Peripheral microcirculatory alterations are associated with the severity of acute respiratory distress syndrome in COVID-19 patients admitted to intermediate respiratory and intensive care units.

BACKGROUND: COVID-19 is primarily a respiratory disease; however, there is also evidence that it causes endothelial damage in the microvasculature of several organs. The aim of the present study is to characterize in vivo the microvascular reactivity in peripheral skeletal muscle of severe COVID-19 patients. METHODS: This is a prospective observational study carried out in Spain, Mexico and Brazil. Healthy subjects and severe COVID-19 patients admitted to the intermediate respiratory (IRCU) and intensive care units (ICU) due to hypoxemia were studied. Local tissue/blood oxygen saturation (StO2) and local hemoglobin concentration (THC) were non-invasively measured on the forearm by near-infrared spectroscopy (NIRS). A vascular occlusion test (VOT), a three-minute induced ischemia, was performed in order to obtain dynamic StO2 parameters: deoxygenation rate (DeO2), reoxygenation rate (ReO2), and hyperemic response (HAUC). In COVID-19 patients, the severity of ARDS was evaluated by the ratio between peripheral arterial oxygen saturation (SpO2) and the fraction of inspired oxygen (FiO2) (SF ratio). RESULTS: Healthy controls (32) and COVID-19 patients (73) were studied. Baseline StO2 and THC did not differ between the two groups. Dynamic VOT-derived parameters were significantly impaired in COVID-19 patients showing lower metabolic rate (DeO2) and diminished endothelial reactivity. At enrollment, most COVID-19 patients were receiving invasive mechanical ventilation (MV) (53%) or high-flow nasal cannula support (32%). Patients on MV were also receiving sedative agents (100%) and vasopressors (29%). Baseline StO2 and DeO2 negatively correlated with SF ratio, while ReO2 showed a positive correlation with SF ratio. There were significant differences in baseline StO2 and ReO2 among the different ARDS groups according to SF ratio, but not among different respiratory support therapies. CONCLUSION: Patients with severe COVID-19 show systemic microcirculatory alterations suggestive of endothelial dysfunction, and these alterations are associated with the severity of ARDS. Further evaluation is needed to determine whether these observations have prognostic implications. These results represent interim findings of the ongoing HEMOCOVID-19 trial. Trial registration ClinicalTrials.gov NCT04689477 . Retrospectively registered 30 December 2020.

Influence of study design on effects of mask wearing on fMRI BOLD contrast and systemic physiology - A comment on Law et al. (2021).

In a study by Law and colleagues recently published in Neuroimage, the authors reported that wearing a surgical mask during an fMRI scan leads to a statistically significant subject-specific change (30%) in the baseline BOLD level in gray matter, although the response to a sensory-motor task was unaffected. An average increase in end-tidal CO2 of 7.4% was found when wearing a mask, despite little support in the literature for major effects of mask wearing on blood gas levels. We comment on these findings, point out a several relevant limitations of the study design and provide alternative interpretations of these data.

In vivo time-domain diffuse correlation spectroscopy above the water absorption peak.

Time-domain diffuse correlation spectroscopy (TD-DCS) is a newly emerging optical technique that exploits pulsed, yet coherent light to non-invasively resolve the blood flow in depth. In this work, we have explored TD-DCS at longer wavelengths compared to those previously used in literature (i.e., 750-850 nm). The measurements were performed using a custom-made titanium-sapphire mode-locked laser, operating at 1000 nm, and an InGaAs photomultiplier as a detector. Tissue-mimicking phantoms and in vivo measurements during arterial arm cuff occlusion in n=4 adult volunteers were performed to demonstrate the proof of concept. We obtained a good signal-to-noise ratio, following the hemodynamics continuously with a relatively fast (1 Hz) sampling rate. In all the experiments, the auto-correlation functions show a decay rate approximately five-fold slower compared to shorter wavelengths. This work demonstrates the feasibility of in vivo TD-DCS in this spectral region and its potentiality for biomedical applications.

In vivo time-gated diffuse correlation spectroscopy at quasi-null source-detector separation.

We demonstrate time domain diffuse correlation spectroscopy at quasi-null source-detector separation by using a fast time-gated single-photon avalanche diode without the need of time-tagging electronics. This approach allows for increased photon collection, simplified real-time instrumentation, and reduced probe dimensions. Depth discriminating, quasi-null distance measurement of blood flow in a human subject is presented. We envision the miniaturization and integration of matrices of optical sensors of increased spatial resolution and the enhancement of the contrast of local blood flow changes.

KidsBrainIT: A New Multi-centre, Multi-disciplinary, Multi-national Paediatric Brain Monitoring Collaboration.

