brain during hypoxemia. J Biomed Opt 12(2):024002   3.  Kolyva C, Ghosh A, Tachtsidis I, et al (2013) Dependence on NIRS source-detector spacing of cytochrome C oxidase response to hypoxia and hypercapnia in the adult brain. Adv Exp Med Biol.   4.  Kolyva C, Tachtsidis I, Ghosh A et al (2012) Systematic investigation of changes in oxidized cerebral cytochrome c oxidase concentration during frontal lobe activation in healthy adults. Biomed Opt Express 3(10):2550–2566   5.  Duncan A, Meek JH, Clemence M et al (1995) Optical pathlength measurements on adult head, calf and forearm and the head of the newborn infant using phase resolved optical  spectroscopy. Phys Med Biol 40(2):295–304   6.  Arridge SR, Cope M, Delpy DT (1992) The theoretical basis for the determination of optical pathlengths in tissue: temporal and frequency analysis. Phys Med Biol 37(7):1531–1560   7.  Kakihana Y, Matsunaga A, Yasuda T, Imabayashi T, Kanmura Y, Tamura M (2008) Brain oxymetry in the operating room: current status and future directions with particular regard to cytochrome oxidase. J Biomed Opt 13(3):033001   8.  Chen-Scarabelli C, Scarabelli TM (2004) Neurocardiogenic syncope. Br Med J 329(7461): 336–341   9.  Cooper CE, Cope M, Springett R et al (1999) Use of mitochondrial inhibitors to demonstrate that cytochrome oxidase near-infrared spectroscopy can measure mitochondrial dysfunction noninvasively in the brain. J Cereb Blood Flow Metab 19(1):27–38  10.  Cooper CE, Springett R (1997) Measurement of cytochrome oxidase and mitochondrial  energetics by near-infrared spectroscopy. Philos Trans R Soc Lond B Biol Sci 352(1354): 669–676 4 Reduction of Cytochrome  c Oxidase During Vasovagal Hypoxia-Ischemia…

Reduction of cytochrome C oxidase during vasovagal hypoxia-ischemia in human adult brain: a case study

