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(Stroke. 2001;32:2492.)
© 2001 American Heart Association, Inc.

Original Contributions

Evaluation of a Near-Infrared Spectrometer (NIRO 300) for the Detection of Intracranial Oxygenation Changes in the Adult Head

Pippa G. Al-Rawi, BSc; Peter Smielewski, PhD Peter J. Kirkpatrick, FRCS(SN)

From the University Department of Neurosurgery, Addenbrooke’s Hospital, Cambridge, UK.

Correspondence to P.J. Kirkpatrick, FRCS(SN), University Department of Neurosurgery, Box 167, Level 4, A-Block, Addenbrooke’s Hospital, Hills Rd, Cambridge CB2 2QQ, UK. E-mail pjk21{at}medschl.cam.ac.uk

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose—— The clinical application of intracranial near-infrared spectroscopy in adults has been hampered by concerns over contamination from extracranial tissues. The NIRO 300 (Hamamatsu Photonics) provides continuous online measurements of hemoglobin and cytochrome oxidase concentrations and a calculated tissue oxygen index (TOI). The present study seeks confirmation of the anatomic source of TOI in the adult cranium.

Methods—— Sixty patients undergoing carotid endarterectomy were studied. The NIRO 300 was incorporated into an established multimodal monitoring system. TOI, oxyhemoglobin, and deoxyhemoglobin changes were assessed and compared with (1) frontal cutaneous laser-Doppler flowmetry and (2) transcranial Doppler measurement of the ipsilateral middle cerebral artery flow velocity.

Results—— Changes in TOI were seen during cross-clamping of the carotid vessels in 49 patients (mean TOI=-9.4%, SD=7.1). Significant correlation was seen between TOI and flow velocity (r=0.56) but not with laser-Doppler flowmetry (r=0.13). In 31 patients, oxyhemoglobin and deoxyhemoglobin concentrations were recorded, showing significant changes during both external carotid artery and internal carotid artery clamping. A change in TOI was predominantly associated with internal carotid artery clamping (n=41). When TOI changed during external carotid artery clamping (n=8), significant blood pressure changes occurred, or extracranial-to-intracranial anastomosis was evident. In the absence of such variables, the sensitivity of TOI to intracranial and extracranial changes was 87.5% and 0%, respectively, and specificity was 100% and 0%, respectively.

Conclusions—— The NIRO 300 reflects changes in cerebral tissue oxygenation when TOI is calculated, with a high degree of sensitivity and specificity.

Key Words: carotid endarterectomy • cerebral ischemia • oxygen • spectroscopy, near-infrared

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The clinical application of cerebral near-infrared spectroscopy (NIRS) has generated concerns over sampling volume and sources of extracranial contamination.^1–4 Current commercial machines detect optical attenuation from several wavelengths of light by methods such as time-resolved spectroscopy,⁵ phase-resolved spectroscopy,⁶ and spatially resolved spectroscopy.⁷ Various algorithms have been applied to attempt quantification.^8–10 However, their accuracy remains controversial, and to date they have not achieved regular clinical use.^11,12

The theory behind NIRS has been described in detail previously.¹³ When one measures from the adult head, changes in hemoglobin chromophore concentrations are derived from a composite block of illuminated tissue.¹⁴ Simulations indicate that near-infrared light may penetrate the cerebral cortex by only 2 to 3 mm, and therefore the region of cerebral tissues sampled probably extends no further than the gray matter.¹⁵ The depth of penetration is dependent on optode separation, and scatter tends to be random and unpredictable.^15–18 In addition, the cerebrospinal fluid layer, by causing a uniform distribution of near-infrared light, may alter the calculated spatially resolved spectroscopy slope and lead to abnormally low values for saturation.^19,20 The skull itself and its interface with other layers in the human head may distort the penetration of near-infrared light by generating an optical channel.²¹

In the adult head NIRS is applied in reflectance mode because pterional transmission is not possible.^2,3,14,16,17 The NIRO 300 (Hamamatsu Photonics) measures tissue oxygenation with the use of spatially resolved reflectance spectroscopy.⁷ Hemoglobin concentration changes and tissue oxygen index (TOI) are measured online and continuously displayed.

TOI has been evaluated both in vitro and by comparing human forearm measurements with a time-resolved spectroscopy instrument.²² These results support the accuracy of the scattering coefficient used in calculating TOI. However, the technique may not be as reliable when one monitors a complex multilayered structure, such as the adult human cranium.

