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1 November 2007 Clinical evaluation of time-resolved spectroscopy by measuring cerebral hemodynamics during cardiopulmonary bypass surgery
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We developed a three-wavelength time-resolved spectroscopy (TRS) system, which allows quantitative measurement of hemodynamics within relatively large living tissue. We clinically evaluated this TRS system by monitoring cerebral circulation during cardiopulmonary bypass surgery. Oxyhemoglobin, deoxyhemoglobin, total hemoglobin and oxygen saturation (SO2) were determined by TRS on the left forehead attached with an optode spacing of 4 cm. We also simultaneously monitored jugular venous oxygen saturation (SjvO2) and arterial blood hematocrit (Hct) using conventional methods. The validity and usefulness of the TRS system were assessed by comparing parameters obtained with the TRS and conventional methods. Although the changes in SO2 were lower than those in SjvO2, SO2 obtained by TRS paralleled the fluctuations in SjvO2, and a good correlation between these values was observed. The only exceptions occurred during the perfusion period. Moreover, there was a good correlation between tHb and Hct values (r2=0.63). We concluded that time-resolved spectroscopy reflected the conditions of cerebral hemodynamics of patients during surgical operations.



Near-infrared spectroscopy (NIRS) at a wavelength between 700 and 900nm is useful for continuously and noninvasively assessing the oxygenation state in vivo. This method is based on the relatively high tissue transparency of near-infrared light in addition to hemoglobin absorption in the region. There are many reports on the clinical applications of NIRS, such as monitoring cerebral oxygen metabolism during surgery1, 2 or for the respiratory management of neonates.3, 4 In particular, it may prove useful to monitoring cerebral circulation during cardiac surgery under extracorporeal circulation, which is associated with high risks of cerebral ischemia, embolism, hyperperfusion after release from the artificial heart-lung machine, and cerebral complications such as postoperative deterioration of neural recognition.5, 6 Commercially available NIRS monitors have been used for comparing oxygen saturation (SO2) with internal jugular vein oxygen saturation (SjvO2) 7, 8, 9, 10, 11, 12, 13, 14 or electroencephalographs15, 16, 17 and for assessing changes in blood volume.18

However, the NIRS apparatus used employs continuous wave (CW) near-infrared light. Therefore, absolute values of hemoglobin concentration and highly reproducible SO2 cannot be obtained. To overcome these difficulties, more sophisticated technologies have been introduced.

Phase modulation spectroscopy (PMS) 19, 20, 21, 22, 23 and time-resolved spectroscopy (TRS) 24, 25, 26, 27 have been developed for this purpose. However, these new technologies have not been evaluated in detail in a clinical study.28

In TRS, the distribution of optical path lengths is directly measured. Its temporal profile is analyzed using a photon diffusion equation25 and the Microscopic Beer-Lambert law,29 thereby enabling determination of the hemoglobin concentration.

Our three-wavelength time-resolved spectroscopy system (TRS-10)30 was tested in cardiopulmonary bypass surgery, during which the absolute concentrations of oxygenated, deoxygenated, and total hemoglobin were estimated. SO2 was simultaneously calculated as a percentage of oxygenated hemoglobin of total hemoglobin. The optically estimated values were compared with those of SjvO2 and hematocrit (Hct) in arterial blood. The validity and usefulness of our optical measurements are demonstrated in this clinical study.


Materials and Methods


Experimental Procedure

Twenty-three patients (mean age 63.4±12.3 ; 15 men, 8 women) who underwent coronary-artery bypass surgery in Kagoshima University Hospital were subjected to the study. Before surgery, blood was drawn in installments. Body temperature was controlled to achieve a mild hypothermic condition (32°C) using α -stat regulation.

