Intraoperative, Quantitative, and Non-Contact Blood Volume Flow Measurement via Indocyanine Green Fluorescence Angiography

In vielen Fällen unterziehen sich Patienten einer Revaskularisationsoperation wenn sie an einer zerebrovaskulären Erkrankung leiden, die eine Hypoperfusion des Gehirns verursacht. Dieser chirurgische Eingriff wird häufig als offene Operation durchgeführt und hat das Ziel, die Gefäßfunktion, insbesondere den Blutfluss, wiederherzustellen. Hierzu wird eine Anastomose (Verbindung von Arterien) angelegt, um den Fluss zu einem hypoperfundierten Gehirnareal zu erhöhen. In ungefähr 10% der Eingriffe treten nach der Operation Komplikationen auf, die zum Teil auf eine unzureichende Durchflusssteigerung zurückgeführt werden. Daher sollte der Blutfluss intraoperativ überprüft werden, um die Qualität des Eingriffs im Operationssaal zu beurteilen und schnell eingreifen zu können. Damit könnte ein negativer Ausgang für den Patienten verhindert werden. Der derzeitige Stand der Technik in der intraoperativen und quantitativen Blutflussmessung ist die Nutzung der Ultraschall-Transitzeit-Durchflusssonde. Sie gibt einen quantitativen Flusswert an, muss jedoch das Gefäß umschließen. Dies ist einerseits umständlich für den Chirurgen und andererseits birgt es das Risiko von Kontaminationen, Gefäßquetschungen und der Gefäßruptur. Eine alternative Methode ist die Indocyaningrün (ICG) Fluoreszenzangiographie (FA), welche eine kamerabasierte Methode ist. Sie ist der Stand der Technik in der hochauflösenden anatomischen Visualisierung des Situs und kann zusätzlich dem Chirurgen eine qualitative funktionelle Darstellung der Gefäße im Sichtfeld liefern. Der Stand der Wissenschaft zur Quantifizierung des Blutflusses mittels ICG-FA konnten bisher keine verlässlichen Fluss- werte liefern. Die vorliegende Arbeit analysiert und verbessert die Eignung von ICG FA zu Bereitstellung von verlässlichen und quantitativen Blutflusswerten, indem 1. geklärt wird, wie akkurat die Messung durchgeführt werden kann. 2. Methoden zur Verbesserung der Genauigkeit entwickelt werden. 3. die Existenz eines systematischen Fehlers abgeleitet wird. 4. eine Methode zur Kompensation des systematischen Fehlers entwickelt wird. 5. ein Algorithmus zur Verarbeitung der eingehenden Videodaten für eine Ausgabe eines Durchflusswertes bereitgestellt wird. 6. die Validierung der vorgeschlagenen Methoden und des Arbeitsablaufs in einer ex vivo und in vivo Studie durchgeführt wird. Die in dieser Arbeit vorgeschlagene Messung basiert auf dem systemic mean transit time theorem für Systeme mit einem Eingang und einem Ausgang. Um den Fluss zu berechnen müssen die Transitzeit eines ICG-Bolus für eine zu bestimmenden Strecke und die Querschnittsfläche des Gefäßes ermittelt werden. Es wurden Methoden entwickelt, um den Blutvolumenstrom zu messen und um Fehlerquellen bei dieser Messung der einzelnen Parameter zu identifizieren, quantifizieren und reduzieren. Die statistischen Fehler bei der Messung der Transitstrecke und der Transitzeit des ICG- Bolus sowie der Querschnittsfläche des Gefäßes werden in der Forschung oft vernachlässigt. In dieser Arbeit wurden die Fehler mit Hilfe von in silico Modellen quantifiziert. Es zeigte sich, dass der Fehler zu groß für eine zuverlässige Blutflussmessung ist und daher Methoden zu seiner Reduzierung benötigt werden. Um