In Vitro Validation of a New Tissue Oximeter Using Visible Light.

There is a clinical need to measure local tissue oxygen saturation (StO2), oxy-, deoxy- and total haemoglobin concentration ([O2Hb], [HHb], [tHb]) in human tissue. The aim was to validate an oximeter called OxyVLS applying visible light spectroscopy (VLS) to determine these parameters without needing to assume a reduced scattering coefficient (µ's). This problem is solved by appropriate calibrations. Compared to near-infrared spectroscopy (NIRS), OxyVLS determines the oxygenation in a much smaller more superficial volume of tissue, which is useful in many clinical cases. OxyVLS was validated in liquid phantoms with known StO2, [tHb], and µ's and compared to frequency domain NIRS as a reliable reference. OxyVLS showed a high accuracy for all the mentioned parameters and was even able to measure µ's. Thus, OxyVLS was successfully tested in vitro.

Not Removing the Glossy White Cover from Adhesive INVOS Neonatal Sensors Affects the Oxygenation Measurement.

The randomized clinical trial, SafeBoosC III, evaluates the effect of treatment guided by cerebral tissue oximetry monitoring in extremely preterm infants. Treatment should be considered, when cerebral oxygen saturation (StO2) drops below a predefined hypoxic threshold. This threshold value differs between different brands of instruments. To achieve high external validity, in this pragmatic trial all commercially available cerebral tissue oximeters have been accepted, provided their specific hypoxic threshold value has been determined in phantom studies. Since most companies produce sensors with an adhesive surface on the patient-contacting side, in the phantom studies these sensors were applied according to the specifications, i.e., the glossy cover was removed from the sensor. However, since the skin of preterm infants is particularly fragile, some neonatologists keep this cover on the adhesive sensors, to avoid the risk of skin injury when removing the sensor. Therefore, the aim of this study was to determine whether keeping this cover on leads to different StO2 values. To evaluate the effect of the cover, we performed multiple deoxygenations in a blood-lipid phantom and compared an INVOS neonatal sensor (Medtronic), with and without the cover, to a reference oximeter (OxiplexTS, ISS). As expected, the relationship of the StO2 between the INVOS neonatal sensor and OxiplexTS was linear (r2 = 0.999) with and without cover, but the cover influenced the linear equation: StO2_INVOS_cover = 1.133*StO2_ISS + 7.1 as opposed to StO2_INVOS_nocover = 1.103*StO2_ISS + 12.0. Furthermore, the hypoxic SafeBoosC III threshold differed as well: 60.3% with cover and 63.8% without cover. In conclusion, keeping the adhesive cover on an INVOS neonatal sensor results in lower measured values. At the hypoxic threshold, this is more than 3% (from 60.3% to 63.8%), and therefore, if clinicians keep the cover on the sensor, they need to be aware of this difference.

Cerebral hemodynamic responses in preterm-born neonates to visual stimulation: classification according to subgroups and analysis of frontotemporal-occipital functional connectivity.

How neurovascular coupling develops in preterm-born neonates has been largely neglected in scientific research. We measured visually evoked (flicker light) hemodynamic responses (HRs) in preterm-born neonates ( n = 25 , gestational age: 31.71 ± 3.37 weeks, postnatal age: 25.48 ± 23.94 days) at the visual cortex (VC) and left frontotemporal lobe (FTL) using functional near-infrared spectroscopy (fNIRS) neuroimaging. We found that the HR characteristics show a large intersubject variability but could be classified into three groups according to the changes of oxyhemoglobin concentration at the VC [(A) increase, (B) decrease, or (C) inconclusive]. In groups A and B, the HRs at the left FTL were correlated with those at the VC, indicating the presence of a frontotemporal-occipital functional connectivity. Neonates in group A had a higher weight at measurement compared to those in group B, and had the lowest baseline total hemoglobin concentration and hematocrit compared to group C. To the best of our knowledge, this is the first fNIRS study showing (1) that the HRs of preterm-born neonates need to be classified into subgroups, (2) that the subgroups differed in terms of weight at measurement, and (3) that HRs can be observed also at the FTL during visual stimulation. These findings add insights into how neurovascular coupling develops in preterm-born neonates.

Absorption spectra of early stool from preterm infants need to be considered in abdominal NIRS oximetry.