After anesthesia, the optical probes connected to the time-resolved spectroscopy system (TRS-10) were attached to the left forehead with an optode distance of 4cm . Each sampling time was 10s , and HbO2 , Hb, tHb, and SO2 were continuously measured for 5min (resting conditions). In 9 of the 23 patients (mean age 65.00±9.4 ; 8 men, 1 woman), the TRS measurements were continued until the surgery was completed. Arterial blood was collected from those patients during surgery, through a 20-gauge catheter placed in the radial artery. Their Hct values were determined from the arterial hemoglobin concentration (Hg) by blood gas analysis (ABL 2; Radiometer, Copenhagen, Denmark) as follows:

Eq. 1

where Hct is the hematocrit [%], Hg is the arterial hemoglobin concentration [g/dl], and MCHC is the mean corpuscular hemoglobin concentration [g/L]; the standard value is 332.

In 6 of the 9 patients (mean age 64.5±6.5 ; 5 men, 1 woman), SjvO2 was also measured using a 5.5 Fr Opticathe (Abbott Critical Care Systems, Mountain View, California) that was regressively placed in the left internal jugular vein bulb.


Time-Resolved Spectroscopy System (TRS-10)

Our time-resolved spectroscopy system (TRS-10) uses the time-correlated single photon counting (TCPC) method to measure the temporal profile of the detected photons, as shown in Fig. 1 . The apparatus is described elsewhere.30

Fig. 1

(a) Appearance of TRS-10 (Hamamatsu Photonics K.K.). (b) Block diagram of the TRS-10 system.


In brief, the system consists of a three-wavelength ( 759nm , 797nm , and 833nm ) light pulser (PLP, Hamamatsu Photonics K.K., Hamamatsu, Japan) as the light source, which generates light pulses with a peak power of 60mW , pulse width of 100ps , pulse rate of 5MHz , and an average power of 30μW . For the detection, a photomultiplier tube (PMT, H6279-MOD, Hamamatsu Photonics K.K.), a constant fraction discriminator (CFD), a time-to-amplitude converter (TAC), an A/D converter, and a histogram memory were all assembled. The three PLPs emit light pulses on a time series, and three-wavelength light pulses are guided into one illuminating optical fiber by a fiber coupler (CH20G-D3-CF, Mitsubishi Gas Chemical Company, Inc., Japan). A single optical fiber (GC200/250L, Fujikura Ltd., Japan) with a numerical aperture (N.A.) of 0.21 and a core diameter of 200μm was used for illumination. An optical bundle fiber (LB21E, Moritex Corporation, Japan) with an N.A. of 0.21 and a bundle diameter of 3mm was used to collect diffuse light from the tissues.


Data Analysis

TRS allows the determination of relative light intensity, mean optical path length, scattering coefficient (μs) , and absorption coefficient (μa) .

The intensity can be obtained by integrating the temporal profiles and modified Beer-Lambert law (MBL) uses this information to calculate the absorbance changes. The mean optical path lengths were calculated from the center of gravity of the temporal profile.31

Applying the diffusion equation for semi-infinite homogeneous media with zero boundary condition in reflectance mode25 into all the observed temporal profiles, we obtained the values of μs and μa using the nonlinear least-squares method.32

We first assumed that absorption in the 700 to 900nm range arises from oxygenated hemoglobin (HbO2) , deoxygenated hemoglobin (Hb), and water. The contributions of myoglobin and cytochrome oxidase could be ignored. The μaλ of the measured wavelengths λ (759, 797, and 833nm ) is expressed as shown in simultaneous Eq. 2:


where εmλ is the molar extinction coefficient of substance m at wavelength λ , and Cm is the concentration of substance m . The water absorption (μaH2Oλ) was measured using a conventional spectral photometer (U-3500, Hitachi High-Technologies Corporation).

After subtracting the water absorption from μa at each wavelength assuming that volume fraction of the water content was constant,33 we determined the concentrations of HbO2 and Hb using the least-squares fitting method.

