Evaluation of Betulinic Acid Derivatives as PET Tracers for Hypoxia-Induced Carbonic Anhydrase IX (CA IX) Expression.

Non-invasive visualisation of the expression of hypoxia-related proteins, such as carbonic anhydrase IX (CA IX), by positron emission tomography (PET) could provide important information on the oxygenation status of tumours. Since betulinic acid derivatives bind specifically to CA IX the aim of the study was the development betulinic acid-based 68Ga-labelled PET tracers and to evaluate the hypoxia detecting properties in vitro and in vivo. The binding of betulinic acid (B-DOTA) and betulinyl-3-sulfamate (BS-DOTA) was assessed in two rat tumour cell lines (AT1 prostate and Walker-256 mammary carcinomas). AT1 cells express CA IX in a hypoxia-dependent manner whereas Walker-256 cells, expressing almost no CA IX in wildtype, were transfected with the rat Car9 gene. In vivo measurements were carried out in a small animal PET/CT in AT1 tumours in rats breathing room air, 8% or 100% O2. In AT1 cells hypoxia-induced overexpression of CA IX led to a stronger binding of BS-DOTA but not of B-DOTA. The BS-DOTA binding correlated linearly with the CA IX protein expression and could be blocked by an excess of unlabelled tracer. In the transfected Walker-256 cells no specific binding of either of the tracers was seen. In vivo the intratumoral accumulation of BS-DOTA was increased in animals kept under inspiratory hypoxia and reduced by hyperoxia. Therefore, betulinyl-3-sulfamate could be used as a PET tracer of CA IX expression in tumours and to provide information about the oxygenation status. However, accumulation data indicated that binding not only depends on hypoxia-induce CA IX expression but also on the tumour-line-specific basal expression and on the initial oxygenation status of the tumour.

Noninvasive optoacoustic imaging of breast tumor microvasculature in response to radiotherapy.

Detailed insight into the radiation-induced changes in tumor microvasculature is crucial to maximize the efficacy of radiotherapy against breast cancer. Recent advances in imaging have enabled precise targeting of solid lesions. However, intratumoral heterogeneity makes treatment planning and monitoring more challenging. Conventional imaging cannot provide high-resolution observation and longitudinal monitoring of large-scale microvascular in response to radiotherapy directly in deep tissues. Herein, we report on an emerging non-invasive imaging assessment method of morphological and functional tumor microvasculature responses with high spatio-temporal resolution by means of optoacoustic imaging (OAI). In vivo imaging of 4T1 breast tumor response to a conventional fractionated radiotherapy at varying dose (14 × 2 Gy and 3 × 8 Gy) has been performed after 2 weeks following treatment. Remarkably, optoacoustic images can generate richful contrast for the tumor microvascular architecture. Besides, the functional status of tumor microvasculature and tumor oxygenation levels were further estimated using OAI. The results revealed the differential (size-dependent) nature of vascular responses to radiation treatments at varying doses. The vessels exhibited an decrease in their density accompanied by a decline in the number of vascular segments following irradiation, compared to the control group. The measurements further revealed an increase of tumor oxygenation levels for 14 × 2 Gy and 3 × 8 Gy irradiations. Our results suggest that OAI could be used to assess the response to radiotherapy based on changes in the functional and morphological status of tumor microvasculature, which are closely linked to the intratumor microenvironment. OAI assessment of the tumor microenvironment such as oxygenation status has the potential to be applied to precise radiotherapy strategy.

The Association Between Oxygenation Status at 24 h After Diagnosis of Pulmonary Acute Respiratory Distress Syndrome and the 30-Day Mortality among Pediatric Oncological Patients.

