The ROx is a retinal oximeter under development with the purpose of non-invasively and accurately measuring oxygen saturation (SO₂) in vivo. It is novel in that it utilizes the blue-green oximetry technique with on-axis illumination. ROx calibration tests were performed by inducing hypoxia in live anesthetized swine and comparing ROx measurements to SO₂ values measured by a CO-Oximeter. Calibration was not achieved to the precision required for clinical use, but limiting factors were identified and improved. The ROx was used in a set of sepsis experiments on live pigs with the intention of tracking retinal SO₂ during the development of sepsis. Though conclusions are qualitative due to insufficient calibration of the device, retinal venous SO₂ is shown to trend generally with central venous SO₂ as sepsis develops. The novel sepsis model developed in these experiments is also described. The method of cecal ligation and perforation with additional soiling of the abdomen consistently produced controllable severe sepsis/septic shock in a matter of hours. In addition, the ROx was used to collect retinal images from a healthy human volunteer. These experiments served as a bench test for several of the additions/modifications made to the ROx. This set of experiments specifically served to illuminate problems with various light paths and image acquisition. The analysis procedure for the ROx is under development, particularly automating the process for consistency, accuracy, and time efficiency. The current stage of automation is explained, including data acquisition processes and the automated vessel fit routine. Suggestions for the next generation of device minimization are also described.

Introduction: Oxygen delivery, or utilization, is a function of retinal blood flow and blood oxygen saturation. The retinal pigment epithelium (RPE), in particular, has been shown to have the highest levels of metabolic activity within the human body. Oxygen delivery is therefore of extreme importance to the maintenance of the health and integrity of the retina. Animal models presuppose that the oxygen tension in the retina is highest in the innermost layers at the level of the choriocapillaris, less in the photoreceptors and further decreases throughout the outer retinal structures. The choroid provides by far the largest component of the oxygen for consumption by the photoreceptors. A lack of oxygen stores in the inner retina therefore makes a constant supply crucial for its normal functioning. Blood flow dysfunction and subsequent hypoxia are both a feature in the pathogenesis of several major ocular diseases such as retinopathy of prematurity (ROP), age-related macular degeneration (ARMD), diabetic retinopathy (DR) and glaucoma. The development of methods to measure retinal blood flow and blood oxygen saturation is crucial to improve understanding of the patho-physiology of major ocular diseases. Purpose: The aims of this work were, firstly, to determine the least variable (range ± standard deviation) wavelength combination (610/548, 600/569 and 605/586) and subsequent ODR with the prototype HRC device. Secondly, using the ODR with the lowest measurement variability, we sought to quantify retinal blood SO2 in arterioles and venules and investigate the relationship between retinal blood SO2 and total retinal blood flow (TRBF) in response to stepwise changes in PETO2 in healthy participants. Retinal blood SO2 and TRBF were assessed using the IRIS HRC (Photon etc. Inc. Montreal, Canada) and the RTvue Doppler Fourier Domain OCT (Optovue Inc, Freemont, CA) instruments, respectively. Methods: Ten healthy participants between the ages of 23 and 37, with an average age of 28.3 years were evaluated in two descriptive cross-sectional studies. Two gas provocation protocols; hyperoxia (end-tidal oxygen; PETO2 of 100, 200, 300, 400mmHg) and hypoxia (PETO2 of 100, 80, 60, 50mmHg) were administered in a fixed sequential order. In each phase of gas provocation (via modulation of