Springer - Publisher Connector

21S. Van Huffel et al. (eds.), Oxygen Transport to Tissue XXXV, Advances 
in Experimental Medicine and Biology 789, DOI 10.1007/978-1-4614-7411-1_4,
© Springer Science+Business Media New York 2013
 Abstract  Near-infrared spectroscopy (NIRS)-derived measurement of oxidized 
cytochrome  c oxidase concentration ([oxCCO]) has been used as an assessment of 
the adequacy of cerebral oxygen delivery. We report a case in which a reduction in 
conscious level was associated with a reduction in [oxCCO]. Hypoxaemia was 
induced in a 31-year-old, healthy male subject as part of an ongoing clinical study. 
Midway through the hypoxaemic challenge, the subject experienced an unexpected 
vasovagal event with bradycardia, hypotension and reduced cerebral blood fl ow 
(middle cerebral artery blood fl ow velocity decrease from 70 to 30 cm s −1 ) that 
induced a brief reduction in conscious level. An associated decrease in [oxCCO] 
was observed at 35 mm (−1.6 μM) but only minimal change (−0.1 μM) at 20-mm 
source-detector separation. A change in optical scattering was observed, but path 
length remained unchanged. This unexpected physiological event provides an 
unusual example of a severe reduction in cerebral oxygen delivery and is the fi rst 
report correlating change in clinical status with changes in [oxCCO]. 
 Chapter 4 
 Reduction of Cytochrome  c Oxidase During 
Vasovagal Hypoxia-Ischemia in Human 
Adult Brain: A Case Study 
 Arnab Ghosh ,  Christina Kolyva ,  Ilias Tachtsidis ,  David Highton , 
 Clare E. Elwell , and  Martin Smith 
 A.  Ghosh () •  D.  Highton 
 Neurocritical Care Unit ,  University College Hospitals ,  WC1N 3BG  London ,  UK 
 e-mail: arnab.ghosh@ucl.ac.uk 
 C.  Kolyva •  I.  Tachtsidis •  C. E.  Elwell 
 Medical Physics & Bioengineering ,  University College London  WC1E 6BT  London ,  UK 
 M.  Smith 
 Neurocritical Care Unit ,  University College Hospitals ,  WC1N 3BG  London ,  UK 
 Medical Physics & Bioengineering ,  University College London ,  WC1E 6BT  London ,  UK 
22
4.1  Introduction 
 Cytochrome  c oxidase is the fi nal electron acceptor in the mitochondrial electron 
transport chain, and its oxidation state, measured by NIRS as [oxCCO], has thus 
been proposed as a marker of the adequacy of cerebral oxygen delivery (DO 2 ) [ 1 ]. 
However, prior studies of moderate hypoxia achieved only modest reductions in 
DO 2 , leaving the relationship between DO 2 and Δ[oxCCO] unclear [ 2 ]. Furthermore, 
interpretation of [oxCCO] measurements is diffi cult as there are no adult human 
data regarding its total concentration or resting oxidation state. 
 We aimed to address some of these concerns with studies using a hybrid NIR 
spectrometer, the pHOS, to measure [oxCCO] and other optical parameters whilst 
modulating DO 2 in a cohort of healthy volunteers [ 3 ]. We report the case of a vaso-
vagal event that occurred during one such study and explore the insights into cere-
bral physiology gleaned from this unexpected event. 
4.2  Methods 
 A single case was selected from a larger group study. This study was approved by 
the Institutional Research Ethics Committee, and written informed consent was pro-
vided by the subject, a 31-year-old male who had been screened for pre-existing 
medical conditions, was selected as he suffered from vasovagal pre-syncope during 
a challenge that comprised induction of isocapnic hypoxia with a target arterial 
oxygen saturation (SpO 2 ) of 80 % [ 3 ]. 
 The pHOS, described in more detail elsewhere [ 4 ], combines frequency domain 
(FD) and broadband (BB) components. Changes in chromophore concentration were 
estimated by using the changes in light attenuation as measured by the BB spectrom-
