Abstract
Light-based approaches to the assessment of a tissue’s oxygen status are attractive to the clinician because they provide the possibility of continuous noninvasive measurements. For example, pulse oximetry, which relies on emission and absorption of light in red and infrared frequencies (660 and 940 nm, respectively), has become widely used in clinical practice. Near-infrared (NIR) spectroscopy technology takes this further and uses light in the near-infrared range (700 to 1000 nm). This chapter reviews the principles of NIR spectroscopy, quantifies physiologic variables, and reports clinically relevant observations that have been made using this technology. Three different methods of using NIR light for monitoring tissue oxygenation that are currently used—(1) continuous wave method, (2) time-of-flight method, and (3) frequency domain method—have been described, along with techniques used to measure oxygen delivery and consumption in cerebral and peripheral tissue.
Keywords
method, near infrared spectroscopy, principles
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Continuous quantitative measurements desirable for clinical practice were not possible using original continuous wave instruments for several years.
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Spatially resolved spectroscopy is a development of NIRS which allowed continuous measurements.
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Large interindividual and intraindividual differences between absolute values from different monitors have been reported requiring further technological developments in the field.
Light-based approaches to the assessment of a tissue’s oxygen status are attractive to the clinician because they provide the possibility of continuous noninvasive measurements. For example, pulse oximetry, which relies on emission and absorption of light in red and infrared frequencies (660 and 940 nm, respectively), has become widely used in clinical practice. However, this technology measures only hemoglobin oxygen saturation, which is variably related to the partial pressure of oxygen in arterial blood and not oxygen delivery. The arterial oxygen saturation is estimated by measuring the transmission of light through the pulsatile tissue bed; the microprocessor analyzes the changes in light absorption due to pulsatile arterial flow and ignores the component of the signal that is nonpulsatile that results from blood in the veins and tissues. Near-infrared (NIR) spectroscopy technology takes this further and uses light in the NIR range (700 to 1000 nm).
Using one NIR spectroscopy technique (the continuous wave method with partial venous occlusion, described in more detail later), venous oxygen saturation ( S v o 2 ) can be determined, and, from this, oxygen delivery and consumption can be measured. Blood flow can also be measured by continuous wave NIR spectroscopy and the Fick approach, either with a bolus of oxygen or with dye. However, these methods allow only for intermittent measurements, and, more recently, another NIR spectroscopy technique (the time-of-flight method, also described in more detail later) has been used to measure an index of tissue oxygenation continuously. Cytochrome activity can also be assessed, but this has not been used in any regular clinical or even research application.
NIR spectroscopy instrumentation consists of fiber optic bundles or optodes placed either on opposite sides of the tissue being interrogated (usually a limb or the head of a baby) to measure transmitted light or close together to measure reflected light. Light enters through one optode, and a fraction of the photons are captured by a second optode and conveyed to a measuring device. Multiple light emitters and detectors can also be placed in a headband to provide tomographic imaging of the brain.
This chapter reviews the principles of NIR spectroscopy, quantifies physiologic variables, and reports clinically relevant observations that have been made using this technology. Clinical aspects of the use of NIR spectroscopy in neonatology are discussed in Chapter 18 .
Principles of Near-Infrared Spectroscopy
NIR spectrophotometers are applied in the food industry, geologic surveys, and in laboratory analysis. Jöbsis et al. first introduced its use for human tissue in 1977. Since 1985 NIR spectrophotometers have been used in newborn infants.
NIR spectroscopy relies on three important phenomena:
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Human tissue is relatively transparent to light in the NIR region of the spectrum.
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Pigmented compounds known as chromophores absorb light as it passes through biologic tissue.
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In tissue, there are compounds whose absorption differs depending on their oxygenation status.
Human tissues contain a variety of substances whose absorption spectra at NIR wavelengths are well defined. They are present in sufficient quantities to contribute significant attenuation to measurements of transmitted light. The concentration of some absorbers, such as water, melanin, and bilirubin, remains virtually constant with time. However, the concentrations of some absorbing compounds, such as oxygenated hemoglobin (HbO 2 ), deoxyhemoglobin (HbR), and oxidized cytochrome oxidase (Cyt aa3), vary with tissue oxygenation and metabolism. Therefore changes in light absorption can be related to changes in the concentrations of these compounds.
Dominant absorption by water at longer wavelengths limits spectroscopic studies to less than approximately 1000 nm. The lower limit of wavelength is dictated by the overwhelming absorption of HbR less than 650 nm. However, between 650 and 1000 nm, it is possible with sensitive instrumentation to detect light that has traversed 8 cm of tissue.
The absorption properties of hemoglobin alter when it changes from its oxygenated to its deoxygenated form. In the NIR region of the spectrum, the absorption of the hemoglobin chromophores (HbR and HbO 2 ) decreases significantly compared with that observed in the visible region. However, the absorption spectra remain significantly different in this region. This allows spectroscopic separation of the compounds using only a few sample wavelengths. HbO 2 has its greatest absorbency at 850 nm. Absorption by HbR is maximum at 775 nm, so measurement at this wavelength enables any shift in hemoglobin oxygenation to be monitored. The isosbestic points (the wavelength at which light absorbance of a substance is constant during a chemical reaction) for HbR and HbO 2 are at 590 and 805 nm, respectively. These points may be used as reference points where light absorption is independent of the degree of saturation.