OBJECTIVES: Validated optimal cerebral perfusion pressure (CPP) treatment thresholds in children do not exist. To improve the intensive care unit (ICU) management of the paediatric traumatic brain injury (TBI) population, we are forming a new paediatric multi-centre collaboration to recruit standardised ICU data for running and reporting upon models for assessing autoregulation and optimal CCP (CPPopt). MATERIALS AND METHODS: We are adapting the adult BrainIT group's approach to develop a new Paediatric Brain Monitoring and Information Technology Group (KidsBrainIT), which will include a repository to store prospectively collected high-resolution physiological, clinical, and outcome data. In the first phase of this project there are 7 UK Paediatric Intensive Care Units, 1 Spanish, 1 Belgium, and 1 Romanian Centre interested in participating. In subsequent phases, we plan to open recruitment to other centres both within Europe, US and abroad. We are collaborating with the Leuven Group and plan to use their LAx (low-frequency autoregulation index), DATACAR (dynamic adaptive target of active cerebral autoregulation), CPPopt and visualisation methodologies. We also plan to use the continuous diffuse optical monitoring and tomography technology developed in Barcelona as an acute surrogate end-point for optimising brain perfusion. This technology allows non-invasive continuous monitoring of deep tissue perfusion and oxygenation in adults but its clinical application in infants and children with TBI has not been studied previously. RESULTS: We report on the current status of setting up this new collaboration and also on pilot analyses in two centres which are the basis of our rationale for the need for a prospective validation study of CPPopt in children. Specifically, we demonstrated that CPPopt varied with time for each patient during their paediatric intensive care unit (PICU) stay, and the median overall CPPopt levels for children aged 2-6 years, 7-11 years and 12-16 years were 68.83, 68.09, and 72.17 mmHg respectively. Among survivors and patients with favourable outcome (GOS 4 and 5), there were significantly higher proportions with CPP monitoring time within CPPopt (p = 0.04 and p = 0.01 respectively). CONCLUSIONS: There is a need and an interest in forming a multi-centre PICU collaboration for acquiring data and performing analyses for determining validated CPPopt thresholds in the paediatric TBI population. KidsBrainIT is being formed to meet that need.

Time domain diffuse correlation spectroscopy with a high coherence pulsed source: in vivo and phantom results.

Diffuse correlation spectroscopy (DCS), combined with time-resolved reflectance spectroscopy (TRS) or frequency domain spectroscopy, aims at path length (i.e. depth) resolved, non-invasive and simultaneous assessment of tissue composition and blood flow. However, while TRS provides a path length resolved data, the standard DCS does not. Recently, a time domain DCS experiment showed path length resolved measurements for improved quantification with respect to classical DCS, but was limited to phantoms and small animal studies. Here, we demonstrate time domain DCS for in vivo studies on the adult forehead and the arm. We achieve path length resolved DCS by means of an actively mode-locked Ti:Sapphire laser that allows high coherence pulses, thus enabling adequate signal-to-noise ratio in relatively fast (~1 s) temporal resolution. This work paves the way to the translation of this approach to practical in vivo use.

Determination of reference values for optical properties of liquid phantoms based on Intralipid and India ink.

A multi-center study has been set up to accurately characterize the optical properties of diffusive liquid phantoms based on Intralipid and India ink at near-infrared (NIR) wavelengths. Nine research laboratories from six countries adopting different measurement techniques, instrumental set-ups, and data analysis methods determined at their best the optical properties and relative uncertainties of diffusive dilutions prepared with common samples of the two compounds. By exploiting a suitable statistical model, comprehensive reference values at three NIR wavelengths for the intrinsic absorption coefficient of India ink and the intrinsic reduced scattering coefficient of Intralipid-20% were determined with an uncertainty of about 2% or better, depending on the wavelength considered, and 1%, respectively. Even if in this study we focused on particular batches of India ink and Intralipid, the reference values determined here represent a solid and useful starting point for preparing diffusive liquid phantoms with accurately defined optical properties. Furthermore, due to the ready availability, low cost, long-term stability and batch-to-batch reproducibility of these compounds, they provide a unique fundamental tool for the calibration and performance assessment of diffuse optical spectroscopy instrumentation intended to be used in laboratory or clinical environment. Finally, the collaborative work presented here demonstrates that the accuracy level attained in this work for optical properties of diffusive phantoms is reliable.

Diffuse Optics for Tissue Monitoring and Tomography.

This review describes the diffusion model for light transport in tissues and the medical applications of diffuse light. Diffuse optics is particularly useful for measurement of tissue hemodynamics, wherein quantitative assessment of oxy- and deoxy-hemoglobin concentrations and blood flow are desired. The theoretical basis for near-infrared or diffuse optical spectroscopy (NIRS or DOS, respectively) is developed, and the basic elements of diffuse optical tomography (DOT) are outlined. We also discuss diffuse correlation spectroscopy (DCS), a technique whereby temporal correlation functions of diffusing light are transported through tissue and are used to measure blood flow. Essential instrumentation is described, and representative brain and breast functional imaging and monitoring results illustrate the workings of these new tissue diagnostics.

Three-dimensional diffuse optical tomography in the parallel plane transmission geometry: evaluation of a hybrid frequency domain/continuous wave clinical system for breast imaging.

