Phil. Trans. R. Soc. A (2011) 369, 4452–4469doi:10.1098/rsta.2011.0242

REVIEW

Shedding light on the adult brain: a review ofthe clinical applications of near-infrared

spectroscopyBY MARTIN SMITH1,2,*

1Department of Neurocritical Care, The National Hospital for Neurology andNeurosurgery, University College London Hospitals, Queen Square, London

WC1N 3BG, UK2Department of Medical Physics and Bioengineering, University College

London, Gower Street, London WC1E 6BT, UK

Near-infrared spectroscopy (NIRS) has potential as a non-invasive brain monitor in awide range of clinical scenarios. In the last decade, there has been a rapid expansion ofclinical experience using NIRS to monitor cerebral oxygenation, particularly in cardiacsurgery, where there is some evidence that NIRS-guided brain protection protocols mightlead to a reduction in peri-operative neurological complications. There are no data tosupport the wider application of NIRS to monitor cerebral oxygenation during routineanaesthesia and surgery, and its application in brain injury, where it might be expected tohave a key monitoring role, is as yet undefined. Technological developments, including theintroduction of broadband and time-resolved spectrometers that are capable of reliablymeasuring changes in oxidized cytochrome c oxidase, offer real potential for a singleNIRS-based device to provide multi-site, regional monitoring of cerebral metabolic statusas well as oxygenation and haemodynamics.

Keywords: near-infrared spectroscopy; brain injury; cerebral oxygenation; cerebral metabolism

1. Introduction

In this journal in 1997, Kirkpatrick established a case for the use of near-infraredspectroscopy (NIRS) for monitoring the adult brain [1]. In this review, I willdevelop that theme and examine progress in the intervening decade. Specifically,I will examine the evidence for the clinical application of NIRS monitoring ofthe healthy but ‘at risk’ brain, as well as its potential roles in monitoring theinjured brain. I will call on the experience of our research group to illustratethe application of novel NIRS techniques to quantify cerebral oxygenation,haemodynamic and metabolic changes, and to discuss the potential value ofintegrating NIRS-derived variables into routine bedside multi-modal cerebralmonitoring to guide brain-directed therapies.*martin.smith@uclh.nhs.uk

One contribution of 20 to a Theo Murphy Meeting Issue ‘Illuminating the future of biomedicaloptics’.

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2. Pathophysiology of brain injury and the role of monitoring

It is not within the remit of this paper to discuss the pathophysiology ofacute brain injury in detail, but it is important to highlight some key aspectsto put the role of brain monitoring into context. Brain injury, particularlytraumatic brain injury, is traditionally classified into primary and secondaryinjury, although this delineation is somewhat artificial. Primary injury occursas a result of mechanical forces applied to the brain at the time of injury orbecause of primary haemorrhagic and ischaemic events. This leads to secondaryinjurious processes, including ionic, metabolic and inflammatory changes, whichworsen the primary injury and adversely affect outcome. Intracranial andsystemic physiological insults, particularly hypotension, hypoxaemia and raisedintracranial pressure, are also potent causes of on-going (‘secondary’) brain injury.Although the pathophysiology of brain injury is complex, two components are ofkey importance—reduction in substrate delivery below critical thresholds andimpaired mitochondrial substrate utilization leading to cerebral cellular energyfailure. Although some pathophysiological processes are disease specific, the finalcommon path is cerebral hypoxia/ischaemia across a wide spectrum of disorders.

It is important to note that hypoxia/ischaemia does not result specificallyfrom a reduction in cerebral blood flow, but rather from a mismatch betweenblood flow and cerebral metabolic demand. Although time-critical windows toprevent or minimize permanent ischaemic neurological injury exist, these arelikely to be disease specific and, in any case, often pass silently because thebedside detection of cerebral hypoxia/ischaemia in real time remains problematic[2]. Measurement of cerebral oxygenation is widely used to assess the balancebetween cerebral metabolic supply and demand, but standard methods havesignificant limitations. Some, such as jugular venous oximetry, are global andmay miss regional ischaemia, whereas others, such as brain tissue oxygen tension,are focal and identification of ischaemia is crucially dependent on the position ofthe probe. Furthermore, these techniques are invasive and not usually availableoutside specialist centres. Non-invasive techniques, such as trans-cranial Dopplerultrasonography or electroencephalography (EEG), are used to assess indirectlythe adequacy of cerebral blood flow or the presence of ischaemia, respectively, buttrans-cranial Doppler is significantly operator dependent and the EEG is difficultto interpret by non-specialists [3].

There is therefore a need for a non-invasive, bedside monitor that can providereliable and real-time data from several regions of the brain simultaneously. NIRSis a non-invasive technique that offers the potential for bedside monitoring ofcerebral oxygenation, haemodynamics and metabolic status over multiple regionsof interest. However, despite the potential of NIRS to address many of theshortcomings inherent in other cerebral monitoring techniques, there has beenlimited adoption into clinical practice more than three decades since its firstdescription.