Background: Pediatric oncology patients with acute respiratory distress syndrome (ARDS) secondary to pneumonia are at high risk of mortality. Our aim was to describe the epidemiology of ARDS in this clinical population and to identify the association between the oxygenation status at 24 h after diagnosis and the 30-day mortality rates, stratified by the severity of ARDS. Methods: This was a retrospective cohort study of 82 pediatric oncology patients, with a median age of 4 years, admitted to our pediatric intensive care unit with a diagnosis of ARDS between 2013 and 2021. Demographic and clinical factors were compared between the survivor (n = 52) and non-survivor (n = 30) groups. Univariate and multivariate Cox proportional hazards regression models were used to determine the association between the oxygenation status at 24 h after diagnosis and the 30-day mortality rates. Results: The mean airway pressure at ARDS diagnosis, PaO2/FiO2 (P/F) ratio, oxygenation index (OI) value, peak inspiratory pressure, and lactate level at 24 h after ARDS diagnosis, as well as complications (i.e., septicemia and more than two extrapulmonary organ failures) and adjunctive continuous renal replacement therapy, were significant mortality risk factors. After adjusting for other covariates, the oxygenation status P/F ratio (Hazard ratio [HR] = 0.98, 95% confidence interval [CI] = 0.96-1.00, P = 0.043) and OI value (HR = 1.12, 95% CI = 1.02-1.23, P = 0.016) at 24 h remained independent mortality risk factors. According to the Kaplan-Meier survival curve, a low P/F ratio (≤ 150) and high OI (>10) were associated with a higher risk of 30-day mortality (50.9 and 52.9%, respectively; both P < 0.05). Conclusion: The P/F ratio and OI value measured at 24 h after ARDS diagnosis can provide a better stratification of patients according to ARDS disease severity to predict the 30-day mortality risk.

Impact of Tocilizumab on Inflammatory Markers and Oxygen Status in Severe COVID-19 Patients: A Single Centre Retrospective Study.

OBJECTIVE: This retrospective study aims to investigate the impact of tocilizumab on inflammatory markers in patients with severe COVID-19. The effect on oxygenation was also assessed. METHODS: This study is a single-centre, retrospective cohort study conducted at NIMS hospital. Data of the eligible patients with severe COVID-19 pneumonia who received injection tocilizumab (max 800 mg) were charted and analysed. Oxygenation and inflammatory markers were compared before and after (day 3 and day 7) tocilizumab injection. Effect of dysglycemia on the efficacy of tocilizumab was assessed. Outcomes were analysed in the form of discharge without oxygen, discharge with oxygen, and death. Data were analysed by SPSS v22. RESULTS: The mean age of the subjects was 57.8 ± 12.2 years, and 78.57% were male. Forty-four percent of the patient had type 2 diabetes. Tocilizumab treatment was associated with reduction in the oxygen requirement [median:10 L/min (IQR6- 14)] v/s 4 L/min (IQR 3-7, p-0.005]. Peripheral oxygen saturation also improved after tocilizumab [92 % (IQR 90-96)] v/s [95 % (IQR 94-96), p-0.01)], respectively. Serum CRP level decreased significantly when evaluated after three days (44±5 v/s 20 ±3 mg/dl, p=< 0.001). Out of the 42, 12 (29%) patients died due to severe COVID-19 or its complications. When compared with the patients who survived, patients who died had a higher level of D-dimer (1.2 ± 0.51 v/s 3.1 ±1.2 ng/dl, p-value- 0.04), and LDH: (845 ±55 v/s 1364 ±198 U/L, p - 0.01). At day seven of the tocilizumab injection, diabetic patients (n-13) had higher IL-6 serum level than nondiabetic patients (n-16) [(median- 311(IQR-1245.5) v/s (209 (IQR-546.2), p-value- 0.048]. CONCLUSION: In this retrospective pre-post analysis, tocilizumab injection was associated with reduced inflammation and improved oxygenation in severe COVID-19. Despite high IL-6 levels, diabetes had no impact on the efficacy of the tocilizumab.

CO-oximetry measurements and antioxidant effects of ascorbic acid and methylene blue in equine methemoglobinemic blood.