PETO2), retinal blood SO2 and TRBF measurements were acquired with the HRC and Doppler FD-OCT. The precise and repeated control of the partial end tidal pressures of oxygen (PETO2) and carbon dioxide (PETCO2) over the pre-determined phase duration, irrespective of the individuals’ respiratory rate, was made possible with the RespirAct (Thornhill Research Inc., Toronto, Canada); a sequential re-breathing gas delivery Results: In arterioles, the group range (±SD) of ODR values for baseline measurements (PETO2 of 100mmHg) was 0.169±0.061 for the 605/586 wavelength combination, 0.371±0.099 for the 600/569 wavelength combination and 0.340±0.104 for the 610/548 wavelength combination. In venules, the group range (±SD) of ODR values was 0.600±0.198 for the 605/586 wavelength combination, 0.569±0.169 for the 600/569 wavelength combination and 0.819±0.274 for the 610/548 wavelength combination. With the 605/586 combination at baseline 1 and 2 in arterioles, the group range (±SD) of ODR values was 0.607 ± 0.224 and 0.619 ± 0.158, respectively (p = 0.370), while in venules the group range (±SD) of ODR at baseline 1 and 2 was 0.289±0.750 and 0.284 ± 0.729, respectively (p = 0.714). For the 600/569 combination at baseline 1 and 2 in arterioles, the group range (±SD) of ODR values was 0.747±0.350 and 0.761±0.391, respectively (p = 0.424) while in venules the group range (±SD) of ODR at baseline 1 and 2 was 0.329±0.675 and 0.366±0.659, respectively (p = 0.372). For the 610/548 combination at baseline 1 and 2 in arterioles, the group range (±SD) of ODR values was 0.604±0.263 and 0.685±0.450, respectively (p = 0.056) while in venules, the group range (±SD) of ODR at baseline 1 and 2 was 0.292±0.746 and 0.285±1.009, respectively (p = 0.131). There was no statistical difference found between baseline ODR values (baseline 1 and 2) across all three wavelength combinations in both arterioles and venules. The mean retinal blood SO2 value at baseline in arterioles for 4 participants was 95.19% ± 31.04% and venules was 53.89% ± 17.24% (p = 0.115). There was a negative linear relationship between group retinal blood SO2 and TRBF values in the 10 participants studied, although the results of any of the 10 individuals did not show evidence of such a relationship using the described methodology. The Pearson’s correlation coefficient (r) between TRBF and SaO2 was r = -0.354 and p = 0.001 and between TRBF and SvO2 was r = - 0.295, p = 0.008 Conclusion: Of the three wavelength combinations investigated (605/586, 600/569 and 610/548), the 605/586 combination was shown to have the overall least variability. It would be unwise at this stage to adopt this wavelength combination for clinical usage, however, since it is presupposed that the 605/586 combination is also the most reliable combination to detect change in retinal blood SO2 i.e. lower variability of the 605/586 combination may be irrelevant if this combination proves to be insensitive to change in retinal blood SO2. The absolute mean ± SD retinal blood SO2 in the arterioles (SaO2) was 95.19% ± 31.04% and in the venules (SvO2) was 53.89% ± 17.24%. These values fell within the range expected and described in the literature. The magnitude of the difference between the SaO2 and SvO2 was also consistent with the literature. These findings were all appropriate for a low flow, high oxygen exchange vascular network typical of the inner retinal vascular system. Using group rather than individual data, TRBF was found in this study to relate inversely with SaO2 (r = -0.354 and p = 0.001) and SvO2 (r = – 0.295 and p=0.008), respectively. This relationship between TRBF and SaO2 and SvO2, was as expected based upon data derived primarily from animal models. This study is ground-breaking and unique, in that, it is the first study to concomitantly measure both retinal blood SO2 and TRBF in human participants. Individual data showed extensive variability and noise, thus limiting the strength of the association between TRBF and SaO2 and SvO2..