3. Commercially available near-infrared spectroscopy systems

There are several commercial NIRS systems, and non-commercial prototypes,available for brain monitoring [4]. Most commercial devices are oximeters

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incorporating spatially resolved spectroscopy, although time-resolved andfrequency-domain (also known as phase modulation) spectroscopy systems arenow being introduced to the market. The technical aspects of commerciallyavailable NIRS devices have recently been reviewed in detail elsewhere [4].

The availability of many clinical systems has, until recently, been limited toEurope and Japan because few instruments have historically been approved bythe US Food and Drug Administration. However, this situation is changing,and commercially available NIRS systems currently include the INVOS series(Somanetics Corporation, Troy, MI, USA), FORE-SIGHT (CAS MedicalSystems, Branford, CT, USA), Nonin 7600 (Nonin Medical, Plymouth, MN,USA), Oxiplex TS (ISS, IL, USA) and the NIRO series (Hamamatsu PhotonicsKK, Hamamatsu City, Japan).

Unfortunately, there is a lack of standardization between commerciallyavailable NIRS devices. Different manufacturers use different nomenclature,although most do provide an absolute measure of regional cerebral tissuesaturation (rScO2) in some form and display this as a simple percentage value.However, the algorithms used, and even the variables actually measured, varybetween systems, and this leads to difficulty when selecting devices for clinicaluse and when comparing between devices or clinical studies using different devices[5,6]. Of particular relevance is the observation that the application of differentalgorithms produces significantly different chromophore concentrations from thesame underlying optical data [7]. Several studies have demonstrated substantialdifferences in rScO2 measured by cerebral oximeters from different manufacturers,highlighting the crucial importance of being able to understand the algorithm onwhich a particular device relies [8,9]. Unfortunately, some manufacturers do notpublish their algorithms, rendering data from such devices of uncertain validityand making it impossible to compare data between devices.

Because NIRS interrogates arterial, venous and capillary blood within thefield of view, the derived saturation represents a ‘tissue’ oxygen saturationmeasured from these three compartments that can be used to identify cerebralhypoxia/ischaemia [10]. This is the rationale for the application of cerebraloximetry in the clinical setting. Current commercially available NIRS devicesare usually designed to be placed on the forehead and, as with other regionalmonitoring techniques, it is impossible to detect changes in areas locateddistant from the monitored site, although global cerebral oxygen sufficiencycan be evaluated [11]. Multi-probe NIRS devices are now available andthese provide regional measurements from multiple areas simultaneously. Thisis particularly important given the significant regional heterogeneity in theinjured brain.

4. Current clinical applications of near-infrared spectroscopy

Despite interest in the clinical application of NIRS for more than three decades,widespread translation into routine clinical practice has not yet occurred. Thereis some recent evidence that treatment guided by NIRS can improve clinicaloutcome in specific clinical scenarios, particularly those where there is anincreased risk of cerebral ischaemic injury, but thus far there is no evidence tosupport the widespread introduction of NIRS as a monitor of cerebral well-being

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[5,12]. In particular, there is little evidence to support its routine applicationduring general anaesthesia and surgery, despite enthusiastic endorsement for thisindication by several manufacturers of NIRS devices.

(a) Cardiac surgery

Poor neurological outcome is a major concern after cardiac surgery, particularlyin patients undergoing cardiopulmonary bypass. Stroke occurs in 1–3 per cent ofpatients, but this is overshadowed by the development of long-standing post-operative cognitive dysfunction in more than 50 per cent. Likely mechanisms ofinjury include emboli and cerebral hypoperfusion, and a variety of managementprotocols have been introduced to minimize these risks. However, it is theintroduction of NIRS-guided ‘brain protection’ protocols aimed at optimizingcerebral oxygen delivery during cardiopulmonary bypass that has recentlygenerated substantial interest [13,14].

Case-control and retrospective studies show a correlation between cerebraldesaturation and adverse outcome after cardiopulmonary bypass, andimprovements in outcome, including a reduced incidence of stroke, which arelinked to cerebral oximetry monitoring during bypass [15,16]. However, suchclear outcome benefits have not been identified in prospective trials. In one suchstudy, 200 patients undergoing coronary artery bypass grafting were randomizedto a control arm where rScO2 was monitored using the INVOS 5100 oximeterbut not displayed, and an intervention arm where a protocol to augmentcerebral oxygen delivery, based on changes in rScO2, was implemented [17].The protocol was targeted to restore rScO2 to baseline, and intervention ledto rapid improvement in rScO2 in 84 per cent of cases. Although there wasno overall difference in the incidence of adverse complications between thetwo groups, there were fewer strokes and other major organ morbidity in theintervention group. Baseline and mean rScO2 values were lower, and therewere more episodes of cerebral desaturation, in patients who died or whodeveloped major organ morbidity, suggesting that rScO2 might be a usefulsurrogate marker for poor outcome after cardiopulmonary bypass. A study usinga similar protocol in 265 patients undergoing coronary artery bypass graftingassessed the burden of cerebral ischaemia as the amount of time that rScO2was less than 50 per cent (measured by the INVOS 5100) and found thatthis was associated with an increased risk of cognitive decline and prolongedhospital stay [18]. Such data suggest that the duration as well as the degreeof cerebral desaturation determine the overall ischaemic burden, raising thepossibility that it is a time-dependent exposure to a certain threshold of cerebralischaemia (a viability-time threshold) that leads to irreversible tissue damageand subsequent functional impairment, a concept supported by data from animalstudies (see below) [19].