OBJECTIVES: To determine the effects of time after sampling on CO-oximetry measurements of equine blood samples and the effects of adding ascorbic acid (AscAc) and methylene blue (MetBlue) to samples with methemoglobinemia. DESIGN: Experimental study. SETTING: University teaching hospital. ANIMALS: Thirty healthy adult horses assigned to 5 groups. INTERVENTIONS: Repeated CO-oximetry determinations were performed on venous (n = 6) and arterial blood samples (n = 7) stored at 0°C for 48 hours. Methemoglobinemia was induced in vitro in 17 additional blood samples. Six were used as untreated controls, 6 had AscAc added, and 5 had MetBlue added. Total hemoglobin, oxyhemoglobin, carboxyhemoglobin, methemoglobin (MetHb), and oxygen saturation of hemoglobin (SO2 ) were measured. MEASUREMENTS AND MAIN RESULTS: Oxyhemoglobin and SO2 increased from 69.8% ± 10.2% and 90% ± 3% to 82.8% ± 7.9% and 99% ± 3%, respectively, after 8 hours in venous blood (mean ± SD, P < 0.001). There was an effect of treatment (P = 0.032) and of time (interaction P = 0.003) on MetHb% in methemoglobinemic samples. The difference in absolute MetHb% from time 0 was as follows: 7.0% (interquartile range [IQR] = 21.2), -0.2% (IQR = 3.5), and -4.4% (IQR = 5.2) at 48 hours in control, AscAc, and MetBlue groups, respectively (P < 0.05). There was no effect of time on MetHb% in the AscAc group (23% [IQR = 52.6] at time 0 to 23.2% [IQR = 56.9] after 48 h). CONCLUSIONS: Storage of blood in ice water to determine O2 Hb and SO2 using a CO-oximeter should not exceed 4 hours. Measurement of MetHb% could be delayed by up to 48 hours if AscAc is added to the sample. MetBlue significantly decreased MetHb% over time. The limitations of this study include the fact that the antioxidant effects of AscAc and MetBlue were evaluated in vitro and not in vivo. Further studies are needed to evaluate different storage temperatures and syringe types.

Comparison of venous hemoglobin saturation measurements obtained by in vivo oximetry and calculated from blood gas analysis in critically ill dogs.

OBJECTIVE: To compare in vivo central venous hemoglobin saturation measurement (ScvO2 ) using a fiber optic catheter with saturation calculated from blood gas analysis in critically ill dogs. DESIGN: Prospective observational study. SETTING: University veterinary teaching hospital intensive care unit. ANIMALS: A convenience sample of 20 dogs with severe illness. INTERVENTIONS: Dogs were instrumented with either a central venous catheter with an integrated fiber optic cable or a conventional catheter with a fiber optic probe inserted through its distal port. Baseline saturation was measured with the fiber optic system (FSO2 ), then monitored continuously. Central venous blood was collected for analysis and FSO2 was recorded by the principal investigator (PI) or nursing staff participating in data collection (staff) at baseline and at 1, 2, 3, and 6 hours. Hemoglobin oxygen saturation (SO2 ) values calculated using human Bohr coefficients were taken directly from the analyzer (GPSO2 ), and were also calculated using temperature-correction and canine Bohr coefficients (RSO2 ). MEASUREMENTS AND MAIN RESULTS: Ninety-seven paired measurements from 20 dogs were analyzed. FSO2 obtained by the PI (n = 41) had better agreement with both GPSO2 (concordance correlation coefficient ρc = 0.926 vs 0.5562) and RSO2 (ρc = 0.75 for PI vs 0.54) than did staff (n = 56). RSO2 values were always smaller than GPSO2 . FSO2 - GPSO2 differences were smaller when measurements were collected by the PI versus Staff (mean difference 0.21 vs -6.6, respectively, P < 0.02). Thirty-six of 41 FSO2 values obtained by PI were within 5% of GPSO2 . CONCLUSIONS: Concordance between FSO2 and either calculation method was low, but was better when performed by PI. The larger difference between methods when using RSO2 suggests a positive bias by FSO2 . Difficulty obtaining stable measurements may have contributed to the poor concordance between methods within Staff.

Portable, consumer-grade pulse oximeters are accurate for home and medical use: Implications for use in the COVID-19 pandemic and other resource-limited environments.

OBJECTIVE: To determine the correlation between 3 lightweight portable pulse oximeter devices compared to a standard wall mount pulse oximetry device. METHODS: We performed a single-center, prospective, observational study of 4 pulse oximetry devices, 3 of which are commercially available to the public. A convenience sample of 200 emergency department (ED) patients with chief complaints of cardiopulmonary origin or a peripheral capillary oxygen saturation ≤ 94 percent were enrolled. Analysis of variance was performed to compare SpO2s and test characteristics of the 3 devices compared to control. RESULTS: Although differences in measured SpO2s were observed (P < 0.001) across groups, the differences were small (mean differences ranged from 1.00% to 1.87%). The correlation between test devices and the control were high (r range 0.70-0.79). Although the test characteristics were not perfect, the devices did have good sensitivity using a cutoff value of 94% (sensitivity ranging from 90% to 92%), which improved with lower SpO2 cutoff values to 92% (sensitivity ranging from 96% to 97%). CONCLUSION: The 3 commercially available devices were accurate enough to be clinically useful when compared to a hospital bedside monitor pulse oximeter. Consumer-grade portable pulse oximeters may be useful if overwhelming numbers of patients require oxygen saturation monitoring, such as during the COVID-19 pandemic.