The total concentrations of hemoglobin (tHb) and oxygen saturation (SO2) were calculated from Eqs. 3, 4:

Eq. 3


Eq. 4



Statistical Analysis

All the numerical data are presented as the mean value ± standard deviation (SD). The correlation of SO2 and SjvO2 was evaluated with Pearson’s correlation coefficient. The Bland-Altman test was also used to study the agreement between SO2 and SjvO2 . The precision of the bias estimate was defined as 2 SD of the mean difference. The correlation of Hct and tHb was evaluated with Pearson’s correlation coefficient, assuming that the cerebral blood volume is constant during surgery.



The variations of mean optical path length, μs , tHb, and SO2 in 23 patients under resting conditions are plotted against age, as shown in Fig. 2 . The mean optical path length was 30.4±2.8cm , μs was 10.0±0.8cm1 , tHb was 42.1±9.2μM , and SO2 was 67.3±3.8% . SO2 varied the least among the patients, while the tHb varied significantly.

Fig. 2

The variations of (a) mean optical path length, (b) μs , (c) tHb, and (d) SO2 in 23 patients under resting conditions are plotted against age.


Figure 3 shows a typical case (Case 4, F, 63Y) of photon count rates (light intensity), mean optical path lengths, μs , and μa at three wavelengths during coronary-artery bypass surgery. These values (except μs ) changed significantly due to hemodilution during extracorporeal circulation.

Fig. 3

Time course of TRS-10 parameters during surgery in a typical case (Case 4: F, 63Y): (a) count rate, (b) mean optical path length, (c) μs , and (d) μa . H: drawing arterial blood to determine hematocrit (Hct).


Figure 4 shows the relationship between the TRS parameters ( μa , μs , and the mean optical path length at three wavelengths) and the Hct value of arterial blood collected during surgery in a typical case (Case 4, F, 63Y). In this patient, the Hct value at the beginning of surgery was 23% but decreased to a minimum of 12% during extracorporeal circulation. μa changed linearly in relation to Hct changes, while μs remained almost unchanged. The mean optical path length increased with the decrease of Hct.

Fig. 4

Relationship TRS parameters at three wavelengths and hematocrit (Hct) value in the typical case (Case 4: F, 63Y): (a) μa , (b) μs , and (c) mean optical path length.


Figure 5a shows the time course of changes in the concentration of HbO2 , Hb, and tHb, and the SO2 and SjvO2 are shown in Fig. 5b. When extracorporeal circulation was started, HbO2 and tHb decreased abruptly, together with decreases in SO2 . After the release of extracorporeal circulation, those values returned to the initial levels.

Fig. 5

Hemoglobin concentrations and SO2 as measured by TRS-10 during surgery in the typical case (Case 4: F, 63Y): (a) HbO2 , Hb, and tHb; (b) TRS SO2 , SjvO2 . H: in arterial blood drawn to determine Hct.


The SO2 estimated by TRS was nearly the same as that of SjvO2 before extracorporeal circulation, but during circulation, they behaved differently. Especially when rewarming was carried out, SO2 did not vary as much as SjvO2 .

Figure 6 shows that fluctuations in SO2 and SjvO2 were separated during extracorporeal circulation in one case (Case 3, M, 52Y). The values of SjvO2 increased significantly when the pump was on, whereas SO2 decreased rapidly.

Fig. 6

Fluctuations of SO2 and SjvO2 were separated during extracorporeal circulation in one patient (Case 3: M, 52Y). When the pump was on, the values of SjvO2 increased significantly. Meanwhile, those of SO2 decreased rapidly. (a) HbO2 , Hb, and tHb; (b) TRS SO2 , SjvO2 . H: in arterial blood drawn to determine Hct.


Figure 7 shows the correlation between the Hct in arterial blood and tHb in nine patients. The correlation among patients was high, with r2=0.63 , showing that tHb measured by TRS has a good linearity with Hct. In addition, intraindividual correlations were also very high ( r2=0.72±0.22 ; data is not shown).

Fig. 7

Relationship between tHb by TRS-10 and hematocrit (Hct) in nine patients.