Three-dimensional diffuse optical tomography (DOT) of breast requires large data sets for even modest resolution (1 cm). We present a hybrid DOT system that combines a limited number of frequency domain (FD) measurements with a large set of continuous wave (cw) measurements. The FD measurements are used to quantitatively determine tissue averaged absorption and scattering coefficients. The larger cw data sets (10(5) measurements) collected with a lens coupled CCD, permit 3D DOT reconstructions of a 1-liter tissue volume. To address the computational complexity of large data sets and 3D volumes we employ finite difference based reconstructions computed in parallel. Tissue phantom measurements evaluate imaging performance. The tests include the following: point spread function measures of resolution, characterization of the size and contrast of single objects, field of view measurements and spectral characterization of constituent concentrations. We also report in vivo measurements. Average tissue optical properties of a healthy breast are used to deduce oxy- and deoxy-hemoglobin concentrations. Differential imaging with a tumor simulating target adhered to the surface of a healthy breast evaluates the influence of physiologic fluctuations on image noise. This tomography system provides robust, quantitative, full 3D image reconstructions with the advantages of high data throughput, single detector-tissue coupling path, and large (1L) imaging domains. In addition, we find that point spread function measurements provide a useful and comprehensive representation of system performance.

Bulk optical properties of healthy female breast tissue.

We have measured the bulk optical properties of healthy female breast tissues in vivo in the parallel plate, transmission geometry. Fifty-two volunteers were measured. Blood volume and blood oxygen saturation were derived from the optical property data using a novel method that employed a priori spectral information to overcome limitations associated with simple homogeneous tissue models. The measurements provide an estimate of the variation of normal breast tissue optical properties in a fairly large population. The mean blood volume was 34 +/- 9 microM and the mean blood oxygen saturation was 68 +/- 8%. We also investigated the correlation of these optical properties with demographic factors such as body mass index (BMI) and age. We observed a weak correlation of blood volume and reduced scattering coefficient with BMI: correlation with age, however, was not evident within the statistical error of these experiments. The new information on healthy breast tissue provides insight about the potential contrasts available for diffuse optical tomography of breast tumours.

Near-field diffraction tomography with diffuse photon density waves.

An angular spectrum algorithm is presented for fast, near-field diffraction tomographic imaging with diffuse photon density waves in highly scattering media. A general relation in K space is derived that connects the spatial variations of the optical properties of heterogeneities to the spatial spectra of the measured scattered diffuse photon density waves. The theory is verified experimentally for situations when boundary effects can be neglected. We further describe how to reconstruct absorption and scattering properties simultaneously, and how to incorporate boundary conditions into this angular spectrum algorithm for a turbid medium of finite size (e.g., the slab medium). Limitations and potential improvements of the near-field diffraction tomography are also discussed.

Imager that combines near-infrared diffusive light and ultrasound.

We introduce an imaging technique that combines complementary features of ultrasound and near-infrared diffusive light imaging. We achieve the combined technology experimentally by mounting an ultrasound array together with multiple laser source and optical detector fibers upon a hand-held probe. The technique is demonstrated with tissue phantoms wherein both acoustic and optical sensors image the volume underneath the probe. Coregistration of acoustic and optical images is achieved with an accuracy of 0.27+/-0.20cm, approximately half of the image pixel size of our prototype. Accurate determination of target optical absorption is also achieved by use of image segmentation on the ultrasound reconstruction. The combined technique may provide improved breast-cancer detection sensitivity and specificity.

Algorithms for 3D localization and imaging using near-field diffraction tomography with diffuse light.

We introduce two filtering methods for near-field diffuse light diffraction tomography based on the angular spectrum representation. We then combine these filtering techniques with a new method to find the approximate depth of the image heterogeneities. Taken together these ideas improve the fidelity of our projection image reconstructions, provide an interesting three dimensional rendering of the reconstructed volume, and enable us to identify and classify image artifacts that need to be controlled better for tissue applications. The analysis is accomplished using data derived from numerical finite difference simulations with added noise.

Does the photon-diffusion coefficient depend on absorption?

We investigate the controversy over the precise form of the photon diffusion coefficient and suggest that it is largely independent of absorption, i.e., Do = v/3mu(s)'. After presentation of the general theoretical arguments underlying this assertion, Monte Carlo simulations are performed and explicitly reveal that the absorption independent diffusion coefficient gives better agreement with theory than the traditionally accepted photon diffusion coefficient, D(mu)a = v/3(mu(s) + mu(a)). The importance of resolving this controversy for the proper characterization of the material optical properties is discussed.

Diffraction tomography for biochemical imaging with diffuse-photon density waves.

The spatial structure of optically heterogeneous turbid media is probed with diffusive light. Projection images are obtained experimentally by deconvolution of the scattered diffuse-photon density waves on a planar boundary by use of a fast Fourier transform. The method is very fast, permitting object localization and characterization in ~1000 volume-element samples on subsecond computational time scales. The optical properties of slice-shape inhomogeneities are accurately determined.