Patients undergoing carotid endarterectomy enable segregation of the NIRS signal between intracranial and extracranial vascular territories by staged application of vascular clamps to the external (ECA) and internal carotid arteries (ICA).^23,24 In this way, we have identified NIRS thresholds for cerebral ischemia by extracting the extracranial signal.²⁵ This study incorporates the NIRO 300 into an established monitoring system for patients undergoing carotid endarterectomy. Our aim was to determine the anatomic source of the calculated TOI (expressed as a percentage) when applied to the adult brain.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Theory
The NIRO 300 (Hamamatsu Photonics K.K.) is a noninvasive bedside monitor that gives simultaneous measurement of TOI and hemoglobin concentration changes. The instrument is based on technology used in the earlier NIRO 500 and a prototype spatially resolved spectrometer.⁷ Four wavelengths of light (775, 810, 850, and 910 nm, respectively) are delivered by 4 pulsed laser diodes, and scattered light is detected by 3 closely placed photodiodes.

The concentration changes of the chromophores oxyhemoglobin (HbO₂), deoxyhemoglobin (Hb), total hemoglobin, and cytochrome oxidase are measured by conventional differential spectroscopy with the use of a modified Beer-Lambert law,^26,27 while the basic principle behind calculation of the TOI is spatially resolved reflectance spectroscopy.^7,27,28 The modified Beer-Lambert law is used in the NIRO 500 machine and can be defined as follows:

where A is light attenuation, L is differential path length, and µa is the absorption-scattering coefficient.

In the NIRO 300, the hemoglobin and cytochrome concentration changes are measured by the middle photodiode, while TOI is measured by the use of all 3.

Spatially resolved spectroscopy has been described in previous publications evaluating the Hamamatsu SRS.^7,28 Spatial resolution relies on the measurement of the attenuation gradient as a function of source-detector separation. With the use of a modified diffusion equation, a product of the absorption and scattering coefficients is calculated.²² When the tissue is treated as homogeneous, the scattering coefficient can be assumed to be a constant (k) in the near-infrared wavelength. To increase the accuracy of the calculation, however, a wavelength dependency for the scattering coefficient is derived in the form of k(1-h), where is wavelength and h is the normalized slope of the scattering coefficient along .^28,29 From here, the relative absorption coefficients and thus the relative concentrations of HbO₂ and Hb can be obtained.

TOI is the ratio of oxygenated to total tissue hemoglobin and can be expressed as follows:

The optodes themselves are held in a light proof holder and can be set at a distance of either 4.5 or 5 cm. A fiberoptic plate is used as the detector window, allowing light to be conducted from the skin surface to the sensors without distorting the spatial distribution. It is important that the detectors are placed in the correct orientation relative to the laser diode bundle to ensure that the 3 photodiodes are at uniformly increasing distances from the source.

Methods
The NIRO 300 was incorporated into an established multimodal monitoring system, enabling registration of cerebral hemodynamic changes under highly controlled conditions during carotid endarterectomy. During surgery, brief periods of cerebral ischemia often occur during cross-clamping of the ICA.^30–33 Routine multimodal monitoring includes frontal cutaneous laser-Doppler flowmetry (LDF), transcranial Doppler mean flow velocity measurements of the ipsilateral middle cerebral artery (FV), and mean arterial blood pressure (ABP) via a 20-guage radial artery catheter.³⁰ The laser-Doppler flowmeter (Moor Instruments Ltd) was modified to use light in the visible spectrum (wavelength 650 nm) to avoid any interference with the NIRS signal.²⁴

Patients
After approval of the local research ethics committee and with informed consent, 60 patients (48 men and 12 women) undergoing elective carotid endarterectomy were studied during an 11-month period (July 1999 to May 2000). The mean age was 69 years (range, 44 to 86 years). Monitoring was applied after induction of anesthesia, when the patient entered the theater. Anesthesia was standardized, and patients were maintained in physiologically stable condition throughout the procedure. NIRS optodes were placed high on the ipsilateral forehead to avoid the temporalis muscle and sufficiently lateral from the midline to avoid the superior sagittal sinus. Optode spacing was kept at 5 cm and avoided any hair. Sequential clamping of the ECA and ICA was performed intraoperatively as previously described, allowing a sufficient time interval (2 minutes) for stabilization of signals after application of each clamp.²⁵

The simultaneous measurement of hemoglobin concentration and TOI changes (TOI) was assessed by observing changes in LDF (LDF) and FV (FV) to identify the extracerebral and intracerebral contribution to the NIRS signal.^1,25 The timing of vascular clamp applications was accurately documented, and any variation in physiological variables was noted.