den Fehler bei der Längenmessung deutlich zu reduzieren, wurde eine Methode vorgestellt, welche die diskrete Mittellinie wieder in eine kontinuierliche überführt. Dabei wird der Fehler in der Längenmessung signifikant reduziert und der Fehler von der räumlichen Orientierung der Struktur entkoppelt. In ähnlicher Weise wurde eine Methode vorgestellt, welche die gemessenen diskreten Indikatorverdünnungskurven (IDCs) ebenso in kontinuierliche überführt, um den Fehler in der Laufzeitmessung des ICG-Bolus zu reduzieren. Der propagierte statistische Fehler der Blutflussmessung wurde auf einen akzeptablen und praktikablen Wert von 20 % bis 30 % reduziert. Die Präsenz eines systematischen Fehlers bei der optischen Messung des Blutflusses wurde identifiziert und aus der Definition des Volumenflusses theoretisch abgeleitet. Folgend wird eine Methode zur Kompensation des Fehlers vorgestellt. Im ersten Schritt wird eine Fluid-Strömungssimulation genutzt, um die räumlich-zeitliche Konzentration des ICG in einem Blutgefäß zu berechnen. Anschließend wird die Konzentration an ein neu entwickeltes Fluoreszenz-Monte-Carlo-Multizylinder (FMCMC) Modell übergeben, das die Ausbreitung von Photonen in einem Gefäß simuliert. Dabei wird der Ort der Fluoreszenzereignisse der emittierten Photonen ermittelt und der systematische Fehler bestimmt. Dies ermöglicht die Kompensation des systematischen Fehlers. Es zeigte sich, dass dieser Fehler unabhängig von dem Volumenfluss ist, solange die Strömung laminar ist, aber abhängig vom Durchmesser des Gefäßes und dem Zeitpunkt der Messung. Die Abhängigkeit vom Durchmesser ist reduziert bei Messungen zu einem früheren Zeitpunkt. Daher ist es vorteilhaft, die erste Ankunft des ICG-Bolus zur Bestimmung der Transitzeit zu verwenden, um den Einfluss des Durchmessers auf den Fehler zu verringern und somit die Messung robuster durchzuführen. Um die Genauigkeit der Messung in einem Experiment zu beweisen, wurde ein ex vivo Experiment unter Verwendung von Schweineblut und Kaninchen Aorten konzipiert und durchgeführt. Es zeigte sich, dass der durch den vorgeschlagenen Algorithmus ermittelte Fluss mit der Referenzmessung (einem industriellem Durchflussmesser) übereinstimmt. Die statistische Streuung der gemessenen Flussdaten durch den Algorithmus stimmte mit der zuvor ermittelten statistischen Fehlerspanne überein, was den in silico Ansatz validiert. Es wurde eine retrospektive in vivo Studie an Menschen durchgeführt, die sich einer extrakraniellen-zu-intrakraniellen (EC-IC) Bypass Operation unterzogen hatten. Die Analyse der FA-Daten ergab eine gute Übereinstimmung mit der klinischen Referenzmethode, jedoch mit dem großen Vorteil, dass kein Kontakt zum Gewebe erforderlich war. Zusätzlich wurde gezeigt, dass simultan Flusswerte für mehrere Gefäße im Sichtfeld der Kamera gemessen werden können. Die vorgestellten Ergebnisse sind ein Proof of Concept für die Eignung der vorgestellten intraoperativen, quantitativen und optischen Messung des Blutvolumenstroms mittels ICG FA. Diese Arbeit ebnet den Weg für den klinischen Einsatz dieser Methode in Ergänzung zum aktuellen klinischen Stand der Technik. Sie könnte zukünftig dem Chirurgen eine neuartige Messung des Blutvolumenstroms zur Verfügung stellen und dabei potentiell das Risiko einer Komplikation reduzieren und damit das Wohl der Patienten verbessern