Doctor of Philosphy (PhD) / This thesis describes the work carried out during four treks, each over 10-11 days, from 1400m to 5000m in the Nepal Himalaya and further work performed during several two-night sojourns at the Barcroft Laboratory at 3800m on White Mountain in California, USA. Nineteen volunteers were studied during the treks in Nepal and seven volunteers were studied at White Mountain. All subjects were normal, healthy individuals who had not travelled to altitudes higher than 1000m in the previous twelve months. The aims of this research were to examine the effects on sleep, and the ventilatory patterns during sleep, of incremental increases in altitude by employing portable polysomnography to measure and record physiological signals. A further aim of this research was to examine the relationship between the ventilatory responses to hypoxia and hypercapnia, measured at sea level, and the development of periodic breathing during sleep at high altitude. In the final part of this thesis the possibility of preventing and treating Acute Mountain Sickness with non-invasive positive pressure ventilation while sleeping at high altitude was tested. Chapter 1 describes the background information on sleep, and breathing during sleep, at high altitudes. Most of these studies were performed in hypobaric chambers to simulate various high altitudes. One study measured sleep at high altitude after trekking, but there are no studies which systematically measure sleep and breathing throughout the whole trek. Breathing during sleep at high altitude and the physiological elements of the control of breathing (under normal/sea level conditions and under the hypobaric, hypoxic conditions present at high altitude) are described in this Chapter. The occurrence of Acute Mountain Sickness (AMS) in subjects who travel form near sea level to altitudes above 3000m is common but its pathophysiology not well understood. The background research into AMS and its treatment and prevention are also covered in Chapter 1. Chapter 2 describes the equipment and methods used in this research, including the polysomnographic equipment used to record sleep and breathing at sea level and the high altitude locations, the portable blood gas analyser used in Nepal and the equipment and methodology used to measure each individual’s ventilatory response to hypoxia and hypercapnia at sea level before ascent to the high altitude locations. Chapter 3 reports the findings on the changes to sleep at high altitude, with particular focus on changes in the amounts of total sleep, the duration of each sleep stage and its percentage of total sleep, and the number and causes of arousals from sleep that occurred during sleep at increasing altitudes. The lightest stage of sleep, Stage 1 non-rapid eye movement (NREM) sleep, was increased, as expected with increases in altitude, while the deeper stages of sleep (Stages 3 and 4 NREM sleep, also called slow wave sleep), were decreased. The increase in Stage 1 NREM in this research is in agreement with all previous findings. However, slow wave sleep, although decreased, was present in most of our subjects at all altitudes in Nepal; this finding is in contrast to most previous work, which has found a very marked reduction, even absence, of slow wave sleep at high altitude. Surprisingly, unlike experimental animal studies of chronic hypoxia, REM sleep was well maintained at all altitudes. Stage 2 NREM and REM sleep, total sleep time, sleep efficiency and spontaneous arousals were maintained at near sea level values. The total arousal index was increased with increasing altitude and this was due to the increasing severity of periodic breathing as altitude increased. An interesting finding of this research was that fewer than half the periodic breathing apneas and hypopneas resulted in arousal from sleep. There was a minor degree of upper airway obstruction in some subjects at sea level but this was almost resolved by 3500m. Chapter 4 reports the findings on the effects on breathing during sleep of the progressive increase of altitude, in particular the occurrence of periodic breathing. This Chapter also reports the results of changes to arterial blood gases as subjects ascended to higher altitudes. As expected, arterial blood gases were markedly altered at even the lowest altitude in Nepal (1400m) and this change became more pronounced at each new, higher altitude. Most subjects developed periodic breathing at high altitude but there was a wide variability between subjects as well as variability in the degree of periodic breathing that individual subjects developed at different altitudes. Some subjects developed periodic breathing at even the lowest altitude and this increased with increasing altitude; other subjects developed periodic breathing at one or two altitudes, while four subjects did not develop periodic breathing at any altitude. Ventilatory responses to hypoxia and hypercapnia, measured at sea level before departure to high altitude, was not significantly related to the development of periodic breathing when the group was analysed as a whole. However, when the subjects were grouped according to the steepness of their ventilatory response slopes, there was a pattern of higher amounts of periodic breathing in subjects with steeper ventilatory responses. Chapter 5 reports the findings of an experimental study carried out in the University of California, San Diego, Barcroft Laboratory on White Mountain in California. Seven subjects drove from sea level to 3800m in one day and stayed at this altitude for two nights. On one of the nights the subjects slept using a non-invasive positive pressure device via a face mask and this was found to significantly improve the sleeping oxyhemoglobin saturation. The use of the device was also found to eliminate the symptoms of Acute Mountain Sickness, as measured by the Lake Louise scoring system. This finding appears to confirm the hypothesis that lower oxygen saturation, particularly during sleep, is strongly correlated to the development of Acute Mountain Sickness and may represent a new treatment and prevention strategy for this very common high altitude disorder.