Despite conflicting outcome data, NIRS is being increasingly used to monitorcerebral oxygenation during cardiac surgery because of the lack of use-associated risk and modest cost [20]. It has recently been suggested that thepotential benefits of NIRS monitoring during very high-risk procedures (suchas hypothermic circulatory arrest) might be enhanced by novel interpretativetechniques that use mathematical modelling of NIRS variables to quantify timelimits for cerebral hypoxia/ischaemia [21].

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Because rScO2 is a measure of (brain) tissue oxygen saturation, it hasbeen suggested that it might also indirectly reflect the adequacy of thesystemic circulation and therefore of cardiopulmonary function. A recentobservational study prospectively investigated the effect on mortality andcardiopulmonary morbidity of pre-operative rScO2 measured with an INVOS 4100or a 5100 cerebral oximeter in 1178 patients undergoing cardiac surgery withcardiopulmonary bypass [22]. The lowest median (range) oxygen-supplementedpre-operative rScO2 was 64 per cent (15–92%). Low pre-operative rScO2 wassignificantly correlated with post-operative biomarkers of cardiac and renal injury,and with cardiac dysfunction (p < 000.1). rScO2 was lower in those who haddied by 30 days compared with those who survived [median (95% confidenceinterval) 58% (50.7–62.0%) versus 64% (64–65%), respectively, p < 000.1], andpre-operative rScO2 less than 50 per cent was an independent risk factor for 30 dayand 1 year mortality. The authors suggest that their data support a link betweenlow rScO2 and cardiopulmonary dysfunction and, because low rScO2 is associatedwith morbidity and mortality, hypothesize that it might be a useful addition to thepre-operative risk stratification of patients undergoing cardiopulmonary bypassas well as a potential non-invasive technology for guiding therapy in patientswith heart failure. As is so often the case in clinical NIRS studies, there is nodebate about the validity and reproducibility of the technology in the particularscenario, although the authors do acknowledge that the INVOS is only approvedas a trend monitor and that they used it here to make ‘one-off’ measurements inisolation. There is no discussion of the large variability (15–92%) of the baselinevalue of rScO2 or the clinical relevance of such observations. Notwithstandingthese comments, this study brings an interesting angle to the debate about theclinical applications of NIRS, and further investigation in this area is warranted.

(b) Carotid endarterectomy

Carotid endarterectomy involves a period of carotid occlusion and an associatedrisk of critical cerebral ischaemia if collateral blood supply is insufficient.Although this risk can be minimized by use of a shunt to maintain cerebral bloodflow during the period of occlusion, placement of the shunt is itself associatedwith substantial risks, particularly of atheromatous emboli. Several methods areused to assess the likely adequacy of collateral supply, and therefore of cerebraloxygen delivery, during the cross-clamp period to inform the decision regardingshunt placement. When carotid endarterectomy is performed under regionalanaesthesia, alteration of mentation is the best monitor of impending ischaemiaand an indication for shunt placement. However, general anaesthesia is requiredin many circumstances, so surrogate measures of cerebral ischaemia, includingEEG and trans-cranial Doppler, have been used. NIRS offers advantages overthese techniques in terms of simplicity and has been employed in some centresas the primary cerebral monitor during carotid endarterectomy for more than10 years. In such circumstances, a 20 per cent reduction in rScO2 from baselineis widely used as the ‘threshold’ for shunt placement or other interventions toincrease cerebral oxygen delivery [23].

The application of NIRS during carotid endarterectomy has been comparedwith established monitoring techniques and is the subject of a recent review [24].In 594 patients undergoing carotid endarterectomy with general anaesthesia, the

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sensitivity, specificity and predictive values of various rScO2 thresholds indicatingthe need for shunt placement or causing neurological complications were assessed[25]. rScO2 was measured using either an INVOS 3100-A or a 4100-SSA cerebraloximeter, and a 12 per cent decrease from baseline was optimal, having asensitivity of 75 per cent, a specificity of 77 per cent, and positive and negativepredictive values of 37 per cent and 98 per cent, respectively. In this study, thepreviously applied threshold of a 20 per cent reduction in rScO2 from baselinehad a low sensitivity (30%) but a very high specificity (98%), with positive andnegative predictive values of 37 per cent and 98 per cent, respectively. Otherstudies have demonstrated similar accuracy and reproducibility for NIRS in thedetection of cerebral ischaemia compared with other monitoring modalities [26].

