Tissue Oxygenation Status Research Articles

Clinical NIRS of the urinary bladder – A demonstration case report

Urinary incontinence is a common affliction among people of all ages throughout the world. There are many causes of incontinence, treatment options are determined by the cause, and current diagnostic methods require urodynamic assessment, which involves urethral and rectal catheterization, which are uncomfortable and distasteful for patients. Since clinical near infrared spectrophotometry (NIRS) is a non‐invasive, rapid means of measuring tissue oxygenation status at the bedside, we examined whether NIRS could be useful as a diagnostic tool for bladder dysfunction. An adult patient attending an incontinence clinic for routine urodynamic testing also had NIRS data collection during the standard bladder filling regimen. NIRS optodes were placed on the skin of the intact abdomen over the supra pubic region. Changes in oxy and de‐oxy hemoglobin concentration and changes in cytochrome c oxidase net redox status via NIRS were collected at 6 Hz. The magnitudes of change that occurred during NIRS data collection are on the order of 0.5 µmol/l and the moments of change correspond to the subject′s reported sensations of bladder filling and emptying, and with conventional urodynamics. These observations suggest that NIRS may be a disruptive technology with a role to play in non‐invasive evaluation of bladder dysfunction in humans.

How a low tissue O2 strategy could be conserved in early crustaceans: the example of the podocopid ostracods

An adaptation strategy whereby O(2) partial pressure, P(O(2)), in the tissues is maintained within a low, narrow range of 1-3 kPa, largely independent of the inspired P(O(2)), has been reported in water- and air-breathing poikilotherms and in homeotherms. Based on the postulate that this basic cellular mechanism has been established since the early stages of evolution, it has been hypothesized that it could be the consequence of an early adaptation strategy to maintain cellular oxygenation within the same low and primitive range. To test this hypothesis we studied the basic mechanisms of oxygen regulation in podocopid ostracods, minute crustaceans that have existed on earth for at least 500 million years. Podocopids lack any regulatory mechanism for adapting their ventilation to cope with changes in water oxygenation, and instead adjust their tissue oxygenation status by migrating through the O(2) gradient to sediment layers where the P(O(2)) of the water is 3-5 kPa. Experimental manipulation of the O(2) profile induced their vertical migration to follow this precise water P(O(2)) and demonstrates the existence of a regulation strategy. This strategy must be associated with the lower P(O(2)) values within the animal's carapace valves, showing that podocopids can actively regulate their tissue P(O(2)) at constant but even lower values than the water. In conclusion, the low tissue P(O(2)) strategy could have existed in early crustaceans and, by extension, in early animals.

MRI of Animal Models of Brain Disease

This chapter elaborates the magnetic resonance imaging (MRI) of animal models of brain disease. The utility of MRI with respect to animal models of disease lies in the sensitivity of the technique to both microscopic and macroscopic molecular motions. In arterial spin labeling, perfusion-weighted images are generated by labeling in flowing blood water by inversion of its longitudinal magnetization. Two images must be acquired, including the labeled image and the control image. The difference between the two images is proportional to the amount of labeled blood that enters the imaging slice during the time between labeling and image acquisition, and therefore, is also proportional to cerebral blood flow. It is found that as blood oxygenation level dependent (BOLD) MRI is sensitive to changes in regional tissue oxygenation status, it can be used to monitor acute deoxygenation following induction of ischemia, as well as reoxygenation after reperfusion. BOLD MR signal intensity drops immediately upon the onset of ischemia and rises when reflow occurs. The experimental models are based on the acute lesioning using GABAergic antagonists or chronic lesioning using systemic administration of 3-nitroproprionic acid are also elaborated.

Amifostine: is there evidence of tumor protection?