This thesis works with measuring possibilities of blood oxygen saturation, analysis methods used and their calibration. It also deals with design of the block diagram of pulse oximeter for measuring blood oxygen saturation.

No description available.

Magnetic Resonance Imaging (MRI) is a widely used, non-invasive imaging technique that provides a means to reveal structural and functional information of different body tissues in detail. Susceptibility Weighted Imaging (SWI) is a field in MRI that utilizes the information from the magnetic susceptibility property of different tissues using the gradient echo phase information. Although longer echo times (TEs) have been widely used in applications involving SWI, there are a few problems related with the long TE data, such as the strong blooming effect and phase aliasing even at macroscopic levels. In this thesis, the use of very short TEs is proposed to study susceptibility mapping. The short TEs can be used to study structures with susceptibilities an order of magnitude larger (such as air and bones in and around the brain sinuses, skull and teeth) than those within soft tissue. Using a new iterative susceptibility mapping technique that we recently developed, it becomes possible to map the geometry of such structures, which to date has proven difficult due to the lack of water content (for sinuses) or due to very short T2* (for bones). The method of phase replacement inside the sinuses proposed in this thesis provides more accurate phase information for the inversion than assuming zero or some arbitrary constant inside these structures. The first and second iterations were responsible for most of the changes in mapping out the susceptibility values. The mean susceptibility value in the sphenoid sinus is calculated as +9.3 ± 1.1ppm, close to the expected value of +9.4ppm for air. The reconstruction of the teeth in the in-vivo data provides a mean Δχ(teeth-tissue)=–3.3ppm, thanks to the preserved phase inside the jaw. The mean susceptibility inside a relatively homogeneous region of the skull bone was measured to be Δχ(bone-tissue)=–2.1ppm. Finally, these susceptibilities can be used to help remove the unwanted background fields prior to applying either SHARP or HPF. In addition, the effects of the background field gradient on flow compensation are studied. Due to the presence of these background gradients, an unwanted phase term is induced by the blood flow inside the vessels. Using a 3D numerical model and in vivo data, the background gradients were estimated to be as large as 1.5mT/m close to the air-tissue interfaces and 0.7mT/m inside the brain (leading to a potential signal loss of up to 15%). The quantitative susceptibility mapping (QSM) results were improved in the entire image after removing the confounding arterial phase thanks to the reduced ringing artifacts. Lastly, a novel approach to improve the susceptibility mapping results was introduced and utilized to monitor the changes in venous oxygen saturation levels as well as the changes in oxygen extraction fraction instigated by the vasodynamic agents, caffeine and acetazolamide. The internal streaking artifacts in the susceptibility maps were reduced by giving an initial susceptibility value uniformly to the structure-of-interest, based on the a priori information. For veins, the iterative results, when the initial value of 0.45 ppm was used, were the best in terms of the highest accuracy in the mean susceptibility value (0.453 ppm) and the lowest standard deviation (0.013 ppm). Using this technique, the venous oxygen saturation levels (inside the internal cerebral veins (ICVs)) for normal physiological conditions, post-caffeine and post-Diamox for the first volunteer were calculated as (mean ± standard deviation): Y_Normal = 69.1 ± 3.3 %, Y_Caffeine = 60.5 ± 2.8 % and Y_Diamox = 79.1 ± 4.0%. For the caffeine challenge, the percentage change in oxygen extraction fraction (OEF) for pre and post caffeine results was calculated as +27.0 ± 3.8%; and for the Diamox challenge, the percentage change in OEF was calculated as −32.6 ± 2.1 % for the ICVs. These vascular effects of Diamox and caffeine were large enough to be easily measured with susceptibility mapping and can serve as a sensitive biomarker for measuring reductions in cerebro-vascular reserve through abnormal vascular response, an increase in oxygen consumption during reperfusion