Many investigators have attempted to define an absolute thresholdfor determination of impending cerebral hypoxia/ischaemia during carotidendarterectomy. In one, EEG was used to define the presence of cerebral ischaemiaafter carotid artery clamping, and no patient with a reduction in the tissueoxygenation index (TOI), a NIRO 300-derived measure of rScO2, of less than13 per cent developed EEG evidence of ischaemia [27]. In another study, anindependent neurologist evaluated clinical and EEG signs of cerebral ischaemia in50 patients undergoing carotid endarterectomy with regional anaesthesia, and theaverage percentage reduction in rScO2 from baseline, measured using the INVOS4100, during carotid clamping was 17 per cent in patients who developed signs ofischaemia and only 8 per cent in those who did not (p = 0.01) [28]. Althougha decrease in rScO2 of 15 per cent or more during carotid clamping in thisstudy was associated with a 20-fold increase in the odds for developing cerebralischaemia, this threshold only had a 44 per cent sensitivity, 82 per cent specificityand a negative predictive value of 94 per cent. Another study using EEG as thecomparator has identified reductions in rScO2 from baseline between 5 and 25 percent as potential ischaemic thresholds [29]. A recent study failed to show a reliablecorrelation between rScO2 and stump pressure [30]. It is therefore currentlyimpossible to specify an accurate NIRS-derived rScO2 threshold that can bewidely applied to guide shunt placement, or detect cerebral hypoxia/ischaemia,during carotid endarterectomy. However, optimism remains that it might in thefuture be possible to use NIRS to guide systemic physiological management inorder to optimize cerebral perfusion and oxygenation during carotid surgery [31].

(c) Routine brain monitoring during anaesthesia

Although the primary endpoint of general anaesthesia is its effect on thebrain, this organ remains the least monitored during anaesthesia and surgery.The potential to monitor cerebral well-being continuously, particularly whenthe brain might be at risk because of dysautoregulation or hypoperfusion, isof course an attractive proposition, since prolonged reductions in systemic bloodpressure that exceed (unknown) critical thresholds for adequate cerebral perfusion(in terms of both severity and duration) may result in permanent neurologicalinjury. Because NIRS allows immediate recognition of cerebral desaturationevents that are undetected by conventional intra-operative monitoring, it hasbeen suggested that it should be introduced more widely into clinical practice[32]. Although enthusiasts argue that early detection of cerebral desaturationwill lead to targeted intervention that will improve peri-operative outcome, theevidence for such benefit has thus far proved elusive.

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In one study, rScO2 was monitored continuously using an INVOS 3100Aoximeter in 16 patients undergoing orthoptic liver transplantation, and clampingthe recipient’s liver led to a significant decline in rScO2 in 50 per cent ofthe patients [33]. This cerebral desaturation correlated significantly with post-operative increases in neuron-specific enolase and protein S-100B, biomarkers ofhypoxia/ischaemia-related cerebral damage. However, there were no significantdifferences in haemodynamic variables between patients with and withoutreductions in rScO2, so potential targets for its prevention are unclear. In anotherstudy, a cohort of otherwise healthy elderly patients undergoing non-vascularabdominal surgery were randomly allocated to an intervention group (n = 56),in which rScO2 measured using an INVOS 4100 oximeter was maintained at75 per cent or more of baseline, or to a control group (n = 66), where anaesthesiawas managed routinely and rScO2 was monitored but not displayed [34]. Althoughthe overall mean (95% confidence interval) rScO2 was higher in patients inthe intervention group than in the control group (66% (64–68%) versus 61%(59–63%), respectively, p = 0.002), there was no difference in the incidence ofcerebral desaturation between the two groups—rScO2 fell below 75 per cent ofbaseline in 11 (20%) and 15 (23%) of patients in the intervention and controlgroups, respectively (p = 0.82). However, control patients with intra-operativecerebral desaturation had a lower Mini Mental State Examination score on theseventh post-operative day and longer hospital length of stay than patients inthe intervention group (p = 0.02). The failure of the intervention to preventcerebral desaturation in 20 per cent of patients merits further consideration ifsuch protocols are to be introduced more widely.