Geodesic length measurement in medical images: Effect of the discretization by the camera chip and quantitative assessment of error reduction methods

After interventions such as bypass surgeries the vascular function is checked qualitatively and remotely by observing the blood dynamics inside the vessel via Fluorescence Angiography. This state-of-the-art method has to be improved by introducing a quantitatively measured blood flow. Previous approaches show that the measured blood flow cannot be easily calibrated against a gold standard reference. In order to systematically address the possible sources of error, we investigated the error in geodesic length measurement caused by spatial discretization on the camera chip. We used an in-silico vessel segmentation model based on mathematical functions as a ground truth for the length of vessel-like anatomical structures in the continuous space. Discretization errors for the chosen models were determined in a typical magnitude of 6%. Since this length error would propagate to an unacceptable error in blood flow measurement, counteractions need to be developed. Therefore, different methods for the centerline extraction and spatial interpolation have been tested and compared against their performance in reducing the discretization error in length measurement by re-continualization. In conclusion, the discretization error is reduced by the re-continualization of the centerline to an acceptable range. The discretization error is dependent on the complexity of the centerline and this dependency is also reduced. Thereby the centerline extraction by erosion in combination with the piecewise Bézier curve fitting performs best by reducing the error to 2.7% with an acceptable computational time

Towards Quantitative ICG Angiography: Fluorescence Monte Carlo Multi Cylinder

Intraoperative blood flow measurement is an effective way to assess the quality of bypass surgery. Flow quantification from indocyanine green (ICG) angiography promises to be an easy, contact-free method. It shows deviations compared to areference. These are given as factor , which dependson the vesseldiameter . The radiation transport within the vessel while recording the ICG passage might cause this. It is analyzed in silicoto disclose its impact on (). A Fluorescence Monte Carlo Multi Cylinder (FMCMC) model was developed as a static model, assuming homogeneous concentration of ICG. In contrast to published approaches utilizing a Monte Carlo MultiLayer (MCML) model assuming the deepest penetration location within a photon packet’s path to be the fluorescence location, the events aremodeled. Fluorescenceevent modeling, Multi Cylinder geometry and a homogeneous illumination as well as combinations of these were implemented in separate aspect models. Resulting ()were compared to ()from MCML. Deviations in ()derived from FMCMC and MCML in each aspect model were present. The Root Mean Square Error ranges from 6,8% to 36 %, ()also varied comparing the aspect models to each other. The model geometry, the modeled fluorescence location and illumination mode show a clear impact on simulated (). Therefore, our study shows that simplifications of previous studies are invalid.The developed FMCMC model considers the named aspects, allowing the analysis of radiation transport in ICG angiography. The FMCMC model assumes a homogeneous concentration of ICG which is not true in clinical cases. Obtaining the heterogeneous distributionof ICG is possible via fluid flow models. Coupling the fluid flow model and the developed radiation transport model as well as including a detailed camera optic is the task for future wor

Transit Time Measurement in Indicator Dilution Curves: Overcoming the Missing Ground Truth and Quantifying the Error

The vascular function of a vessel can be qualitatively and intraoperatively checked by recording the blood dynamics inside the vessel via fluorescence angiography (FA). Although FA is the state of the art in proving the existence of blood flow during interventions such as bypass surgery, it still lacks a quantitative blood flow measurement that could decrease the recurrence rate and postsurgical mortality. Previous approaches show that the measured flow has a significant deviation compared to the gold standard reference (ultrasonic flow meter). In order to systematically address the possible sources of error, we investigated the error in transit time measurement of an indicator. Obtaining in vivo indicator dilution curves with a known ground truth is complex and often not possible. Further, the error in transit time measurement should be quantified and reduced. To tackle both issues, we first computed many diverse indicator dilution curves using an in silico simulation of the indicator\u27s flow. Second, we post-processed these curves to mimic measured signals. Finally, we fitted mathematical models (parabola, gamma variate, local density random walk, and mono-exponential model) to re-continualize the obtained discrete indicator dilution curves and calculate the time delay of two analytical functions. This re-continualization showed an increase in the temporal accuracy up to a sub-sample accuracy. Thereby, the Local Density Random Walk (LDRW) model performed best using the cross-correlation of the first derivative of both indicator curves with a cutting of the data at 40% of the peak intensity. The error in frames depends on the noise level and is for a signal-to-noise ratio (SNR) of 20 dB and a sampling rate of f$_{s}$ = 60 Hz at f$^{-1}$$_{s}$⋅0.25(±0.18), so this error is smaller than the distance between two consecutive samples. The accurate determination of the transit time and the quantification of the error allow the calculation of the error propagation onto the flow measurement. Both can assist surgeons as an intraoperative quality check and thereby reduce the recurrence rate and post-surgical mortality