A large body of experimental evidence suggests that amifostine (Ethyol, WR-2721; MedImmune, Inc, Gaithersburg, MD) is a selective cytoprotector of normal tissues. Nevertheless, several experimental studies, most of which were conducted in the early 1980s, suggest that amifostine may protect tumor tissues, although to a much lower degree than its protective effect on normal tissues. Based on a critical literature review, we conclude that any experimental evidence suggesting tumor protection is weak. The effects of anesthesia and hypotension on normal and tumor tissue oxygenation status of animals, the consequences of such events on amifostine activity, and the impact of this complex situation on host immunity and radiotherapy efficacy in the experimental setting do not reliably simulate the clinical setting. Analyses of radiobiologic and histologic results of the Canine Sarcoma Study show that, if any conclusion is to be made, amifostine protected normal tissues and preserved (or even enhanced) the antitumor activity of radiotherapy. The Ormaplatin Study clearly showed a 10-fold decreased concentration of platinum in tumor compared with normal tissues, and does not therefore support evidence of lack of amifostine selectivity. Finally, not one clinical study suggests tumor protection with amifostine. On the contrary, the majority of clinical data strongly suggest that patients who receive amifostine with radiotherapy and/or chemotherapy do better than controls. Rather than organizing large-scale, randomized clinical trials to exclude tumor protection by amifostine, it seems more useful to design trials that would measure amifostine benefits in terms of improved quality of life, tumor control, and survival rates in patients being treated with standard or novel chemotherapy/radiotherapy regimens.

Muscle perfusion and oxygen consumption by near-infrared spectroscopy in septic-shock and non-septic-shock patients.

To measure muscle blood flow (Qtis) and oxygen consumption (VO(2)tis) in septic and non-septic critically ill patients by near-infrared spectroscopy (NIRS). Surgical intensive care unit of a university hospital. Four patients with septic shock, eight post-surgical critically ill patients and ten healthy volunteers. Oxyhaemoglobin (HbO(2)) and deoxyhaemoglobin (HbH) variations after venous occlusion were measured by NIRS in the brachioradialis muscle. We calculated Qtis by the rate of HbO(2) and HbH increase in the first 30 s of venous occlusion divided by haemoglobin blood concentration. VO(2)tis was calculated by subtraction of the arterial HbH from the initial increase of HbH after venous occlusion extrapolated to 1 min. Tissue oxygenation index [TOI = HbO(2)/(HbO(2)+HbH)] was also measured before venous occlusion. Two measurements in patients with septic shock, and one measurement in non-septic-shock patients and healthy subjects, were obtained. Of the measurements, 35% were repeated because of low-quality NIRS signal. VO(2)tis and Qtis were two times larger ( P<0.05) in patients with septic shock than in patients without and in healthy subjects. The TOI was very similar among the three groups. In septic-shock patients the increase in VO(2)tis was associated with an equivalent increase in Qtis. Therefore, tissue O(2) supply does not seem to be a limiting factor for muscle O(2) consumption. NIRS combined with venous occlusion allows a rapid, non-invasive and simultaneous assessment of regional perfusion and oxygen consumption. In case of microcirculatory shunt occurrence, the TOI should be cautiously used to assess tissue oxygenation state.

Detección intraoperatoria de hipoxia cerebral isquémica mediante sensores de presión tisular de oxígeno

Detection of intraoperative ischemic events could lead to the resolution of their cause and to the prevention of the definitive establishment of a postoperative infarct. We want to illustrate the possibilities that intraoperative monitoring of oxygen tissue pressure (PtiO2) in critical areas during a neurosurgical vascular procedure offers, enhancing its reliability and immediacy in obtaining information about tissue oxygenation status as a marker of ischemia in the vascular territory at risk. We report the case of a 32 year-old male with a deep arteriovenous malformation (AVM) localised in the insular region. The patient had been previously treated with radiosurgery without achieving a satisfactory result. AVM removal was performed through a transylvian transinsular approach. PtiO2 was monitorised at the temporal pole (reference area) and at the posterior temporal region (risk area). Both probes maintained close tissue oxygenation levels until the last stage of the AVM resection when, during the coagulation of a supposed afferent vessel, a brisk fall of the oxygen tissue pressure in the posterior temporal region was detected. An ischemic infarct in this area was observed postoperatively. PtiO2 monitoring has a high reliability in the detection of intraoperative tissue hypoxia. Data obtained could lead to early identification of these events and, whatever possible, to resolve this situation preventing the definitive establishment of an ischemic infarct.