There has been most recent interest in the application of NIRS during surgeryon patients operated on in the 45–90◦ head-up position (often called the beachchair position) because they may be at (minimal) risk for adverse neurologicalevents. It is hypothesized that the unopposed hypotensive effects of the uprightposition consequent on the attenuation by anaesthesia of normal autonomicresponses, in association with the direct vasodilating effects of anaesthetic agents,might lead to cerebral desaturation [35]. In one study, the incidence of cerebraldesaturation, defined as a 20 per cent or more reduction in rScO2 from baseline, oras an absolute value of rScO2 55 per cent or less for more than 15 s, measured usingthe FORE-SIGHT device, was compared in 124 patients undergoing shouldersurgery under general anaesthesia in the beach chair or lateral decubitus positions[36]. Although intra-operative haemodynamic variables did not differ betweenthe two groups, rScO2 values were lower in the beach chair position groupthroughout the intra-operative period (p < 0.0001). The incidence of cerebraldesaturation was also higher in the beach chair position compared with thelateral decubitus position (80.3% versus 0%, respectively, p < 0.0001), as wasthe median number of cerebral desaturation events per subject (4, range 0–38,versus 0, range 0–0, respectively, p < 0.0001). While impressive at first glance,these data require further consideration. First, this apparently high incidenceof cerebral desaturation does not easily relate to the exceedingly low incidenceof post-operative neurological damage in the huge numbers of patients whoundergo surgery in the head-up position each year. It is also not clear whatthese episodes of ‘cerebral desaturation’ actually represent. Cardiorespiratoryvariables (the ‘input’ to the brain) were unaffected by the operative positionand the cerebral metabolic rate is unlikely to have changed substantially during

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the study period. It is therefore important that further studies are undertakento determine whether potentially confounding effects, such as position-relatedchanges in tissue geometry, might contribute to the measured changes in rScO2under such circumstances.

5. Brain injury

The logical application for a non-invasive, real-time cerebral monitor is afteracute brain injury, where secondary ischaemic injury is common and associatedwith adverse outcome. However, this is an area where there has been limitedresearch of the utility of NIRS, and no outcome studies. This is in part relatedto the significant difficulties in the application of NIRS after brain injury, notleast because the challenges of describing NIRS variables in the normal brainare accentuated by the optical complexity of oedematous brain tissue and thepresence of intracranial haematomas. These factors have in fact been used toadvantage in studies using NIRS to identify intracranial haematomas [37] andcerebral oedema [38].

(a) Monitoring cerebral oxygenation after brain injury

To date, studies of NIRS in adult brain injury have been observationaland highlight two key difficulties in investigating cerebral oxygenation in thiscontext—the problem of defining a threshold for hypoxia/ischaemia, particularlyin the presence of acutely disordered cerebral metabolic function, and the lackof a gold standard against which NIRS-derived variables can be compared [39].It is also of note that structurally and physiologically different regions of thebrain are monitored by different modalities, making comparison between monitors(including NIRS) difficult.

One study identified an association between the increasing length of time thatrScO2 (measured with an INVOS 4100 oximeter) was below 60 per cent andintracranial hypertension, low cerebral perfusion pressure and increased mortalityin 18 patients with severe traumatic brain injury [40]. A more recent study foundthat brain tissue oxygen tension and rScO2 (measured using an INVOS 5100)were directly and significantly related in 22 patients with severe traumatic braininjury [41]. rScO2 less than 60 per cent predicted ‘severe’ brain hypoxia, definedin this study as brain tissue oxygen tension less than 1.6 kPa, with a sensitivityand specificity of 73 per cent and 86 per cent, respectively, whereas the sensitivityand specificity of rScO2 less than 70 per cent for ‘moderate’ brain hypoxia (braintissue oxygen tension 1.6–2.0 kPa) was only 62 per cent and 49 per cent. Theauthors concluded that (non-invasive) rScO2 monitoring cannot be considered asubstitute for routine (invasive) brain tissue oxygen tension monitoring.

There has also been interest in the application of rScO2 monitoring to detectcortical changes related to cerebral vasospasm after aneurysmal subarachnoidhaemorrhage. In a case series of 32 patients undergoing endovascular treatment ofa ruptured cerebral aneurysm, there was a correlation between the rate of declineof ipsilateral rScO2 measured using an INVOS 3100 oximeter and vasospasmconfirmed by digital subtraction angiography, with the rate of decline in rScO2being 3.5% min−1 greater in patients with vasospasm than in those without [42].A recent study used time-resolved spectroscopy (TRS-20, Hamamatsu Photonics)