Necrotizing enterocolitis (NEC) is the most common gastrointestinal emergency of the preterm infant. Low abdominal tissue oxygen saturation (StO2) measured by near-infrared spectroscopy (NIRS) oximetry may be an early sign of NEC relevant for treating or even preventing NEC. However, current commercial NIRS oximeters provide inaccurate StO2 readings because they neglect stool as an abdominal absorber. To tackle this problem, we determined the optical properties of faeces of preterm infants to enable a correct abdominal StO2 measurement. In 25 preterm born infants (median age 31 0/7 ± 2 1/7 weeks, weight 1478 ± 511 g), we measured their first five stool probes with a VIS/NIR spectrometer and calculated the optical properties using the Inverse Adding Doubling (IAD) method. We obtained two absorption spectra representing meconium and transitional stool. Probabilistic cluster analysis correctly classified 96 out of 107 stool probes. The faeces spectra need to be considered to enable correct abdominal StO2 measurements with NIRS oximetry.

Characterization of the optical properties of color pastes for the design of optical phantoms mimicking biological tissue.

Clinicians need a way to rapidly and reliably test the correct functioning of near-infrared spectroscopy (NIRS)-based oximeters. Therefore, optical phantoms for quality assessment of NIRS oximeters are needed. The fabrication of such phantoms that mimic the optical properties of biological tissue in the NIR range represents a challenge. To enable their development, the aim was to characterize the absorption and scattering spectra of different dyes. The optical properties of silicone SILPURAN 2420 with 11 color pastes of type ELASTOSIL were measured in the 500 to 1000 nm range by a spectrometer with an integrating sphere. In addition, two commercial frequency-domain NIRS devices, the ISS OxiplexTS and the ISS Imagent, were used to assess the optical properties at specific wavelengths. The evaluated colors present mostly features in the visible range below 650 nm, but two colors include peaks in the near-infrared region, simulating low tissue oxygenation values. These colors were used to create an optical phantom, which matched the designed StO2 value within an error of only 4%. This set of dyes already enables simulating many different spectra, thus achieving a first step on the way to a long-term stable comparison and validation method.

In Vitro Comparisons of Near-Infrared Spectroscopy Oximeters: Impact of Slow Changes in Scattering of Liquid Phantoms.

Several cerebral oximeters based on near-infrared spectroscopy (NIRS) are commercially available that determine tissue oxygen saturation (StO2). One problem is an inconsistency of StO2 readings between different brands of instruments. Liquid blood phantoms mimicking optical properties of the neonatal head enable quantitative device comparisons. However, occasionally, the reduced scattering coefficient (µs') of these phantoms decreases over time. AIM: To investigate whether this decrease in µs' affects the validity of comparison of these devices. StO2 was measured by several NIRS oximeters simultaneously on a phantom, which exhibited a particularly strong decrease in µs'. We found that a decrease in µs' by ≤16% from baseline led to deviations in StO2 of ≤3%.

Liquid Blood Phantoms to Validate NIRS Oximeters: Yeast Versus Nitrogen for Deoxygenation.

Liquid blood phantoms are a tool to calibrate, test and compare near-infrared spectroscopy (NIRS) oximeters. They comprise a mixture of saline, blood and Intralipid, which is subsequently oxygenated and deoxygenated to assess the entire range of tissue oxygen saturation (StO2) from 0% to 100%. The aim was to investigate two different deoxygenation methods: yeast versus nitrogen (N2) bubbling. The phantom was oxygenated with pure O2 in both experiments, but deoxygenated by bubbling N2 in the first and by addition of yeast and glucose in the second experiment. A frequency domain NIRS instrument (OxiplexTS) was used as reference and to monitor changes in the reduced scattering coefficient (µs') of the phantom. Both deoxygenation methods yielded comparable StO2 values. The deoxygenation was slower by a factor 2.8 and µs' decreased faster when bubbling N2. The constant bubbling of N2 mechanically stresses the Intralipid emulsion and causes a decrease in µs', probably due to aggregation of lipid droplets. Deoxygenation by N2 requires a more complex, air tight phantom. The gas flow cools the liquid and temperature needs to be monitored more closely. Consequently, we recommend using yeast for phantom deoxygenation.

In vivo precision assessment of a near-infrared spectroscopy-based tissue oximeter (OxyPrem v1.3) in neonates considering systemic hemodynamic fluctuations.

The aim was to determine the precision of a noninvasive near-infrared spectroscopy (NIRS)-based tissue oximeter (OxyPrem v1.3). Using a linear mixed-effects model, we quantified the variability for cerebral tissue oxygenation (StO2) measurements in 35 preterm neonates to be 2.64%, a value that meets the often-articulated clinicians' demand for a precise tissue oxygenation measurement. We showed that the variability of StO2 values measured was dominated by spontaneous systemic hemodynamic fluctuations during the measurement, meaning that precision of the instrument was actually even better. Based on simultaneous and continuous measurements of peripheral arterial oxygenation and cerebral StO2 with a second sensor, we were able to determine and quantify the physiological instability precisely. We presented different methods and analyses aiming at reducing this systematic physiological error of in vivo precision assessments. Using these methods, we estimated the precision of the OxyPrem tissue oximeter to be ≤ 1.85 % . With our study, we deliver relevant information to establish highly precise cerebral oxygenation measurements with NIRS-based oximetry, facilitating the further development toward a substantially improved diagnosis and treatment of patients with respect to brain oxygenation.