Tumor oxygenation and its relevance to tumor physiology and treatment.

For many years, the identification of tumor hypoxia, its systematic characterization and the assessment of its clinical relevance were not possible due to lack of methods suitable for the routine measurement of intratumoral oxygen tensions in patients. In the late 1980s, a novel and clinically applicable standardized procedure was established enabling the determination of the tissue oxygenation status in primary tumors, local recurrences, and metastatic lesions in patients using a computerized polarographic needle electrode system. Within a relatively short period of time, the significance of tumor oxygenation for therapy outcome became evident in numerous experimental and clinical studies.

Infrared spectroscopy: shedding light on synovitis in patients with rheumatoid arthritis.

It is difficult to determine the extent of synovial involvement early in the course of rheumatoid arthritis. A spectroscopic technique was used to characterize the synovium of the small finger joints in both early and late rheumatoid arthritis. This synovium was also compared against normal joints. Near-infrared spectroscopy assesses the absorption of near-infrared light by specific joints, giving a characteristic "fingerprint" of the properties of the underlying tissues. Triple measurements by infrared spectroscopy were taken at the bilateral second and third metacarpophalangeal joints. Multivariate analysis was applied. Analysis was able to demonstrate relationships between the specific sources of spectral variation and joint tenderness or swelling as well as radiographic damage. Further use of multivariate analysis allowed recognition of the spectral patterns seen in early disease vs late rheumatoid arthritis and correct classification of over 74% of the joints. The spectral regions where differences occurred were in the absorption bands related to tissue oxygenation status, allowing the provocative implication that this technique could be detecting ischaemic changes within the joint. Near-infrared spectroscopy may thus be able to provide us with some information about the biochemical changes associated with synovitis.

Circulatory oxygen transport in the water flea Daphnia magna.

To determine the contribution of circulatory convection to tissue oxygen supply in animals of Daphnia magna, heart rate ( f(H)), in-vivo Hb oxygen-saturation ( S(Hb)) and NADH fluorescence intensity ( I(NADH)) as a measure of the tissue oxygenation state were simultaneously measured using digital motion analysis, microabsorption spectroscopy and fluorescence microscopy. In addition, the relationship between stroke volume and body size was established. Groups of differently sized animals (small: 1.4-1.6 mm, medium: 2.7-2.9 mm, large: 3.3 mm) with either low (Hb-poor) or high Hb concentration (Hb-rich) in the hemolymph were exposed to a gradual decrease in ambient oxygen partial pressure ( P(O2amb)) between normoxia and anoxia. In all groups, f(H) increased in response to progressive hypoxia. The hypoxic maximum in f(H) was highest in medium-sized Hb-poor animals, whereas perfusion rate increased continuously with increasing body size in Hb-poor and Hb-rich animals. The P(O2amb) at which Hb in the heart region was half-saturated (in-vivo P(50)) was higher in medium-sized (Hb-poor: 3.2 kPa, Hb-rich: 2.0 kPa) than in small (Hb-poor: 2.1 kPa, Hb-rich: 1.5 kPa) and large animals (Hb-poor: 1.9 kPa). The in-vivo P(50) was always lower in Hb-rich than in Hb-poor animals. The I(NADH) indicated an impairment of tissue oxygenation starting at higher critical P(O2amb) with increasing body size and with lower Hb concentration. Model calculations suggest that at the respective critical P(O2amb), circulatory convection delivers less than half of the oxygen demand in Hb-poor animals. In contrast, in Hb-rich animals, the contribution of circulatory convection to tissue oxygen supply at respective critical P(O2amb) was much greater due to the higher concentration of Hb.

Oxygen as a regulator of cellular phenotypes in pregnancy and cancer.

Cellular phenotype is determined by genetic and microenvironmental factors. There is evidence that tissue oxygenation status is one of the microenvironmental factors regulating cellular behaviour. Both normal and pathological processes such as blastocyst implantation in the uterus, placentation, and rapidly growing tumours occur under conditions characterized by relatively low oxygen levels. In this review, we address the effects of low oxygen concentrations on the phenotype of trophoblast and cancer cells. We provide evidence that oxygenation levels play an important role in the regulation of normal and pathological cellular invasiveness as it occurs during trophoblast invasion of the uterus and in tumour progression and metastasis, drug resistance in cancer, and antitumour activity of natural killer cells of the immune system.