The major part of the NIR spectroscopy signal is derived from hemoglobin, but other hemoglobin compounds, such as carboxyhemoglobin, also absorb light in the NIR region. However, the combined error due to ignoring these compounds in the measurement of the total hemoglobin (HbT) signal is probably less than 1% in normal blood. Nevertheless, when monitoring skeletal muscle using NIR spectroscopy, myoglobin and oxymyoglobin must also be considered because their NIR absorbance characteristics are similar to hemoglobin.
Near-Infrared Spectrophotometers
Three different methods of using NIR light for monitoring tissue oxygenation are currently used:
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Continuous wave method
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Time-of-flight method (also known as time-domain or time-resolved)
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Frequency domain method
The continuous wave method has a very fast response but registers relative change only, and it is therefore not possible to make absolute measurements using this technique. Nevertheless, these instruments have been widely used for research studies. The time-of-flight method needs extensive data processing but provides more accurate measurements. It enables one to explore different information provided by the measured signals and has the potential to become a valuable tool in research and clinical environments. The third approach, which uses frequency domain or phase modulation technology , has a lower resolution than that of the time-of-flight method but has the potential to provide estimates of oxygen delivery sufficiently quickly for clinical purposes. Thus frequency domain or phase modulation technology is potentially the best candidate in the neonatal intensive care setting and for bedside use. The principles used in the three methods are described later.
Continuous Wave Instruments
In continuous wave spectroscopy, changes in tissue chromophore concentrations from the baseline value can be obtained from the modified Beer-Lambert law. The original Beer-Lambert law describes the absorption of light in a nonscattering medium and states that, for an absorbing compound dissolved in a nonabsorbing medium, the attenuation is proportional to the concentration of the compound in the solution and the optical pathlength. Therefore A = E × C × P , where A = absorbance (no units), E = extinction coefficient or molar absorptivity (measured in L/mol/cm), P = pathlength of the sample (measured in cm), and C = concentration of the compound (measured in mol/L). Wray and colleagues characterized the extinction coefficient of hemoglobin and HbO 2 between the wavelengths of 650 and 1000 nm. The extinction coefficients determined by them at four specific wavelengths are as shown in Table 17.1 . Mendelson and colleagues showed that the absorption coefficients of fetal and adult hemoglobin are virtually identical.
| Wavelength (nm) | HbO 2 | Hb |
|---|---|---|
| 772 | 0.71 | 1.36 |
| 824 | 0.983 | 0.779 |
| 844 | 1.07 | 0.778 |
| 907 | 1.2520 | 0.892 |
However, the application of the Beer-Lambert law in its original form has limitations. Its linearity is limited by:
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Deviation in the absorption coefficient at high concentrations (>0.01 M) due to electrostatic interaction between molecules in close proximity; fortunately, such concentrations are not met in biologic media;
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Scattering of light due to particulate matter in the sample; and
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Ambient light.
When light passes through tissue, it is scattered because of differences in the refractive indices of various tissue components. The effect of scattering is to increase the pathlength traveled by photons and the absorption of light within the tissue. Cell membranes are the most important source of scattering. In neonates, skin and bone tissue become important when the optodes are placed less than 2.5 cm apart.
Thus for light passing through a highly scattering medium, the Beer-Lambert law has been modified to include an additive term, K , due to scattering losses, and a multiplier to account for the increased optical pathlength due to scattering.
Where the true optical distance is known as the differential pathlength (DP), P is the pathlength of the sample, and the scaling factor is the DP factor ( L ): thus DP = P × L . The modified Beer-Lambert law, which incorporates these two additions, is then expressed as A = P × L × E × C + K , where A is absorbance, P is the pathlength, E is the extinction coefficient, C is the concentration of the compound, and K is a constant. Unfortunately, K is unknown and is dependent on the measurement geometry and the scattering coefficient of the tissue investigated. Hence this equation cannot be solved to provide a measure of the absolute concentration of the chromophore in the medium. However, if K is constant during the measurement period, it is possible to determine a change in concentration (Δ C ) of the chromophore from a measured change in attenuation (Δ A ). Therefore Δ A = P × L × E × Δ C , or
Δ C = Δ A / P × L × E
The DP factor describes the actual distance traveled by light. Because it is dependent on the amount of scattering in the medium, its measurement is not straightforward. The DP factor has been calculated on human subjects of different ages and in various tissues. Van der Zee and colleagues and Duncan and colleagues conducted optical pathlength measurements on human tissue and their results are as shown in Table 17.2 .
| Van der Zee et al. | Duncan et al. | |
|---|---|---|
| Preterm head | 3.8 ± 0.57 | — |
| Term head | — | 4.99 ± 0.45 |
| Adult forearm | 3.59 ± 0.78 | 4.16 ± 0.78 |
There is a small change in optical pathlength with gestation, but this is negligible and a constant relationship is assumed. Despite gross changes in oxygenation and perfusion before and after death in experimental animals, the optical pathlength at NIR wavelengths was found to be nearly constant (maximum difference <9%).
In a medium containing several chromophores ( C 1 , C 2 , and C 3 ) the overall absorbance is simply the sum of the contributions of each chromophore. Therefore:
A = ( E 1 C 1 + E 2 C 2 + E 3 C 3 ) P × L
For a medium containing several chromophores C 1 , C 2 , C 3 :
Δ C 1 = Q 1 Δ A 1 + R 1 Δ A 2 + S 1 Δ A 3 + T 1 ΔA 4
Δ C 2 = Q 2 Δ A 1 + R 2 Δ A 2 + S 2 Δ A 3 + T 2 Δ A 4
Δ C 3 = Q 3 Δ A 1 + R 3 Δ A 2 + S 3 Δ A 3 + T 3 Δ A 4
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