Data Processing and Analysis
Data signals from all the monitored parameters were digitized and collected on a computer with the use of specialized multimodality software.^34,35 Maximum physiological stability is generally observed at the time of application of clamps rather than removal, and therefore data from this period were used for analysis. For purposes of comparison, multivariable linear regression was used to calculate the correlation coefficient between (1) TOI and FV and (2) TOI and LDF. To account for baseline variation in TOI, interrupted time series analysis was applied, as described in our previous reports.^24,25 From these data a baseline threshold of 2% was derived, and therefore a TOI >2% was considered significant.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The values obtained before and after clamping of the ECA and ICA for all 60 patients are given in Table 1 and Table 1A. Of the 60 patients, a significant TOI was seen in 49 patients (mean=-9.4%; SD=7.1) accompanied by significant changes in FV. A significant correlation was seen between TOI and FV (r=0.56, P<0.0001; Figure 1). In contrast, there was no correlation between TOI and LDF (r=0.13; Figure 2).

View this table: [in this window] [in a new window]   Table 1. Baseline and Percent Change in FV, ABP, TOI, and LDF During Sequential Clamping for All 60 Patients*

View this table: [in this window] [in a new window]   Table 1A. Continued

View larger version (17K): [in this window] [in a new window]   Figure 1. Scatterplot of percent change in FV vs percent change in TOI from baseline to after application of ICA clamp for all 60 patients. The vertical dotted lines show the range outside of which TOI was considered significant.

View larger version (13K): [in this window] [in a new window]   Figure 2. Scatterplot of percent change in LDF vs percent change in TOI from baseline to after application of ICA clamp for all 60 patients.

In 31 patients, HbO₂ and Hb were recorded and analyzed offline. All showed significant concentration changes on both ECA and ICA clamping. Typical data obtained during carotid endarterectomy for an individual patient are demonstrated in Figure 3. Sequential clamping was performed with the ECA clamp being applied before the ICA clamp. LDF can be seen to fall only when the ECA clamp is applied. In this case, the drop in FV is seen to be specific to ICA clamping, as is the drop in TOI. On insertion of an ICA vascular shunt, FV and TOI were restored to values approaching baseline levels.

View larger version (25K): [in this window] [in a new window]   Figure 3. Data obtained from a patient during elective carotid endarterectomy. The vertical lines demonstrate time of application of vascular clamps.

Individual Patients
In all 60 patients, LDF showed a significant fall on clamping the ECA. Changes in TOI on ECA clamping were seen in 8 patients (Figure 4). Four patients (patients 17, 22, 26, and 36) experienced a concomitant and significant change in ABP with a related FV, and 2 (patients 33 and 60) showed an increase in ABP (mean=10%) with associated rises in TOI (mean=4.6%); in the remaining 2 patients (patients 5 and 29), a fall in FV accompanied the drop in TOI without change in ABP. In 9 patients, LDF dropped further on ICA clamping, with an associated fall in ABP occurring in 5.

View larger version (14K): [in this window] [in a new window]   Figure 4. Scatterplot of percent change in LDF vs percent change in TOI from baseline to after application of ECA clamp for all 60 patients. The vertical dotted lines show the range outside of which TOI was considered significant.

Significant changes in FV from baseline levels to after clamping of the ICA were seen in 7 patients, which were not associated with changes in TOI. In 3 patients (patients 45, 47, and 49) there was a drop in FV on clamping of both the ECA and ICA. In patient 51, both LDF and ABP fell significantly on application of the ICA clamp; and in patient 45, a 10% drop in FV from baseline to ICA clamping was accompanied by an 8% increase in ABP. Two others (patients 46 and 55) showed no fall in FV on ECA clamping, but on ICA clamping demonstrated a significant drop in FV (28% and 31%, respectively), with no accompanying change in TOI or ABP.

Sensitivity and Specificity
The sensitivity and specificity of TOI to intracranial changes (determined by observing FV on ICA clamping) were 87.5% and 100%, respectively (Table 2). The sensitivity and specificity of TOI to extracranial changes (detected by observing LDF on ECA clamping) were 13% and 0%, respectively (Table 3). When those patients who demonstrated significant changes in ABP during clamping and those highly suggestive of significant extracranial-to-intracranial collaterals (FV on ECA clamping) are excluded (n=8), the corrected sensitivity of TOI to extracranial changes is 0%.

View this table: [in this window] [in a new window]   Table 2. Contingency Table of Change in FV by Change in TOI on ICA Clamping

View this table: [in this window] [in a new window]   Table 3. Contingency Table of Change in LDF by Change in TOI on ECA Clamping

The positive predictive value for TOI in relation to intracranial changes is 1.0. The negative predictive value for TOI in relation to intracranial changes is 0.36. When those patients with unstable ABP and/or extracranial-to-intracranial collaterals are excluded, the corrected positive and negative predictive value for TOI in relation to extracranial changes is 0.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
This study has addressed the issue of extracranial contamination when NIRS is used to monitor the adult brain. Previous work has demonstrated that despite the use of large optode distances, there is still a significant contribution from the extracranial tissues.^24,36 Our approach has been to sequentially clamp the ECA and ICA during carotid endarterectomy, allowing the opportunity to separate the intracranial and extracranial signal contributions and to identify changes in the cutaneous circulation affecting the NIRS measurements.^25,30 We have previously found that once the extracranial component is subtracted, NIRS can accurately identify severe cerebral ischemia.¹ In defining the extracranial contribution to the NIRS signal, we have made the assumption that changes in skin blood flow, as detected by LDF, are representative of the majority of extracranial blood flow changes.