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to make repeated measurements of cortical oxygen saturation (CoSO2) andhaemoglobin concentration in 14 patients over a 14 day period after subarachnoidhaemorrhage [43]. In six patients with only small temporal changes in CoSO2(less than 5% from baseline) and stable haemoglobin concentrations, there wasno angiographic evidence of cerebral vasospasm. In contrast, there was anabrupt fall in CoSO2 and total haemoglobin concentration between days 5 and9 after subarachnoid haemorrhage in eight patients, six of whom had severevasospasm confirmed by angiography. The onset of vasospasm was associatedwith a significant decrease in CoSO2 (p = 0.007) and in total (p = 0.0038) and oxy-haemoglobin (p = 0.0025) concentrations—changes that are suggestive of corticalischaemia. Interestingly, trans-cranial Doppler failed to detect vasospasm in fourof the six cases that were correctly diagnosed by time-resolved spectroscopy,presumably because NIRS detects changes in the cerebral cortex and trans-cranial Doppler those in basal vessels. This is of potential clinical relevancebecause many of the neurological deficits that result from vasospasm are relatedto cortical ischaemia. From their data, the authors estimated a 3.9–6.4 per centreduction in CoSO2 from baseline as the cut-off values predicting vasospasm withhigh sensitivity (100%) and specificity (85.7%). Also of interest is the finding ofsignificantly higher CoSO2 (p = 0.048) and lower deoxyhaemoglobin concentration(p = 0.002) in patients on day 1 after subarachnoid haemorrhage compared withcontrols. The authors speculate that, because there was no associated change inthe total haemoglobin concentration, this implies a reduction in cerebral oxidativemetabolism, rather than hypoperfusion. There is some evidence that aneurysmalsubarachnoid haemorrhage is associated with a reduction in oxidative metabolism[44], and the potential for NIRS to monitor this is an exciting possibility. Anothernovel aspect of this study was the use of image-guided positioning of the NIRSoptodes to facilitate consistent monitoring of the same cortical area on consecutivedays. This approach addresses one of the factors limiting the repeatability of NIRSmeasurements over time.

(b) Viability-time thresholds of cerebral hypoxia/ischaemia

Although low rScO2 has been associated with poor outcome after brain injury[40], the application of NIRS in outcome studies, or to guide treatment, ishampered by the absence of a gold standard for comparison, as well as by theinability to define NIRS-derived ‘thresholds’ for cerebral hypoxia/ischaemia [39].Viability-time thresholds for brain tissue hypoxia/ischaemia have been studiedmost widely in adult stroke research, where the concept of ‘time is brain’ isincreasingly recognized, and interventions to restore perfusion prior to the onset ofirreversible tissue damage are associated with improved functional outcomes [45].While the mechanisms of injury and potential interventions are different in othertypes of brain injury, it is likely that similar windows for targeted interventioncan be identified [46,47]. The use of NIRS to identify rScO2-derived viability-time thresholds predictive of neurological outcome is therefore an attractiveproposition that would have wide clinical application.

In one study, a piglet model was used to investigate the temporaldevelopment of brain damage when rScO2 was maintained at 35 per cent, athreshold previously demonstrated by the same group to be associated withneurophysiological impairment [19]. Hypoxia/ischaemia lasting 2 h or less was

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not associated with subsequent neurological deficit, whereas, for longer episodesof hypoxia/ischaemia, the incidence of neurological injury increased by about15% h−1 and was heralded by abnormalities in NIRS variables during reperfusion.These findings suggest not only that it is possible to define a viability-timethreshold using rScO2, but also that a several-hour window of opportunityexists during severe hypoxia/ischaemia that might be used to deliver targetedneuroprotective strategies and potentially prevent or minimize irreversible tissuedamage and subsequent neurological injury. The possibility that NIRS mightidentify treatment windows before irreversible tissue changes have occurred,and that changes during reperfusion might also predict outcome, is an excitingprospect.

(c) Monitoring cerebral autoregulation after brain injury

Cerebrovascular autoregulation is frequently impaired after brain injury andis associated with poor outcome because it renders the brain more susceptibleto ischaemic insults. Cerebrovascular pressure reactivity is a key component ofcerebrovascular autoregulation and has been incorporated into several bedsidemethods of assessing autoregulation. These include the pressure reactivity index(PRx), the moving correlation between slow waves in arterial blood pressureand intracranial pressure, and the mean velocity index (Mx), where trans-cranialDoppler-measured blood flow velocity is substituted for intracranial pressure [48].Pressure reactivity and mean velocity indices can be monitored continuously andhave been used to define individual brain-directed targets and improve outcomeafter head injury [49].

Cerebral autoregulation has recently been assessed non-invasively using NIRS-derived haemoglobin variables in 40 patients with severe traumatic brain injury[50]. In this study, there was a significant correlation (r = 0.49, p < 0.001) betweenTHx, a measure of autoregulation derived from the total haemoglobin index(measured using spatially resolved spectroscopy with a Hamamatsu NIRO 200)and arterial blood pressure, and the PRx. The same group has also demonstrateda correlation between TOIx, a measure of autoregulation derived from theTOI (Hamamatsu NIRO 200), and the Mx in a group of 27 patients followingpoor-grade subarachnoid haemorrhage [51].