hyperoxia or locally varying oxygen saturation levels in regions surrounding damaged tissue. In conclusion, our new approach to QSM offers a means to monitor venous oxygen saturation reasonably accurately and may provide a new means to study neurovascular diseases where there are changes in perfusion that affect the oxygen extraction fraction. / Thesis / Doctor of Philosophy (PhD) / Magnetic Resonance Imaging (MRI) is a widely used, non-invasive imaging technique that provides a means to reveal structural and functional information of different body tissues in detail. Susceptibility Weighted Imaging (SWI) is a field in MRI that utilizes the information from the magnetic susceptibility property of different tissues using the gradient echo phase information. Firstly, we demonstrate that using our phase replacement technique, it becomes possible to map the geometry of structures with almost no MR signal, which to date has proven difficult due to the lack of water content (for sinuses) or due to very short T2* (for bones). Secondly, the effects of the background field gradient on flow compensation were studied. Due to the presence of these background gradients, an unwanted phase term is induced by the blood flow inside the vessels. And, lastly, we present our new approach utilizing SWI data, offering a means to monitor venous oxygen saturation reasonably accurately and, potentially, a new means to study neurovascular diseases where there are changes in perfusion that affect the oxygen extraction fraction.

No description available.

<p>Quantitatively measuring oxygen saturation is important to characterize the physiological or pathological state of tissue function. In this thesis, we demonstrate the possibility of using susceptibility mapping to noninvasively estimate the venous blood oxygen saturation level. Accurate susceptibility quantification is the key to oxygen saturation quantification. Two approaches are presented in this thesis to generate accurate and artifact free susceptibility maps (SM): a regularized inverse filter and a k-space iterative method. Using the regularized inverse filter, with sufficient resolution, major veins in the brain can be visualized. We found that different sized vessels show a different level of contrast depending on their partial volume effects; larger vessels show a bias toward a reduced susceptibility approaching 90% of the expected value. Also, streaking artifacts associated with high susceptibility structures such as veins are obvious in the reconstructed SM. To further improve susceptibility quantification and reduce the streaking artifacts in the SMs, we proposed a threshold-based k-space iterative approach that used geometric information from the SM itself as a constraint to overcome the ill-posed nature of the inverse filter. Both simulations and in vivo results show that most streaking artifacts inside the SM were suppressed by the iterative approach. In simulated data, the bias toward lower mean susceptibility values inside vessels has been shown to decrease from around 10% to 2% when choosing an appropriate threshold value for the proposed iterative method, which brings us one step closer to a practical means to map out oxygen saturation in the brain.</p> / Doctor of Philosophy (PhD)

The objective of this study was to evaluate the relationship between tissue oxygen saturation (StO2) and oxygen delivery index (DO2I). Oxygen delivery index is product of two factors arterial oxygen content (CaO2) and cardiac index (CI). In this study the relationship between DO2I and StO2 was evaluated by manipulating both of these factors independently. In phase one of the study, CaO2 was altered by manipulating the fractional inspired oxygen (FiO2) concentration. Anesthetized dogs were evaluated at both high (0.40 and 0.95) and low (0.15 and 0.10) FiO2 sequences. In phase two of the study, CI was altered by manipulating the volemic state. Anesthetized dogs were evaluated at hypovolemic, normovolemic and hypervolemic states. In each phase dogs were instrumented for thermodilution cardiac index (CI) and sartorius muscle StO2. Data collected included hemoglobin concentration, heart rate (HR), MAP, CI, StO2. Arterial oxygen content and DO2I were calculated at each time point. Data analysis included Pearson's correlation and mixed model ANOVA (p < 0.05). In both phases one (r = 0.97; p = 0.0013) and two (r = 0.97; p = 0.005) there was a strong correlation between StO2 and DO2I. Under the conditions of this study, there was a strong correlation between StO2 and DO2I, suggesting that StO2 may be used to estimate the adequacy of oxygen delivery in dogs. / Master of Science