Figure 8 shows the linear regression plot and the Bland-Altman plot of SO2 and SjvO2 for all data of six patients: during the whole surgery (a), during the surgery except perfusion (b), during partial perfusion (c), and during total perfusion (d). The correlation coefficients were r2=0.33 in (a), r2=0.46 in (b), r2=0.29 in (c), and r2=0.42 in (d). The bias and the precision ( ±2 SD) were 0.66±19.6% in (a), 2.90±18.7% in (b), 0.92±16.5% in (c), and 5.21±17.9% in (d). The correlation coefficient in (c) and bias in (d) were lower than those in other stages of the operation. This variation was split into inter- and intraindividual analysis, and the results of correlation, bias, and precision among six patients and the mean of these values within six patients are shown in Table 1 . Precisions become smaller for intraindividual analysis, although biases did not show such changes.

Fig. 8

Linear regression correlation between SO2 and SjvO2 (upper) and difference plots for SO2 and SjvO2 using the Bland-Altman method (lower) in all data points of six patients: (a) during the whole surgery, (b) during the surgery except perfusion, (c) during partial perfusion, and (d) during total perfusion.


Figure 9a shows the plot of the μs during the surgery in one patient (Case 5, M, 69Y). The μs decreased gradually during perfusion only in this case. The other eight patients did not show such changes of μs during surgery [Fig. 9b, Case 7, M, 66Y].

Fig. 9

(a) μs decreased gradually during perfusion in one case (Case 5: M, 69Y). This trend was observed only in this case. (b) μs remained unchanged in a typical case (Case 7: M, 66Y). A similar pattern was observed in the other eight patients except Case 5.


Table 1

The correlation and agreement between SO2 and SjvO2 .

Mean for each patient (n=6) All individual values
r2 BiasPrecision r2 BiasPrecision
(a) During surgery0.231.29 ±14.72 0.330.66 ±19.6
(b) Except perfusion0.473.52 ±12.35 0.462.90 ±18.7
(c) Partial perfusion0.412.88 ±9.52 0.290.92 ±16.5
(d) Total perfusion0.20 5.73 ±9.79 0.42 5.21 ±17.9



In the present study, the observed values of tHb showed wide variation in resting conditions, reflecting different preoperative blood drawing for each patient. In contrast, SO2 in resting conditions was very similar among patients. This parameter, which is independent of patient age and Hct, is very useful for monitoring the brain tissue oxygenation of each patient.

During surgery under extracorporeal circulation, the Hct value decreased further due to hemodilution to prevent the formation of thrombi. The various parameters (count rate, mean optical path length, μa ) determined by TRS and tHb responded well to changes in such hemodilution as shown in Figs. 3 and 4. In particular, μa varied linearly with Hct. Although several conventional approaches use CW-methods that assume a constant value of the mean optical path length in the calculation, it should be noted that there are large fluctuations among the patients. Thus, the quantitative measurements employed here are necessary to continuously monitor the condition of patients during the operation. Although μa and the mean optical path length were affected by Hct changes, μs showed almost constant values without being affected by Hct changes. This result supports the proposition that absorption and scattering can be handled independently.

In this study, we observed the decrease of μs during perfusion in one patient, as shown in Fig. 9a. The trend of HbO2 , Hb, tHb, and SO2 were not much different from other cases. System drift was significantly smaller than the change in μs of the patient. The chief contributor to the scattering of tissues is their organelle contents such as mitochondria, endo-plasmic reticulum, nucleus, and so forth.34 There are reports on the relationship between the μs and the developmental stages of a newborn baby’s brain.35 Moreover, change in μs of a piglet brain caused by the depolarization has been demonstrated when the piglets were exposed to hypoxia.27, 36 The possibility of inducing scattering changes by almost any kind of solute (particularly glucose, mannitol, and sucrose) has been suggested.34 Although more research is necessary for ascertaining the clinical implications of scattering change, it has been reported that such information is important. 27, 34, 35, 36 It may be used to prevent risks leading to brain damage, such as cerebral edema.