Simulating a Ground Truth for Transit Time Analysis of Indicator Dilution Curves

Transit times of a bolus through an organ can provide valuable information for researchers, technicians and clinicians. Therefore, an indicator is injected and the temporal propagation is monitored at two distinct locations. The transit time extracted from two indicator dilution curves can be used to calculate for example blood flow and thus provide the surgeon with important diagnostic information. However, the performance of methods to determine the transit time Δt cannot be assessed quantitatively due to the lack of a sufficient and trustworthy ground truth derived from in vivo measurements. Therefore, we propose a method to obtain an in silico generated dataset of differently subsampled indicator dilution curves with a ground truth of the transit time. This method allows variations on shape, sampling rate and noise while being accurate and easily configurable. COMSOL Multiphysics is used to simulate a laminar flow through a pipe containing blood analogue. The indicator is modelled as a rectangular function of concentration in a segment of the pipe. Afterwards, a flow is applied and the rectangular function will be diluted. Shape varying dilution curves are obtained by discrete-time measurement of the average dye concentration over different cross-sectional areas of the pipe. One dataset is obtained by duplicating one curve followed by subsampling, delaying and applying noise. Multiple indicator dilution curves were simulated, which are qualitatively matching in vivo measurements. The curves temporal resolution, delay and noise level can be chosen according to the requirements of the field of research. Various datasets, each containing two corresponding dilution curves with an existing ground truth transit time, are now available. With additional knowledge or assumptions regarding the detection-specific transfer function, realistic signal characteristics can be simulated. The accuracy of methods for the assessment of Δt can now be quantitatively compared and their sensitivity to noise evaluated

Investigation on Non-Segmentation Based Algorithms for Microvasculature Quantification in OCTA Images

Optical Coherence Tomography Angiography (OCTA) is an imaging modality that provides three-dimensional information of the retinal microvasculature and therefore promises early diagnosis and sufficient monitoring in ophthalmology. However, there is considerable variability between experts analysing this data. Measures for quantitative assessment of the vasculature need to be developed and established, such as fractal dimension. Fractal dimension can be used to assess the complexity of vessels and has been shown to be independently associated with neovascularization, a symptom of diseases such as diabetic retinopathy. This investigation assessed the performance of three fractal dimension algorithms: Box Counting Dimension (BCD), Information Dimension (ID), and Differential Box Counting (DBC). Two of those, BCD and ID, rely on previous vessel segmentation. Assessment of the added value or disturbance regarding the segmentation step is a second aim of this study. The investigation was performed on a data set composed of 9 in vivo human eyes. Since there is no ground truth available, the performance of the methods in differentiating the Superficial Vascular Complex (SVC) and Deep Vascular Complex (DVC) layers apart and the consistency of measurements of the same layer at different time-points were tested. The performance parameters were the ICC and the Mann-Whitney U tests. The three applied methods were suitable to tell the different layers apart and showed consistent values applied in the same slab. Within the consistency test, the non-segmentation-based method, DBC, was found to be less accurate, expressed in a lower ICC value, compared to its segmentation-based counterparts. This result is thought to be due to the DBC’s higher sensitivity when compared to the other methods. This higher sensitivity might help detect changes in the microvasculature, like neovascularization, but is also more likely prone to noise and artefacts

Automated vessel centerline extraction and diameter measurement in OCT Angiography