Thesis (MScEng)--Stellenbosch University, 2012. / ENGLISH ABSTRACT: The monitoring of patients in healthcare is of prime importance to ensure their efficient treatment. The monitoring of blood oxygen saturation in tissues affected by diseases or conditions that may negatively affect the function is a field that has grown in importance in recent times. This study involved the development and testing of a highly sensitive noninvasive blood oxygen saturation device. The device can be used to continuously monitor the condition of tissue affected by diseases which affect the blood flow through the tissue, and the oxygen usage in tissue. The device’s system was designed to specifically monitor occluded tissue which has low oxygen saturations and low perfusion. With the use of the device, it is possible to monitor the status of tissue affected by diseases such as meningococcemia and diabetes mellitus or conditions such as the recovery after plastic surgery. The study delved into all aspects involved in the development of a non-invasive artificial pulse oximeter, including but not limited to that of a detailed device design, signals analysis, animal in-vivo and laboratory in-vitro system design for the calibration of the system as well as human clinical validation and testing procedures. All these aspects were compared to determine the relative accuracies of the different models. Through testing it was shown that it is possible to non-invasively measure the mixed oxygen saturation in occluded tissue. However, without accurate validation techniques and methods of obtaining both arterial and venous blood samples in occluded tissue the system could not be fully validated for determining both the arterial and venous oxygen saturations in the human invivo study. Although the system was unable to accurately measure specifically the venous oxygenation it was able to measure the mixed oxygen saturation. With further research it would be possible to validate the system for measuring both the arterial and venous oxygen saturations. / AFRIKAANSE OPSOMMING: Die monitering van pasiënte in gesondheidsorg is van uiterste belang om doeltreffende behandeling te verseker. Die monitering van bloedsuurstofversadiging in weefsels wat geaffekteer word deur siektes of toestande wat ’n negatiewe impak kan hê op die funksie daarvan is ’n gebied wat aansienlike groei getoon het in die onlangse verlede. Die studie het die ontwikkeling en toetsing van ’n hoogs sensitiewe nieindringende bloedsuurstofversadigingsensor ingesluit. Hierdie sensor kan gebruik word om deurentyd die toestand van weefsel te monitor wat geaffekteer word deur siektes wat bloedvloei deur weefsel affekteer sowel as die suurstofgebruik in die weefsel. Die stelsel is ontwerp om spesifiek die ingeslote weefsel wat lae suurstofversadiging en lae perfusie het, te monitor. Deur gebruik te maak van die toestel is dit moontlik om die toestand van die weefsel wat geaffekteer word deur siektes soos meningococcemia en diabetes mellitus of toestande soos die herstel na plastiese sjirurgie te monitor. Die studie het gekyk na alle aspekte wat betrokke is in die ontwikkeling van ’n nie-indringende kunsmatige pols-oksimeter, insluitend maar nie beperk tot gedetailleerde ontwerp nie, sein analise, dier in-vivo en laboratorium in-vitro stelselontwerp vir die kalibrasie van die stelsel sowel as menslike kliniese bekragtiging en toetsprosedures. Al hierdie aspekte is vergelyk om die relatiewe akkuraatheid van die verskillende modelle te bepaal. Die toetse het gewys dat dit moontlik is om nie-indringend die gemengde suurstofversadiging in weefsel te bepaal. Sonder akkurate bekragtigingstegnieke en metodes om beide arteriële en vene bloedmonsters te versamel in ingeslote weefsel kan die stesel nie ten volle bekragtig word om beide arteriële- en veneversadigings in menslike in-vivo studie te bepaal nie. Hoewel die stelsel nie ’n akkurate meting van die aarsuurstof kon kry nie, is daar wel ’n akkurate meting geneem van die gemengde suurstofversadiging. Toekomstige navorsing kan lei tot die bekragtiging van die stelsel om beide arteriële en slagaar suurstofversadigings te meet.