eter, using the UCLn algorithm to resolve for three  chromophores – oxyhaemoglobin 
(HbO 2 ), deoxyhaemoglobin (HHb) and oxCCO – between 780 and 900 nm. A fi xed 
differential path length factor (DPF) of 6.26 [ 5 ] was used to enable comparison with 
previous studies. The FD component measured the absolute absorption and scatter-
ing coeffi cients (μa and μs, respectively) at discrete wavelengths 690, 750, 790 and 
850 nm, allowing the estimation of DPF at each of these wavelengths using the dif-
fusion approximation [ 6 ]. The pHOS optode was placed over the FP1 point on the 
right side of the forehead. 
 Other monitoring included beat-to-beat SpO 2 , continuous non-invasive arterial 
blood pressure, and transcranial Doppler (TCD) ultrasonography was used to mea-
sure middle cerebral artery fl ow velocity (Vmca), insonating through the right tem-
poral window, ipsilateral to pHOS monitoring. Estimated relative cerebral oxygen 
delivery (ecDO 2 ) was calculated as the product of changes in SpO 2 and Vmca (rela-
tive to their initial values) [ 2 ]. Synchronization between the pHOS and other 
A. Ghosh et al.
23
monitors was performed by means of a signal voltage output by the frequency 
domain spectrometer for the length of recording; all data were resampled to a sam-
ple period of 3.2 s across the length of recording. Twenty-second data windows 
were selected for the reporting of summary data. Changes in hemoglobin species 
concentration are expressed as total hemoglobin (Δ[HbT] = Δ[HbO 2 ] + Δ[HHb]) and 
hemoglobin difference (Δ[HbDiff] = Δ[HbO 2 ] − Δ[HHb]). All analysis was carried 
out in Matlab® 2011b. 
4.3  Results 
 Approximately 600 s after the commencement of recording, during the nadir of 
hypoxia, the subject suffered from sudden-onset bradycardia and hypotension 
(a typical vasovagal episode), resulting in a reduction in ecDO 2 to 41.5 % of base-
line values (Table  4.1 and Fig.  4.1 ). During this time, the subject became briefl y 
unresponsive. When this occurred, he was laid fl at and the breathing circuit replaced 
with a Mapleson C circuit delivering high-fl ow oxygen.
 Hemoglobin species showed a consistent pattern of change with a decrease in 
both [HbT] and [HbDiff] seen at all source-detector separations (Fig.  4.2 ). By con-
trast, [oxCCO] showed a source-detector separation-dependent decrease 
(Δ[oxCCO] −1.6 μM at 3.5 cm c.f. −0.1 μM at 2.0-cm source-detector separation), 
with larger decreases seen at further source-detector separations (Fig.  4.3 ). 
Comparison of Δ[oxCCO] (observed at the 3.5-cm detector) with ΔecDO 2 suggests 
a linear relationship (Fig.  4.4 ) between the two variables ( r 2 = 0.81,  p < 0.001). 
There appeared to be a roughly 10 % decrease in the μs observed at all four discrete 
wavelengths, but this did not translate into an apparent change in DPF (Fig.  4.5 ).
 Table 4.1  Mean values of systemic and cerebral physiological parameters observed during four 
observed phases 
 Baseline  Hypoxia  Hypoxia-ischemia  Recovery 
 ABP (mmHg)  85.4  88.9  32.1  83.5 
 HR  78.0  117  41.3  101 
 Vmca (cm s  −1  )  70.4  73.9  34.1  57.8 
 SpO 
 2   (%)  100  72.6  86.3  99.4 
 ecDO 
 2   (%)  99.8  75.8  41.5  81.2 
 Δ[oxCCO] (μM)  3.5 cm  0  −0.74  −1.56  −0.13 
 3.0 cm  0  −0.38  −0.62  0.008 
 2.5 cm  0  −0.30  −0.55  0.045 
 2.0 cm  0  −0.14  −0.16  0.23 
4 Reduction of Cytochrome  c Oxidase During Vasovagal Hypoxia-Ischemia…
24
 Fig. 4.1  Changes in systemic and physiological parameters. Data averaging periods  A baseline, 
 B hypoxia,  C hypoxia-ischemia,  D recovery 
 Fig. 4.2  Changes in hemoglobin concentrations at four source-detector separations 
 