Tissue oxygen saturation in dogs with acute hemorrhage.

OBJECTIVE: To evaluate initial tissue hemoglobin oxygen saturation (StO2 ) in dogs presenting to an emergency room (ER) for acute hemorrhage. DESIGN: Prospective, observational study. SETTING: University veterinary teaching hospital. ANIMALS: Thirty-eight dogs with acute hemorrhage were enrolled between July 2009 and October 2010. Seventy-eight normal dogs from a previous observational study were included to represent healthy controls ("no shock"). INTERVENTIONS: Tissue oxygen saturation measurement was obtained at enrollment on dogs presented to the ER for acute hemorrhage. Baseline clinicopathologic (CBC, serum biochemical profile, prothrombin time, and activated partial thromboplastin time) and physiologic (plasma lactate concentration, venous blood gas, blood pressure, and hemoglobin oxygen saturation by pulse oximetry) data were recorded from all patients with hemorrhage. An ER clinician blinded to the StO2 value guided patient management. Patient survival to discharge from the hospital in the study group was recorded. Once data collection was complete, 3 emergency and critical care clinicians blinded to the StO2 data retrospectively classified patients into 1 of 4 shock categories (no shock, mild, moderate, or severe shock). MEASUREMENTS AND MAIN RESULTS: The historical group of healthy dogs had higher StO2 concentrations compared to the dogs classified with shock at all 3 levels (mild, moderate, and severe, P = 0.0006, <0.0001, and 0.0018, respectively); however, there was no statistical difference in StO2 between the levels of shock. A cut-off StO2 value of 87.6% identified a patient as having shock (area under the curve: 0.824, 95% confidence interval 0.749, 0.899). CONCLUSIONS: Dogs with hemorrhagic shock have lower StO2 than a population of healthy dogs.

Feasibility study on oxygen saturation related diffusion index for assessing oxygenation status / 中华护理杂志

Objective To explore the feasibility of oxygen saturation related diffusion index for assessing oxygenation status,and to establish the critical value of the oxygen saturation related diffusion index,so as to provide more approaches to monitoring oxygenation status.Methods A total of 30 patients with acute respiratory distress syndrome (ARDS) receiving mechanical ventilation support were retrospectively reviewed.Totally 340 cases were collected at corresponding time points,and were divided into mild,moderate and severe groups according to ARDS Berlin criteria.Results There was a positive correlation between oxygen saturation related diffusion index and oxygenation index (r=0.698,P＜0.001);the critical value between the moderate and severe groups of oxygen saturation related diffusion index was 171(sensitivity 84.7％,specificity 68.2％),and the critical value between mild group and moderate group was 440 (sensitivity 56.9％,specificity 91.9％).Conclusion The oxygenation index was consistent with the oxygen saturation related diffusion index in judging the oxygenation status of ARDS patients.As a noninvasive and continuous index,the oxygen saturation related diffusion index provides a new method for nursing assessment.

The Quarter Prone Position Increases Oxygen Saturation in Premature Infants Using Continuous Positive Airway Pressure.

A primary problem that occurs in premature infants is oxygenation disorders, thus requiring respiratory support, including continuous positive airway pressure (CPAP). The effectiveness of CPAP can be improved by adjusting the body's position, so the aim of this study was to examine the effect of the quarter prone position on the oxygenation status of preterm infants using CPAP. This study used a randomized controlled trial with a crossover design. A group of 15 preterm infants receiving CPAP was selected, and randomization of allocation was done to divide the respondents into the intervention group (quarter prone) or the control group (supine). Oxygenation status was measured using an observation form, and the result showed a significant difference in the oxygen saturation levels of premature infants using CPAP in the quarter prone group compared to that in the supine group (p = .045). The quarter prone position was effective for improving the oxygenation status of premature infants using CPAP. It is recommended that the quarter prone position be applied as part of nursing care in neonatal nursing.

Effects of noninvasive positive pressure ventilation on oxygenation status and prognosis in patients with acute paraquat-induced lung injury.