Monitoring tissue oxygen availability with near infrared spectroscopy (NIRS) in health and disease.

Near infrared spectroscopy (NIRS) is becoming a widely used research instrument to measure tissue oxygen (O2) status non-invasively. Continuous-wave spectrometers are the most commonly used devices, which provide semi-quantitative changes in oxygenated and deoxygenated hemoglobin in small blood vessels (arterioles, capillaries and venules). Refinement of NIRS hardware and the algorithms used to deconvolute the light absorption signal have improved the resolution and validity of cytochrome oxidase measurements. NIRS has been applied to measure oxygenation in a variety of tissues including muscle, brain and connective tissue, and more recently it has been used in the clinical setting to assess circulatory and metabolic abnormalities. Quantitative measures of blood flow are also possible using NIRS and a light-absorbing tracer, which can be applied to evaluate circulatory responses to exercise along with the assessment of tissue O2 saturation. The venular O2 saturation can be estimated with NIRS by applying venous occlusion and measuring changes in oxygenated vs. total hemoglobin. These various measurements provide the opportunity to evaluate several important metabolic and circulatory patterns in very localized regions of tissue and may be fruitful in the study of occupational syndromes and a variety of diseases.

Further characterisation of a thromboembolic model of stroke in the rat

We have used magnetic resonance imaging (MRI) techniques to characterise a rat model of thromboembolic stroke. The consequences of acute perfusion deficit associated with a middle cerebral artery occlusion (MCAo) by a newly formed thrombus was mapped by interrogation of the tissue oxygenation status using gradient echo methods and production of T2* maps. Final infarct size was subsequently assessed at 24-h post-ischaemia by histology with 2,3,5-triphenyltetrazolium chloride (TTC) staining. Animals displayed an infarct volume of 178.7±84.2 mm 3 (mean±S.D.) with a large coefficient of variation (47%) and range of values (85.6–265.5 mm 3). This variability provided us with an opportunity to assess the relationships between early imaging observations and eventual infarct size. For a single cerebral slice, at the centre of the MCA territory, a relationship between the area of reduced T2* at 1 and 2 h post MCAo correlated highly with final lesion area (Spearman rank correlation, r=0.98, P<0.01, n=9). Lesion volumes in the thromboembolic MCAo model were compared with a 120-min occlusion, 22-h reperfusion protocol using an intraluminal thread MCAo approach. For the thromboembolic model, the total lesion volume was found to be smaller (178.7±84.2 vs. 243.3±50.1 mm 3, mean±S.D., Student’s t-test P=0.046) and showed a greater variability (coefficient of variations: 47% vs. 21%). These data underline the relative variability of this embolic model and provide important preliminary information regarding the value of early changes in T2* in predicting eventual infarct size.

Radiation-induced DNA damage in tumors and normal tissues. VI. Estimation of the hypoxic fraction of experimental tumors.

For several years, we have concentrated our efforts on validating the use of radiation-induced DNA strand breaks and DNA-protein crosslinks to assess the oxygenation status of tumors and normal tissues. We have demonstrated that (1) the oxygen dependence of strand break formation is identical to that of radiation-induced cell killing; (2) the oxygen dependence of DNA-protein crosslink formation is the mirror image of that of radiation-induced cell killing; and (3) the formation of these radiation-induced DNA lesions is predominantly dependent on the oxygen concentration near the DNA and is independent of the cell type, metabolic status, proliferative status, pH of the surrounding environment, and composition or properties of the proteins tightly associated with the DNA. In the present study, the hypoxic fraction of three experimental tumors was estimated using our assay of radiation-induced DNA damage. The average hypoxic fraction of a large number of tumors estimated with this assay of radiation-induced DNA damage for (1) WiDR human colorectal carcinoma xenografts (40.8 +/- 4.2%), (2) 66 mouse mammary adenocarcinoma tumors (41.8 +/- 3.1%), and (3) subcutaneous tumors grown from 9L rat brain tumor cells (95% CI =-8.2-4.2%) was not statistically different from that of a large number of tumors measured for each of these tumor models by the paired survival curve method (38.3 +/- 6. 3%, 28.9 +/- 5.5%, 95% CI = 2.2-4.4%, respectively). When the hypoxic fraction measured by the alkaline elution method on one half of an individual tumor was compared to that measured by the paired survival curve method on the other half of the same tumor, no statistical correlation was found for either 66 or WiDR tumors. Although this assay of radiation-induced DNA damage can be used effectively in the laboratory to answer a number of important questions about the oxygenation status of animal tumors and normal tissues, failure to reliably estimate the hypoxic fraction of individual tumors and technical considerations make it unlikely that the assay can be used in the clinic to estimate the hypoxic fraction of human tumors.