We have demonstrated the usefulness of our TRS system for monitoring the state of brain oxygenation, as well as tissue optical parameters related to physiological conditions of cerebral tissue. The TRS allows the quantification of HbO2 , Hb, and tHb of the brain. Both correlations between Hct and tHb within patients and among patients were high, even though the anatomical structure such as the thicknesses of the scalp and skull might be different in individuals. The effect of the outer layer may be smaller in time-resolved spectroscopy than that of the conventional CW method.37, 38

The trends of SO2 and SjvO2 matched during the surgery. Especially in the rewarming period, both values temporarily declined (Figs. 5 and 6), reflecting the oxygen demand-supply imbalance due to the increased metabolism of the brain and temperature effect on the hemoglobin dissociation curve. However, the SjvO2 value changed between approximately 40% and 90%, while the SO2 value changed within 50% and 80%. Thus, the SO2 variation tended to be smaller than the SjvO2 variation. In addition, the correlation and bias between the SO2 and SjvO2 also differed depending on the conditions of extracorporeal circulation, although a good correlation was observed except for perfusion for the period. These values do not necessarily match, as seen in Fig. 6, because SjvO2 shows a balance between blood flow and metabolism in the whole brain, making it difficult to measure very small changes. Moreover, there is a report of increase in the shunt of arterial and venous blood flow,10 resulting in increase of SjVO2 .

In contrast, the TRS may be able to perform localized tissue measurements. Thus, the SO2 is not necessarily higher than the SjvO2 , due to the SO2 showing average saturation of arterial, capillary, and venous blood, because the SjvO2 shows information of the whole brain hemodynamics, including the deeper region that extracts less oxygen than the neocortex region.12 Some studies on the correlation between NIRS SO2 and SjvO2 have shown that it almost matches,7, 28 while others have shown that it does not. 8, 9, 12, 39 The contradiction between these results is attributable to surgery without extracorporeal circulation or differences in the method of inducing anesthesia or the temperature control conditions.

SjvO2 is used as an indicator of cerebral oxygenation, where higher SjvO2 shows better oxygenation conditions. However, there is a report of postoperative disturbance of higher brain functions in patients who showed high SjvO2 during extracorporeal circulation.40 Therefore, the judgment of normoxia-hypoxia by SjvO2 may be insufficient, and simultaneous measurements of SO2 by TRS can give more accurate information about the oxygenation conditions of patients.



We have developed a time-resolved spectroscopy system (TRS-10) and have used it in cardiopulmonary bypass surgery as a brain oxygenation monitor. SO2 measured by TRS paralleled fluctuations in SjvO2 , although these correlations depended on the perfusion conditions. Further detailed studies are necessary to clarify the relation between these values.

A good correlation was noted between tHb by TRS and Hct value (12% to 37.8%) in arterial blood (r2=0.63) . Intra-cerebral hemodynamics of patients were captured well by TRS in real time and noninvasively.

Consequently, our results indicate that TRS is a valid spectroscopic method for quantifying cerebral hemodynamics and is useful for clinical monitoring.

Clarification of the relationship between μs and the pathological condition of the patient and improvement of the analytical approach 40, 41, 42, 43 for measuring deeper regions are future challenges.


The authors would like to thank T. Hiruma and Y. Suzuki for their constant support and encouragement.



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©(2007) Society of Photo-Optical Instrumentation Engineers (SPIE)
Etsuko Ohmae, Motoki Oda, Toshihiko Suzuki, Yutaka Yamashita, Yasuyuki Kakihana M.D., Akira Matsunaga, Yuichi Kanmura, and Mamoru Tamura "Clinical evaluation of time-resolved spectroscopy by measuring cerebral hemodynamics during cardiopulmonary bypass surgery," Journal of Biomedical Optics 12(6), 062112 (1 November 2007).
Published: 1 November 2007

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