Tissue oximetry by diffusive reflective visible light spectroscopy: Comparison of algorithms and their robustness.

It is essential to measure tissue oxygen saturation (StO2 ) locally and in thin layers of tissue, for example, the bronchial mucosa, skin flaps and small bones. Visible light spectroscopy (VLS) with a shallow penetration depth is suitable method. Although several VLS algorithms have been developed and described, they have not yet been compared to each other. This hinders attempts to compare the clinical results obtained by different algorithms. To address this issue, we compared the algorithms of Harrison, Knoefel, Pittman-Duling, Sato and our OxyVLS oximeter, which applies the algorithm from Wodick and Lübbers, in a liquid phantom with optical properties of human tissue. We generally observed considerable differences between the algorithms, which were StO2 dependent. Exceptions were OxyVLS and Sato, showing a high level of agreement with negligible StO2 dependency. In spite of the considerable deviation between the other algorithms, the difference of StO2 between them in clinically normal StO2 was <10%. We did not observe any dependency of the algorithms on hemoglobin content of the phantom or temperature.

Development and Validation of a Sensor Prototype for Near-Infrared Imaging of the Newborn Brain.

Imaging brain oxygenation is crucial for preventing brain lesions in preterm infants. Our aim is to build and validate a near-infrared optical tomography (NIROT) sensor for the head of neonates. This sensor, combined with an optoacoustic device, will enable quantitative monitoring of the structural and functional information of the brain. Since the head of preterm infants is small and fragile great care must be taken to produce a comfortable and compact device in which a sufficient number of light sources and detectors can be implemented. Here we demonstrate our first prototype. Heterogeneous silicone phantoms were produced to validate the prototype's data acquisition, data processing, and image reconstruction. Reconstructed optical properties agree well with the target values. The mechanical performance of the new NIROT sensor prototype confirms its suitability for the clinical application.

Quantifying the effect of adipose tissue in muscle oximetry by near infrared spectroscopy.

Change of muscle tissue oxygen saturation (StO2), due to exercise, measured by near infrared spectroscopy (NIRS) is known to be lower for subjects with higher adipose tissue thickness. This is most likely not physiological but caused by the superficial fat and adipose tissue. In this paper we assessed, in vitro, the influence of adipose tissue thickness on muscle StO2, measured by NIRS oximeters. We measured StO2 of a liquid phantom by 3 continuous wave (CW) oximeters (Sensmart Model X-100 Universal Oximetry System, INVOS 5100C, and OxyPrem v1.3), as well as a frequency-domain oximeter, OxiplexTS, through superficial layers with 4 different thicknesses. Later, we employed the results to calibrate OxyPrem v1.3 for adipose tissue thickness in-vivo.

Local Measurement of Flap Oxygen Saturation: An Application of Visible Light Spectroscopy.

The aim was to develop and test a new device (OxyVLS) to measure tissue oxygen saturation by visible light spectroscopy independently of the optical pathlength and scattering. Its local applicability provides the possibility of real time application in flap reconstruction surgery. We tested OxyVLS in a liquid phantom with optical properties similar to human tissue. Our results were in good agreement with a conventional near infrared spectroscopy device.

Characterizing Fluctuations of Arterial and Cerebral Tissue Oxygenation in Preterm Neonates by Means of Data Analysis Techniques for Nonlinear Dynamical Systems.

The cerebral autoregulatory state as well as fluctuations in arterial (SpO2) and cerebral tissue oxygen saturation (StO2) are potentially new relevant clinical parameters in preterm neonates. The aim of the present study was to test the investigative capabilities of data analysis techniques for nonlinear dynamical systems, looking at fluctuations and their interdependence. StO2, SpO2 and the heart rate (HR) were measured on four preterm neonates for several hours. The fractional tissue oxygenation extraction (FTOE) was calculated. To characterize the fluctuations in StO2, SpO2, FTOE and HR, two methods were employed: (1) phase-space modeling and application of the recurrence quantification analysis (RQA), and (2) maximum entropy spectral analysis (MESA). The correlation between StO2 and SpO2 as well as FTOE and HR was quantified by (1) nonparametric nonlinear regression based on the alternating conditional expectation (ACE) algorithm, and (2) the maximal information-based nonparametric exploration (MINE) technique. We found that (1) each neonate showed individual characteristics, (2) a ~60 min oscillation was observed in all of the signals, (3) the nonlinear correlation strength between StO2 and SpO2 as well as FTOE and HR was specific for each neonate and showed a high value for a neonate with a reduced health status, possibly indicating an impaired cerebral autoregulation. In conclusion, our data analysis framework enabled novel insights into the characteristics of hemodynamic and oxygenation changes in preterm infants. To the best of our knowledge, this is the first application of RQA, MESA, ACE and MINE to human StO2 data measured with near-infrared spectroscopy (NIRS).