Changes in blood perfusion and hypoxia after irradiation of a human squamous cell carcinoma xenograft tumor line.

The effect of irradiation depends on the oxygenation status of the tissue, while irradiation itself also changes the oxygenation and perfusion status of tissues. A better understanding of the changes in tumor oxygenation and perfusion over time after irradiation will allow a better planning of fractionated radiotherapy in combination with modifiers of blood flow and oxygenation. Vascular architecture (endothelial marker), perfusion (Hoechst 33342) and oxygenation (pimonidazole) were studied in a human laryngeal squamous cell carcinoma tumor line grown as xenografts in nude mice. The effect of a single dose of 10 Gy X rays on these parameters was evaluated from 2 h to 11 days after irradiation. Shortly after irradiation, there was an 8% increase in perfused blood vessels (from 57% to 65%) followed by a significant decrease, with a minimum value of 42% at 26 h after irradiation, and a subsequent increase to control levels at 7 to 11 days after irradiation. The hypoxic fraction showed a decrease at 7 h after treatment from 13% to 5% with an increase to 19% at 11 days after irradiation. These experiments show that irradiation causes rapid changes in oxygenation and perfusion which may have consequences for the optimal timing of radiotherapy schedules employing multiple fractions per day and the introduction of oxygenation- and perfusion-modifying drugs.

3453 Mucosal hemodynamics in the watershed area of the normal colon and in hemodialysis and oxygendependent patients.

Patients on chronic hemodialysis (HD) are prone to develop ischemic colitis. The effect of the state of tissue oxygenation upon the regulation of tissue blood flow has not been well described in human studies. Aim:We used the endoscopic reflectance spectrophotometry technique which provides an index of hemoglobin concentration (IHb) and index of oxygen saturation (ISO2) to evaluate the above issues. Methods: Controls (n=11), oxygendependent (n=7) and HD (n=9) patients underwent sigmoidoscopy and IHb and ISO2 readings were obtained at the watershed area (20 cm from the anal verge) of the sigmoid colon. In the O2-dependent patients, measurements were made off and on O2 supplementation while peripheral O2 saturation was monitored by pulse oxymetry. Results: The results are summarized in the Table below. In O2-dependent patients pulse oxymetry readings were significantly lower off O2 than on O2 (85.2 ± 0.3% vs. 94.1 ± 0.2%; p

Increased uptake of99mTc-HL91 in tumor cells exposed to X-ray radiation

99mTc-HL91, a hypoxic marker, may be a predictor of tumor response to radiotherapy and an indicator of tumor oxygenation in the course of treatment. In this study, serial changes in 99mTc-HL91 uptake were observed in the normoxic condition in a human bladder cancer cell line exposed to a single dose or a fractionated dose of 10 Gy with an x-ray beam. The uptake per cell increased during cell growth retardation induced by the irradiation. This finding indicates that 99mTc-HL91 uptake is affected by injury to cells due to radiation; it may therefore be difficult to correctly assess the tissue oxygenation status during radiotherapy with 99mTc-HL91.