The hemodynamic effects of carotid stenosis are complex.^37,38 A previous study showed that cross flow at the anterior communicating artery toward the operative side, as determined by angiography, does not always protect from severe ischemia.³⁹ In some patients with carotid artery occlusion, the ECA may become a major source of blood flow to the cerebral tissues, particularly in cases in which the circle of Willis is incomplete. By comonitoring of intracranial and extracranial blood flow with transcranial Doppler sonography and LDF, respectively, these influences may be identified.

Relative changes in chromophore concentration and a quantified TOI are provided with the NIRO 300. In this study TOI was closely correlated with FV but not with LDF. The overall mean TOI (including those patients in whom TOI increased on clamping), was -9.4%. Most importantly, TOI was not seen without an associated FV. As expected, the typical biphasic changes seen with the chromophores HbO₂ and Hb on sequential clamping (Figure 4) correspond to the patterns we have previously identified with the NIRO 500, and TOI was only associated with ICA-related chromophore changes.^23,24 These observations lend further support to the contention that TOI is largely derived from the intracranial (ICA) vascular bed. The HbO₂ and Hb values derived by the NIRO 300 cannot reliably be taken to represent the intracranial compartment in the same way.

While the specificity of TOI to intracranial changes was found to be 100% (Table 2), the lower sensitivity (87.5%) reflects cases in which a fall in FV occurred in the absence of TOI (n=7). In addition to the contaminating influence of variable ABP, NIRS measurements from the frontal region may not always be representative of the ipsilateral ICA territory. In some cases the frontal cortex derives a blood supply from the contralateral ICA via the anterior communicating complex.⁴⁰ Hillen et al^41–44 suggested that the territorial distribution of the major cerebral arteries can be variable and that it may be difficult to define the most common territorial distribution. It is also known that the anterior communicating artery is absent in 2% of individuals and is <1 mm in diameter in 3%.⁴⁵ Thus, the divergence between TOI and FV may indicate differing cerebrovascular anatomy.

A divergence between FV and TOI may also reflect NIRS sampling from a composite tissue of arteries, capillaries, and veins. Quaresima et al²⁹ demonstrated good agreement between direct measurements of forehead TOI and calculated cerebral venous oxygen saturation during venous occlusion in adult volunteers. They concluded that the cerebral cortex hemoglobin oxygen saturation measured by the spatially resolved spectroscopy method reflects predominantly the saturation of the intracranial venous compartment. In addition, changes in ABP causing a reduction in FV may not be sufficient to effect oxygen desaturation, particularly if patients are metabolically suppressed under propofol anesthesia.

All 60 patients demonstrated a drop in LDF on clamping of the ECA (Table 3). For those patients in whom TOI was seen on clamping of the ECA (n=8), 5 were thought to be due to the ABP instability, which may be a reflection of baroreceptor stimulation during vascular clamping. In 2 cases a fall in FV on clamping the ECA was seen, with a similar drop in TOI while the ABP remained stable. We believe that these observations may reflect reverse flow from ECA to ICA via collaterals. Similar considerations can be applied to the situations in which LDF fell on application of the ICA clamp. In 1 patient an increase in FV was seen on ECA clamping, while ABP and TOI decreased. In this case, the lack of correlation between TOI, FV, and ABP cannot be explained by the presence of simple extracranial-to-intracranial anastomosis or ABP instability but may reflect more complex vascular anatomy and extracranial-to-intracranial connections.

In summary, by adopting a (relatively) stable clinical model for monitoring adult cerebral hemodynamic change, the study shows that the calculated TOI provided by the NIRO 300 reflects cerebral oxygenation to a high degree of sensitivity and specificity. Contaminating physiological and anatomic variables have been identified and excluded. Accurate quantification of the derived TOI against cerebral hemoglobin oxygen saturation is now required. In addition, confirmation that these findings apply in different clinical scenarios is needed, especially those in which scalp swelling (eg, trauma and postoperative patients) is present.

	Acknowledgments

 
The authors would like to thank K. Varty and M. Gaunt for their assistance with sequential clamping during the carotid endarterectomy and Hamamatsu Photonics K.K. for the loan of the NIRO 300 for the duration of this study.

Received January 22, 2001; revision received July 27, 2001; accepted August 7, 2001.

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