PURPOSE: The aim of this study was to evaluate the effects of noninvasive positive pressure ventilation (NIPPV) on oxygenation status and prognosis in patients with acute lung injury induced by paraquat (PQ) poisoning. METHODS: Patients with acute PQ-induced lung injury treated with NIPPV were admitted to an emergency intensive care unit. Changes in oxygenation status (respiratory rate and the partial pressure of alveolar O2 and CO2 [PaO2 and PaCO2, respectively]) after initial NIPPV were observed. Differences in inspiratory pressure (PI) between nonsurvivors and survivors were compared. The relationship between PI and the prognosis of patients with acute PQ-induced lung injury was evaluated. FINDINGS: A total of 86 patients (47 women, 39 men; mean age, 33.5 [24.5] years [range, 22-61 years]) were included. There were significant differences in respiratory rate, PaO2, and PaCO2 from before to after initial NIPPV (respiratory rate, 35 [14] vs 26 [16] min(-1) [P = 0.037]; PaO2, 61.8 [19.6] vs 73.5 [26.8] mm Hg [P = 0.046]; and PaCO2, 27.7 [16.4] vs 34.6 [19.2] mm Hg [P = 0.039]). The overall mortality rate was 75.6% (65/86) during a 28-day follow-up period. We observed a significant difference in initial PI (PIinit) between nonsurvivors and survivors (8.2 [4.3] vs 6.6 [3.8] cm H2O; P = 0.043). Furthermore, nonsurvivors had a greater maximal PI (PImax) than did survivors (21.6 [9.8] vs 15.4 [8.5] cm H2O; P = 0.022). Correlation analysis revealed that both PIinit and PImax were associated with a poor prognosis in patients with acute PQ-induced lung injury (PIinit, r = -0.29 [P = 0.038]; PImax, r = -0.31 [P = 0.042]). IMPLICATIONS: NIPPV may effectively improve oxygenation status in patients with acute PQ-induced lung injury, thereby relieving dyspnea and promoting the recovery of pulmonary function. PIinit and PImax may be important determinants of prognosis in acute PQ-induced lung injury. These findings need further verification in a large-scale, multicenter, randomized controlled study that combines other factors with a relatively long-term follow-up.

Radiosensitivity and Capacity to Recover from Radiation-Induced Damage in Pimonidazole-Unlabeled Intratumor Quiescent Cells Depend on p53 Status.

BACKGROUND: Using our method for selectively detecting the response of intratumor quiescent (Q) cells to irradiation, the Q cells was shown to have a much larger hypoxic fraction (HF) than total (= proliferating (P) + Q) tumor cell population irrespective of the p53 status of tumor cells. However, the size of the HF was clearly less than 100%, meaning the Q cell population was never fully hypoxic. Thus, the dependency of the radio-sensitivity and recovery capacity from radiation-induced damage on p53 status was investigated in pimonidazole-unlabeled oxygenated Q tumor cells. METHODS: Human head and neck squamous cell carcinoma cells transfected with mutant TP53 (SAS/mp53), or with neo vector as a control (SAS/neo), were inoculated subcutaneously into left hind legs of Balb/cA nude mice. The tumor-bearing mice received 5-bromo-2'-deoxyuridine (BrdU) continuously to label all intratumor P cells. Tumors were irradiated with γ-rays at a high dose-rate or a reduced dose-rate at 1 h after the administration of pimonidazole. The responses of Q and total cell populations were evaluated with the frequencies of micronucleation and apoptosis using immunofluorescence staining for BrdU. The response of pimonidazole unlabeled tumor cell fractions was assessed with apoptosis frequency using immunofluorescence staining for pimonidazole. RESULTS: The pimonidazole-unlabeled tumor cell fraction showed significantly enhanced radio-sensitivity compared with the whole tumor cell fraction more remarkably in Q cells and p53-mutated tumors than total cells and p53-wild type tumors, respectively. However, a significantly greater decrease in radio-sensitivity in the pimonidazole-unlabeled than the whole cell fraction, evaluated using a delayed assay or a decrease in radiation dose rate, was more clearly observed in Q cells and p53-wild type tumors than total cells and p53-mutated type tumors, respectively. Concerning the whole tumor cell fraction, the Q cells showed significantly greater radio-resistance and recovery capacity from radiation-induced damage than the total cells both in p53-wild and p53-mutated type tumors. CONCLUSIONS: The pimonidazole-unlabeled sub-fraction of the Q tumor cells, probably oxygenated, may be a critical target in the control of solid tumors, although its radio-sensitivity and recovery capacity from radiation-induced damage depend on p53 status of the tumor cell.