Abstract
A new technique known as tissue dye densitometry (TDD) has been developed to simultaneously measure cerebral blood volume (CBV) and total circulating blood volume (TCV) using near infrared (NIR) spatially resolved spectroscopy (SRS) and the injection of indocyanine green (ICG). Using a medical NIR spectrometer with SRS capability (NIRO-300, Hamamatsu KK), a new parameter is calculated known as the ICG Hb index (IHI), which represents the ratio of ICG concentration to Hb concentration in tissue. Acting as a tracer, ICG is cleared by the liver over 15 min, providing a change of tracer concentration (ΔCICG,tis), which allows the calculation of the total Hb concentration in tissue (tcHb) using the equation:tcHbtis (μ molar) = ΔCICG,tis/ΔIHI. The CBV can subsequently be calculated from tcHbtis given the absolute Hb concentration in blood (g/dL), from which the ICG concentration in blood (ΔCICG,bl) is obtained. By back-extrapolating the ΔCICG,bl curve to the peak time, the initial ICG concentration in tissue blood (C0ICG,bl) can be found and TCV can then be calculated. The TCV of 17 neonates were measured using the TDD technique and for comparison using the previously reported fetal Hb dilution technique (FHD). The mean TCV measured by the FHD and TDD techniques were 70.19 ± 13.73 mL/kg and 70.80 ± 32.54 mL/kg. The Bland Altman plot showed that the bias was 0.61 ± 34.34 mL/kg and limits of agreement (2 SD) were −68.07 mL/kg and 69.30 mL/kg. The agreement is limited and the TDD technique needs further validation and development for use in a clinical environment.
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Abbreviations
- CBV:
-
cerebral blood volume
- DPF:
-
differential pathlength factor
- FHD:
-
fetal Hb dilution
- ICG:
-
indocyanine green
- IHI:
-
ICG Hb index
- NIR:
-
near infrared
- PDD:
-
pulse dye densitometry
- SRS:
-
spatially resolved spectroscopy
- TCV:
-
total circulating blood volume
- TDD:
-
tissue dye densitometry
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Acknowledgements
The authors would like to thank all the patients and their parents participated in this study, medical and nursing staff in the NICU and the department of hematology Homerton University Hospital for their cooperation, the Wellcome Trust for funding (TSL), and Hamamatsu KK for providing a spectrometer.
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Funded by a grant from the Wellcome Trust (Grant 054762).
APPENDIX
APPENDIX
It has been reported that the preterm neonatal brain consists of 90% water (19) and the background optical absorption in cerebral tissues account for approximately 30% of the total absorption coefficient (16, 17). This background absorption includes all sorts of chromophores found in tissue including melanin, lipids and etc. The background absorption appears as a constant offset in the absorption coefficient over all wavelengths. In general in the NIR spectroscopy, we can consider 5 major chromophores in tissue: oxy-Hb, deoxy-Hb, ICG, water and background substances. Based on the modified Beer-Lambert law, we can write:
where μ^a(λ1) is the absorption coefficient at wavelength λ1, ε is the specific extinction coefficient of a chromophore, C is the concentration of the chromophore and b is a constant absorption coefficient representing the background absorption. In matrix form,
where
Using published data and data measured in our laboratory for the specific extinction coefficients for Hb (34, ICG and water (λ1=778 nm, λ2=813 nm, λ3=850 nm):
In this paper, we consider the background absorption to account for 22% of μ^a at all wavelengths and can be approximated by:
The NIRO-300 spectrometer used in these studies includes a measurement at a wavelength at 813 nm. The effect of the background absorption can be minimized by subtracting it from the calculated total μa. Equation 1 is now rewritten as:
where represents the absorption estimated to arise from the four known chromophores. The NIRO-300 spectrometer uses a measurement of attenuation gradients at 3 wavelengths to calculate μ^. The concentrations of the 3 chromophores (HHb, HbO2, and ICG) can then be estimated using least square minimization.
where Ĉ is the estimated concentrations and εR−1 is the inverse of the reduced matrix. Both matrices account for only HHb, HbO2, and ICG:
The estimated concentration based on a 3-wavelength SRS spectrometer becomes:
Solving the simultaneous equations results in,
It can be seen from Equation 7 that the estimated concentrations are affected by the volume assumed for the water content of the tissue. Assuming 90% water in neonatal brains (recall 100% pure water corresponds to 55.4 Molar), CH2O can be calculated
Substituting Equations 7 and 8 into the expression for ΔIHI, we obtain:
The above result shows that if no correction is made for the effects of water absorption, then using ΔIHI and ΔCICG to estimate tcHb will lead to an over-estimate of 15.15 μ molar. To compensate for this offset, in this paper the value obtained from the expression tcHb = ΔCICG/ΔIHI has been corrected by subtracting 15.15 μ mol. To assess the sensitivity of the results obtained to the assumptions made in these calculations, we have looked at the sensitivity of the correlation coefficient and the mean difference between TCVTDD and TCVFHD over a range of different values of water content (70% to 95%) and assumed background absorption contribution (5% to 35%). A high correlation coefficient (>0.8) was maintained with water content variation over the whole range (70% to 95%) and for background absorptions of <35%. The mean difference was as high as 42.09 mL with the rather un-physiologic assumptions of a background absorption = 5% and water content = 70%. The mean difference changed by −1.68 mL per % change in background absorption and by −0.70 mL per % for the water content. The minimum mean difference (0.0219 mL) was obtained when the water content = 85% and the background absorption = 24%, close to the values of 90% and 22% used in this paper and derived from independently measured data (16, 19).
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Leung, T., Aladangady, N., Elwell, C. et al. A New Method for the Measurement of Cerebral Blood Volume and Total Circulating Blood Volume Using Near Infrared Spatially Resolved Spectroscopy and Indocyanine Green: Application and Validation in Neonates. Pediatr Res 55, 134–141 (2004). https://doi.org/10.1203/01.PDR.0000099775.87684.FB
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DOI: https://doi.org/10.1203/01.PDR.0000099775.87684.FB
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