Evaluation of a textile-based near infrared spectroscopy system in calf muscle oxygenation measurements.

We recently introduced a novel textile-based NIRS sensor (TexNIRS). Here, we evaluate TexNIRS in ten subjects (16 legs, age 28.5 ± 2.32 years, adipose tissue thickness (ATT) 4.17 ± 1.71 mm). Three venous occlusions at 50 mmHg were performed on their calf muscle. After 3 min of occlusion, oxy/deoxy hemoglobin concentration ([O2Hb], [HHb]) changes were 3.71 ± 1.89/1.79 ± 1.08 µM; venous oxygen saturation (SvO2) was 75 ± 9.7 %, oxygen consumption (VO2) was 0.02 ± 0.01 mL/100 g/min, hemoglobin flow (HF) was 0.93 ± 0.48 µmol/100 mL/min, and blood flow (BF) was 2.01 ± 1.04 mL/100 mL/min. Our results are in good agreement with the literature, but the TexNIRS enables a much higher level of comfort.

A review on continuous wave functional near-infrared spectroscopy and imaging instrumentation and methodology.

This year marks the 20th anniversary of functional near-infrared spectroscopy and imaging (fNIRS/fNIRI). As the vast majority of commercial instruments developed until now are based on continuous wave technology, the aim of this publication is to review the current state of instrumentation and methodology of continuous wave fNIRI. For this purpose we provide an overview of the commercially available instruments and address instrumental aspects such as light sources, detectors and sensor arrangements. Methodological aspects, algorithms to calculate the concentrations of oxy- and deoxyhemoglobin and approaches for data analysis are also reviewed. From the single-location measurements of the early years, instrumentation has progressed to imaging initially in two dimensions (topography) and then three (tomography). The methods of analysis have also changed tremendously, from the simple modified Beer-Lambert law to sophisticated image reconstruction and data analysis methods used today. Due to these advances, fNIRI has become a modality that is widely used in neuroscience research and several manufacturers provide commercial instrumentation. It seems likely that fNIRI will become a clinical tool in the foreseeable future, which will enable diagnosis in single subjects.

Calibration of a prototype NIRS oximeter against two commercial devices on a blood-lipid phantom.

In a blood-lipid liquid phantom the prototype near-infrared spectroscopy oximeter OxyPrem was calibrated against the INVOS® 5100c adult sensor in respect to values of regional tissue oxygen haemoglobin saturation (rStO2) for possible inclusion in the randomised clinical trial - SafeBoosC. In addition different commercial NIRS oximeters were compared on changing haemoglobin oxygen saturation and compared against co-oximetry. The best calibration was achieved with a simple offset and a linear scaling of the OxyPrem rStO2 values. The INVOS adult and pediatric sensor gave systematically different values, while the difference between the NIRO® 300 and the two INVOS sensors were magnitude dependent. The co-oximetry proved unreliable on such low haemoglobin and high Intralipid levels.

Textile integrated sensors and actuators for near-infrared spectroscopy.

Being the closest layer to our body, textiles provide an ideal platform for integrating sensors and actuators to monitor physiological signals. We used a woven textile to integrate photodiodes and light emitting diodes. LEDs and photodiodes enable near-infrared spectroscopy (NIRS) systems to monitor arterial oxygen saturation and oxygenated and deoxygenated hemoglobin in human tissue. Photodiodes and LEDs are mounted on flexible plastic strips with widths of 4 mm and 2 mm, respectively. The strips are woven during the textile fabrication process in weft direction and interconnected with copper wires with a diameter of 71 µm in warp direction. The sensor textile is applied to measure the pulse waves in the fingertip and the changes in oxygenated and deoxygenated hemoglobin during a venous occlusion at the calf. The system has a signal-to-noise ratio of more than 70 dB and a system drift of 0.37% ± 0.48%. The presented work demonstrates the feasibility of integrating photodiodes and LEDs into woven textiles, a step towards wearable health monitoring devices.