Although NIRS-derived indices of cerebrovascular autoregulation are relatedto both pressure reactivity and mean velocity indices, agreement is limitedby the complex and nonlinear relationships between intracranial pressure,flow velocity and NIRS variables. Specific frequency bands that characterizeautoregulatory processes with analysis in the time and frequency domains maymore accurately identify the relationship between NIRS and other signals,including those features that are most closely related to autoregulation.In particular, wavelet-based techniques aid the interpretation of complex time-variant signals, since they focus analysis to specific features of interest withinthe time and frequency domains simultaneously, producing qualitative andquantitative evidence of cerebrovascular autoregulation that is not possible usingother methods [52]. This is an interesting area of research that is likely totranslate readily into clinical practice. Figure 1 shows an example of how NIRSmonitoring of cerebrovascular autoregulation can be optimized using a waveletanalysis technique.

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Figure 1. Monitoring cerebral autoregulation with near-infrared spectroscopy. The upper panelsshow the individual mean arterial blood pressure (MAP), trans-cranial Doppler-derived blood flowvelocity (TCD), intracranial pressure (ICP) and NIRS-derived (NIRO 100, Hamamatsu Photonics)total haemoglobin concentration (HbT) waveforms from a single patient. Note the almost identicalcyclic activity. The lower panels demonstrate the wavelet transform of the MAP and HbT signalstogether with a comparison of their phase. The darker red appearance of the lower plot indicateshigh agreement in phase alignment across the frequencies shown (1–0.003 Hz) and therefore absenceof cerebral autoregulation. (Adapted from D. Highton 2011, unpublished observations. Reproducedby permission.)

(d) Monitoring metabolic failure after brain injury

The importance of cellular energy failure as a key component of thepathophysiology of acute brain injury is now well recognized, and cerebralcellular energy status has been quantified at the bedside using cerebral

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Figure 2. Changes in cerebral cytochrome c oxidase concentration during hypoxaemia in healthyvolunteers. (a) The changes in estimated cerebral oxygen delivery (DecDO2), haemoglobindifference concentration (D[Hbdiff]) and CCO concentration (D[CCO]), measured using a custom-made broadband spectroscopy system, between hypoxia and baseline in healthy adults. (b) Thecorrelation of DecDO2 and D[CCO] and D[Hbdiff]. The box-and-whisker plots show group medianand interquartile range. Significant differences between hypoxia and baseline are indicated by∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001 and ∗∗∗∗p < 0.0001. (Adapted from Tisdall, M. 2009 Non-invasivenear-infrared spectroscopy: a tool for measuring cerebral oxygenation and metabolism in patientswith traumatic brain injury. MD thesis, University College London. Reproduced by permission.)

microdialysis [53]. Cytochrome c oxidase (CCO) is the terminal electron acceptorin the mitochondrial electron transport chain and responsible for over 95 percent of oxygen metabolism; its oxidation status reflects the balance betweencerebral energy supply and demand. NIRS-derived measurement of CCO has beenvalidated as a measure of cellular energy status in animal models [54] and offersthe potential to assess cerebral mitochondrial redox state, and the adequacy ofoxygen delivery and utilization, after human brain injury [39].

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Our group has recently developed and tested in healthy volunteers and brain-injured patients a multi-modal monitoring strategy that incorporates a novelmulti-wavelength NIRS system optimized for CCO measurement in adults.In a study in healthy adult volunteers, we used a custom-built broadbandspectroscopy system to measure changes in the cerebral concentrations of oxidizedCCO (D[CCO]), oxyhaemoglobin (D[HbO2]) and deoxyhaemoglobin (D[HHb])during arterial hypoxaemia, and related these to changes in estimated cerebraloxygen delivery (DecDO2) [55]. At the nadir of hypoxaemia (SpO2 approx. 80%),the median (interquartile range) ecDO2 decreased by 9.2 (5.4–12.1) per cent(p < 0.0001), and this was associated with an increase in total haemoglobinconcentration (D[HbT] = D[HbO2] + D[HHb]) of 2.83 (2.27–4.46) mmol l−1 (p <0.0001) and decreases in the haemoglobin difference concentration (D[Hbdiff] =D[HbO2] − D[HHb]) of 12.72 (11.32–16.34) mmol l−1 (p < 0.0001) and in D[CCO]of 0.24 (0.06–0.28) mmol l−1 (p < 0.01). These haemoglobin changes suggest areduction in cerebral oxygen delivery despite an increase in cerebral bloodvolume, the latter presumably related to hypoxic cerebral vasodilatation.DecDO2 correlated significantly with D[CCO] (r = 0.78, p < 0.001) but not withD[HbT] (r = 0.33, p = 0.584) or D[Hbdiff] (r = 0.49, p = 0.145), suggesting thatD[CCO] might be a superior marker of reduced cellular oxygen availability thanconventional haemoglobin-derived NIRS variables (figure 2).