Peripheral Oxygenation in Preterm Infants

When tissue oxygenation is impaired, compensatory mechanisms occur, including a redistribution of blood flow in order to maintain oxygen delivery to vital organs, resulting in a fall in peripheral blood flow. Monitoring peripheral oxygenation therefore has potential benefits as it may provide an early warning of changes in the state of tissue oxygenation. Clinical assessments of the state of peripheral perfusion are common, and several physiological measurements have been described or used which are able to monitor peripheral oxygenation. Some of the available methods and their clinical implications will be reviewed. Near infrared spectroscopy is a particularly promising technique that has only recently been used in the preterm neonate to quantify peripheral oxygenation. It may be of potential value in understanding pathophysiological changes that occur in certain situations and needs further assessment to determine whether it may be useful to guiding clinical interventions.

Clinical Application: Using Oxygenation Profiles to Manage Patients

Cellular oxygenation is dependent on both tissue oxygenation and pulmonary oxygenation. The use of profiles can help to make the assessment of tissue and pulmonary oxygenation more thorough. Although oxygenation profiles have limitations, an understanding of them can provide useful information to the critical care nurse. Oxygenation profiles enable the nurse to trend a patient's progress and response to nursing and medical interventions. A sophisticated assessment relies not merely on physical assessment alone but incorporates continuous mixed venous oxygenation and oxygenation profiles to assess a patient's tissue and pulmonary oxygenation status.

Oxygenation in patients with a functionally univentricular circulation and complete mixing of blood: are saturation and flow interchangeable?

Perioperative management of patients with complete mixing of pulmonary and systemic blood centers on approximately equating pulmonary (Qp) and systemic (Qs) blood flow (Qp/Qs approximately 1). This empirically derived target is opposed by theoretical studies advocating a target Qp/Qs well below 1. We studied the cause of this persistent discrepancy. Classic theoretical studies have concentrated on maximizing 1 of many potential combination parameters of arterial oxygen content (CaO(2)) and systemic blood flow: total oxygen delivery (DO(2))=CaO(2)xQs. We defined "useful" oxygen delivery as the amount of oxygen above a notional saturation threshold (Sat(Thresh)): D(u)O(2)=carrying capacityx(SaO(2)-Sat(Thresh))xQs. Whereas DO(2) peaks at Qp/Qs ratios <1, D(u)O(2) peaks at higher Qp/Qs ratios, nearer to (or exceeding) 1. Systemic venous saturation (which mirrors tissue oxygen tension) peaks at Qp/Qs=1. First, the standard model of single-ventricle physiology can be reexpressed in a form allowing analysis by differential calculus, which allows broader conclusions to be drawn than does computer modeling alone. Second, the classic measure DO(2) fails to reflect the fact that proportional changes in saturation and flow are not clinically equivalent. Recognizing this asymmetry by using D(u)O(2) can give a target Qp:Qs balance that better represents clinical experience. Finally, to avoid an arbitrary choice of Sat(Thresh), systemic venous oxygen saturation (SsvO(2)) may be a useful parameter to maximize: this occurs at a Qp/Qs ratio of 1. Attempts to increase DO(2) by altering Qp/Qs away from this value will inevitably reduce SsvO(2) and therefore tissue oxygenation. Oxygen delivery is far from synonymous with tissue oxygen status.

Tissue oxygen distribution in head and neck cancer patients.

The importance of hypoxia in limiting the sensitivity of tumor cells to ionizing radiation has long been known. We evaluated the tissue oxygenation status with a polarographic needle electrode system in 37 patients with malignancies of the head and neck and correlated the pO2 of 25 patients with treatment outcome. Sixteen tumors contained areas of severe hypoxia, defined by pO2 values below 2.5 mm Hg. Tumor oxygenation parameters were not correlated with hemoglobin, age, and history of tobacco use. There were no subcutaneous PO2 values below 10 mm Hg (ie, no areas of moderate or severe hypoxia), whereas this degree of hypoxia was commonly found in the tumors. Though not statistically significant, hypoxic tumors showed trends for poorer treatment outcome. Our data demonstrate a great interindividual variability in the oxygenation of head and neck cancers and appears unassociated with clinical parameters. The method is capable of identifying patients with poorly oxygenated tumors, thereby providing important information for selecting patients who might need customized therapy designed to kill hypoxic tumor cells. Hypoxic tumors show a consistent trend for poor treatment outcome.