 
A. Ghosh et al.
25
 Fig. 4.3  Changes in [oxCCO] at four source-detector separations 
 Fig. 4.4  Relationship between ecDO 2 and Δ[oxCCO] at 3.5 cm source-detector separation 
 Fig. 4.5  Changes in μs and DPF 
 
 
 
4 Reduction of Cytochrome  c Oxidase During Vasovagal Hypoxia-Ischemia…
26
4.4  Discussion 
 We report a reduction in cranial [oxCCO] measured with the pHOS during a  vasovagal 
pre-syncope in a healthy adult volunteer. This reduction was larger in further 
(3.5 cm) than closer (2.0 cm) source-detector separations. The pattern of [oxCCO] 
reduction has been related to neurological outcome following cardiopulmonary 
bypass [ 7 ], and asymptomatic reductions in [oxCCO] have been reported during 
moderate hypoxia [ 2 ], but this is the fi rst change in [oxCCO] to be correlated to 
changes in conscious level and the largest change to be reported in humans. 
 Whilst hypoxia is a recognized cause of syncope, the occurrence of bradycardia 
and hypotension indicates a vasovagal etiology [ 8 ], in this case, provoked by – as 
the subject reported – the shock of seeing his reduced SpO 2 reading. This vasovagal 
response resulted in a profound reduction in cerebral blood fl ow (observed by both 
NIRS and TCD), and this led to a signifi cant reduction in DO 2 . 
 Prior experiments have achieved only modest reductions in DO 2 , leaving ques-
tions unanswered about the relationship between DO 2 and Δ[oxCCO] [ 2 ]. In par-
ticular, it was unclear whether the relationship between DO 2 and Δ[oxCCO] was 
linear or whether there was a DO 2 threshold below which rapid CCO reduction 
occurs. However, our data (Fig.  4.4 ) suggest a linear relationship between Δ[oxCCO] 
and ΔecDO 2 ( r 2 = 0.81,  p < 0.001). From this, the extrapolated value of Δ[oxCCO] of 
−2.6 μM with zero cerebral oxygen delivery is suggestive of a resting oxidized CCO 
concentration of around 2.6 μM. Although no reduction of this size has been 
reported in humans – understandably as a reduction in DO 2 to nothing is impractical 
in humans – these values are consistent with animal anoxia models [ 9 ,  10 ]. 
 Given the distance dependence of the [oxCCO] but not hemoglobin changes, we 
consider spectral crosstalk to be unlikely. Similarly, the modest μs changes that 
were observed appeared consistent in their spectral expression across 690–850 nm 
and thus are unlikely to account for the [oxCCO] changes seen. DPF showed no 
signifi cant qualitative change during the hypoxic or ischaemic phases of the study, 
although the absolute values were larger than those that were previously reported 
[ 5 ]; using the measured values of DPF rather than the fi xed value of 6.26 would thus 
change the magnitude, but not the qualitative profi le of our observed chromophore 
changes. 
 Whilst we are aware of the limitations of extrapolating from a single case report, 
these data, especially when considered in conjunction with the results of the larger 
cohort of (uncomplicated!) hypoxia and hypercapnia studies [ 3 ], further underline 
confi dence in the ability to use NIRS to measure [oxCCO] as a marker of cellular 
energy status. 
 Acknowledgments This work was undertaken at University College London Hospitals and par-
tially funded by the Department of Health’s National Institute for Health Research Centers funding 
scheme, the Medical Research Council and Wellcome Trust. 
A. Ghosh et al.
27
 References 
  1.  Smith M, Elwell C (2009) Near-infrared spectroscopy: shedding light on the injured brain. 
Anesth Analg 108(4):1055–1057 
  2.  Tisdall MM, Tachtsidis I, Leung TS, Elwell CE, Smith M (2007) Near-infrared spectroscopic 
quantifi cation of changes in the concentration of oxidized cytochrome c oxidase in the healthy 
human brain during hypoxemia. J Biomed Opt 12(2):024002 
  3.  Kolyva C, Ghosh A, Tachtsidis I, et al (2013) Dependence on NIRS source-detector spacing of 
cytochrome C oxidase response to hypoxia and hypercapnia in the adult brain. Adv Exp Med 
Biol. 
  4.  Kolyva C, Tachtsidis I, Ghosh A et al (2012) Systematic investigation of changes in oxidized 
cerebral cytochrome c oxidase concentration during frontal lobe activation in healthy adults. 
Biomed Opt Express 3(10):2550–2566 
  5.  Duncan A, Meek JH, Clemence M et al (1995) Optical pathlength measurements on adult 
head, calf and forearm and the head of the newborn infant using phase resolved optical 
 spectroscopy. Phys Med Biol 40(2):295–304 
  6.  Arridge SR, Cope M, Delpy DT (1992) The theoretical basis for the determination of optical 
pathlengths in tissue: temporal and frequency analysis. Phys Med Biol 37(7):1531–1560 
  7.  Kakihana Y, Matsunaga A, Yasuda T, Imabayashi T, Kanmura Y, Tamura M (2008) Brain 
oxymetry in the operating room: current status and future directions with particular regard to 
cytochrome oxidase. J Biomed Opt 13(3):033001 
  8.  Chen-Scarabelli C, Scarabelli TM (2004) Neurocardiogenic syncope. Br Med J 329(7461): 
336–341 
  9.  Cooper CE, Cope M, Springett R et al (1999) Use of mitochondrial inhibitors to demonstrate 
that cytochrome oxidase near-infrared spectroscopy can measure mitochondrial dysfunction 
noninvasively in the brain. J Cereb Blood Flow Metab 19(1):27–38 
 10.  Cooper CE, Springett R (1997) Measurement of cytochrome oxidase and mitochondrial 
 energetics by near-infrared spectroscopy. Philos Trans R Soc Lond B Biol Sci 352(1354): 
669–676 
4 Reduction of Cytochrome  c Oxidase During Vasovagal Hypoxia-Ischemia…


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Reduction of cytochrome C oxidase during vasovagal hypoxia-ischemia in human adult brain: a case study

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