Optical Coherence Tomography Angiography (OCTA) is a non-invasive imaging technique that enables the visualizationof perfused vasculature in vivo. In ophthalmology,it allows the physician to monitor diseases affecting the vascular networks of the retina such as age-related macular degeneration or diabetic retinopathy. Due to the complexity of the vasculature in the retina,it is of interest to automatically extract vascular parameters which describe the condition of the vessels. Suitable parameters could improve the diagnosis and the treatment during the course of therapy.We present an automated algorithm tocompute the diameters of the vessels in en face OCTA images. After segmentingthe images, the vessel centerlinewascomputed using a thinningalgorithm.The centerline wasrefined by detecting invalid pixelssuch as spursandbycontinuing the centerline until the endsof the vessels. Lastly, the diameter wascomputed by dilating a discrete circle at the position of the centerline or by measuring the distance between both borders of the vessels. The developed algorithms were applied to in vivo images of human eyes. Certainly, no ground truth was available. Hence, a plausibility check was performed by comparing the measured diameters of two different layers of the retina (Superficial Vascular Complex (SVC) and Deep Vascular Complex (DVC)). Each layer exhibits a different characteristic vasculature.The algorithm clearly reflectedthe differences from both retinal layers. The measured diameters demonstrate that the DVC consists of more capillaries and considerably smaller vessels compared to the SVC.The presented method enables automated analysis of the retinal vasculature and forms thereby the basis for monitoringdiseases influencing the vasculature of the retina. The validation of the method using an artificial ground truth is still neede

Bi - Domain Intraoperative Registration of Vessels

The segmentation and registration of structures are gaining importance due to the increasing demand of automated image enhancement and understanding. Especially in medicine and life science, assistance systems could have a large impact on diagnosis, treatment and quality control. Dye driven procedures, such as fuorescence imaging with Indocyanine green (ICG), are nowadays indispensable because they enhance contrast, reveal structures and deliver the operator with important information. The contact free ICG angiography is providing the surgeon spatial and temporal information on blood flow within a vessel. The processing of those information is done manually or semi automated but is very helpful for the surgeon. Extending the degree of automatism, the amount of information processed and even augment or transfer it into another domain could deliver the operator useful support and improve surgical work fow. Using, analyzing and transferring those information from ICG-IR domain into the RGB domain is the focus of this project. We are introducing a vessel registration method in the RGB domain driven by the spatial fu-orescence behavior of the vessel in the ICG-IR domain. The method includes Superpixel based segmentation of the vessel in the ICG-IR domain, the spatial gradient based transfer and registration in the RGB domain and the continuous segmentation of the vessel in a RGB video. This paper show a proof of concept of the method. The results show an successful inter domain information transfer and registration of the vessel. Further tracking of the vessel over all frames is possible. Nevertheless limitations are revealed and discussed

Bi - Domain Intraoperative Registration of Vessels

The segmentation and registration of structures are gaining importance due to the increasing demand of automated image enhancement and understanding. Especially in medicine and life science, assistance systems could have a large impact on diagnosis, treatment and quality control. Dye driven procedures, such as fluorescence imaging with Indocyanine green (ICG), are nowadays indispensable because they enhance contrast, reveal structures and deliver the operator with important information. The contact free ICG angiography is providing the surgeon spatial and temporal information on blood flow within a vessel. The processing of those information is done manually or semi automated but is very helpful for the surgeon. Extending the degree of automatism, the amount of information processed and even augment or transfer it into another domain could deliver the operator useful support and improve surgical work flow. Using, analyzing and transferring those information from ICG-IR domain into the RGB domain is the focus of this project. We are introducing a vessel registration method in the RGB domain driven by the spatial fluorescence behavior of the vessel in the ICG-IR domain. The method includes Superpixel based segmentation of the vessel in the ICG-IR domain, the spatial gradient based transfer and registration in the RGB domain and the continuous segmentation of the vessel in a RGB video. This paper show a proof of concept of the method. The results show an successful inter domain information transfer and registration of the vessel. Further tracking of the vessel over all frames is possible. Nevertheless limitations are revealed and discussed