We subsequently extended this work into the clinic and incorporated thebroadband spectroscopy system into bedside multi-modal cerebral monitoring. Ineight mechanically ventilated adult head-injured patients, cerebral microdialysisand broadband spectroscopy were added to the measurement of brain tissueoxygen tension to investigate the effects of normobaric hyperoxia on cellularand mitochondrial redox states assessed by the brain tissue lactate/pyruvateratio and D[CCO], respectively [56]. Mean (range) brain tissue oxygen tensionincreased by 7.2 (4.5–9.6) kPa (p < 0.0001) during ventilation with 100 per centoxygen, the lactate/pyruvate ratio decreased by 1.6 (1.0–2.3) (p = 0.02) andD[CCO] increased by 0.21(0.13 − 0.38) mmol l−1 (p = 0.0003). D[CCO] correlatedwith changes in brain tissue oxygen tension (r = 0.57, p = 0.005) and in thelactate/pyruvate ratio (r = −0.53, p = 0.006). These changes are suggestive ofhyperoxia-induced oxidation in cerebral cellular and mitochondrial redox statesand are consistent with an increase in aerobic metabolism. Further studies thatare powered to determine any potential outcome benefits of such improvementsin cerebral metabolic state are warranted.

The challenges of measuring CCO using NIRS are substantial and particularlycomplex in the clinical setting. CCO is present in much lower concentrationsin the tissue than oxy- and deoxyhaemoglobin and has an absorption spectrumoverlapping that of these chromophores. The low signal-to-noise ratio also raisesthe question of whether the CCO signal contains sufficient information to be ofclinical relevance. Furthermore, different algorithms produce markedly differentresults when analysing the same dataset, highlighting the unreliable nature of theCCO signal [7]. In an attempt to address these issues, we have recently developeda hybrid optical spectrometer comprising a novel combination of broadband andfrequency-domain near-infrared systems. The hybrid optical spectrometer hasbeen described in detail elsewhere but, in brief, comprises two identical broadbandspectroscopy systems and a two-channel frequency-domain spectrometer capable

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30

4

3

2

Δ[ox

CC

O]

(μm

ol l–1

)

1

0

–1

–2

20Pb

rO2

(mm

Hg)

10

0FiO2 = 30% FiO2 = 60%

0 500 1000 1500time (s)

25002000

Figure 3. Simultaneous measurement of changes in right frontal cortical brain tissue oxygen partialpressure (PbrO2) (black) and cytochrome c oxidase concentration (D[oxCCO]) (grey), during aperiod of normobaric hyperoxia in a patient with diffuse axonal injury following a traumatic headinjury. PbrO2 was measured using a commercially available Clarke-type electrode (Licox, IntegraLifescience, Plainsboro, NJ, USA) and D[oxCCO] using a custom-built hybrid optical spectrometer.(Adapted from A. Ghosh 2011, unpublished observations. Reproduced by permission.)

of absolute measurement of optical absorption and scattering at 690, 750, 790 and850 nm over two regions of interest [57]. [HHb], [HbO2] and [CCO] are calculatedusing the UCLn algorithm [7] by fitting changes in attenuation from 740 to 860 nmusing a 35 mm source–detector separation. We have made some preliminarymeasurements with the hybrid optical spectrometer in healthy volunteers [58] andare currently collecting data in further volunteer studies and also in brain-injuredpatients. Figure 3 demonstrates changes in CCO during normobaric hyperoxiameasured using the hybrid optical spectrometer in a patient with acute braininjury; complete data will be presented shortly.

6. Mathematical model-assisted data interpretation

NIRS and other multi-modal monitoring generates large and complex datasetswhose interpretation is not always straightforward. Furthermore, what can bemeasurable at the bedside and what clinicians really need to know are oftenvery different. As with the assessment of cerebrovascular autoregulation frominformation contained in the arterial blood pressure and intracranial pressuresignals, clinically relevant information may be hidden within the signals ofother commonly measured intracranial variables. Mathematical models of thecerebral circulation and energy metabolism have been developed that can beused to interpret multi-modal monitor-derived data and maximize their clinical

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usefulness [59]. Such models produce new data streams, allowing the clinician toaccess simultaneously measured signals and model predictions of measured andunmeasured variables. Although the CCO signal has great potential as a markerof cellular oxygen metabolism, it is also the hardest to interpret. Combiningmeasurement with modelling might allow information that is of potential clinicalimportance to be extracted [60]. Further validation of the model against in vivodata is required to determine whether it has potential to identify artefactualtrends in the measured CCO signal and, importantly for clinical applications,to make predictions about cerebral blood flow and metabolism. A multi-modalphysiological modelling approach integrating directly with the measurementof multiple physiological variables has enormous potential to deliver enhancedinformation that can be used to support clinical decision making in real time.

This work was undertaken at University College London Hospitals and partially funded by theDepartment of Health’s National Institute for Health Research Centres funding scheme.

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