Tissue Partial Pressure Research Articles

Apatinib Combined With Radiotherapy Enhances Antitumor Effects in an In Vivo Nasopharyngeal Carcinoma Model.

Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) are highly expressed in nasopharyngeal carcinoma; therefore, blocking the binding of VEGF and VEGFR may be a potential way to treat nasopharyngeal carcinoma. Apatinib inhibits tumor angiogenesis. Previous studies have suggested that treatment with apatinib has an antitumor effect on nasopharyngeal carcinoma. This study will investigate the effect of apatinib combined with radiotherapy. In this study, nude mice injected with CNE-2 nasopharyngeal carcinoma cells were randomly divided into 6 groups. Therapeutic effects were assessed by evaluating tumor inhibition rate, phosphorylation of VEGFR-2, CD31, partial oxygen pressure, and tumor metabolism. We found that the tumor inhibition of mice in the treated groups was better compared to that of the control group. In mice treated with apatinib alone, angiogenesis was prevented, and the tumor tissue partial oxygen pressure was reduced, thereby achieving an antitumor effect. Moreover, the tumor inhibitory effect of combined treatment was stronger than treatment with either apatinib or radiotherapy alone. Compared with monotherapy treatment, combined treatment better resisted angiogenesis. Apatinib combined with radiotherapy to treat nasopharyngeal carcinoma has synergistic effects, which may be related to enhanced antiangiogenesis.

Computational Model to Predict Tissue Concentration of Drugs Delivered via Intravital Fluid Exchange Devices

The microcirculation is capable of precise blood flow regulation enabling fine control over the distribution of oxygen (O2) to tissues in the body. The objective is to determine the role of capillaries in sensing and reporting local O2 concentration within tissue to upstream arterioles. It is hypothesized that red blood cells (RBCs) release ATP into the vessel lumen following O2 desaturation; ATP in the plasma binds to purinergic receptors on the endothelium triggering a signalling cascade that leads to a conducted vasodilatory response. Luminal application of ATP is known to initiate conducted dilation in arterioles yet whether or not this conducted response is present in capillaries has yet to be demonstrated.To investigate this mechanism of vascular control, we developed gas and liquid microfluidic devices for use in intravital video microscopy experiments to enable the local control of gases and agonists in skeletal muscle. These devices consist of a microfluidic flow channel interfaced with a glass slide with a laser cut micro‐outlet to allow exchange between the device and skeletal muscle during in vivo experiments. Experimentally, the gas exchange device was used to control the spatial distribution of O2 in the tissue to cause a highly localized hypoxic condition, to induce the release of ATP from RBCs. The liquid device was used to introduce ATP to a localized region of the capillary bed to stimulate ATP mediated mechanisms downstream. Further, we used acetylcholine (ACh) and phenylephrine (PE) as positive and negative controls, respectively. All animal protocols were approved by Memorial University’s Institutional Animal Care Committee.To quantify the local distribution of solutes in skeletal muscle we developed a transient, 3D transport model to predict the concentration of solutes applied experimentally in skeletal muscle. The transport equation was discretized and solved in parallel on a graphics processing unit. The computational model predicts highly localized spatial distributions of these solutes. As expected, the highest concentration of simulated solutes was at the surface of the tissue in contact with the exchange window, with steep decreases in concentration with increasing distance from the exchange window, falling by two orders of magnitude within 240 μm of the edge of the window in both the x and y directions, and by 300 μm in the z direction (see Fig. 1& 2). Logarithmic increases in applied drugs within the simulated microfluidic channel raise relative tissue concentrations proportionally. Predicted steady state concentrations of ACh, PE, and ATP varied due to the assumed rate of enzymatic degradation and efflux into the vasculature.In conclusion, our novel intravital video microscopy devices allow the exchange of gas and drugs to tissue to investigate the mechanisms of regulation in the microcirculation. Further, we quantified the localization of our devices using computational models of molecular transport, confirming the highly‐localized concentration gradients.Support or Funding InformationProject funded through NSERC Discovery Grant to GM Fraser.Tissue model results for 15 mmHg oxygen. The colour map shows the predicted tissue concentrations with 15 mmHg oxygen at the micro‐outlet. The top panel shows the gradients at the surface of the tissue closest to the gas‐based microfluidic device, in the x–y plane. The bottom panel illustrates the tissue partial pressure of oxygen perpendicular to the x–z plane centred at the middle of the micro‐outlet.Figure 1Tissue model results for adenosine triphosphate 10−4 M. The log scale colour map shows predicted tissue concentrations with 10−4 M adenosine triphosphate (ATP) at the micro‐outlet. The top panel shows the gradients at the surface of the tissue at the micro‐outlet. The bottom panel illustrates tissue ATP levels in the x–z plane centred on the micro‐outlet. ATP levels within the volume were above 3.47 × 10−7 M due to the initial assumption of blood ATP concentration.Figure 2

Microvessel density, lipid chemistry and N2 solubility in human and pig adipose tissue

Decompression sickness (DCS) occurs when nitrogen gas (N2) comes out of solution too quickly, forming bubbles in the blood and tissues. These bubbles can be a serious condition; thus it is of extreme interest in the dive community to model DCS risk. Diving models use tissue compartments to calculate tissue partial pressures, often using data obtained from other mammalian species (i.e., pigs). Adipose tissue is an important compartment in these models because N2 is five times more soluble in fat than in blood; at any blood/ tissue interface N2 will diffuse into the fat and can lead to bubble formation on ascent. Little is known about many characteristics of adipose tissue relevant to diving physiology. Therefore, we measured microvessel density and morphology, lipid composition, and N2 solubility in adipose tissue from humans and pigs. Human adipose tissue has significantly higher microvascular density (1.79 ± 0.04 vs. 1.21 ± 0.30%), vessel diameter (10.25 ± 0.28 vs. 6.72 ± 0.60 μm), total monounsaturated fatty acids (50.1 vs. 41.2 mol%) and N2 solubility (0.061 ± 0.003 vs. 0.054 ± 0.004 mL N2 mL-1 oil) compared to pig tissue. Pig adipose tissue has significantly higher lipid content (76.1 ± 4.9 vs. 64.6 ± 5.1%) and total saturated fatty acids (38.8 vs. 29.5 mol%). Though two important components in gas kinetics within adipose tissue during diving (blood flow rates and degree of perfusion) are not well understood, our results indicate differences between the adipose tissue of humans and pigs. This suggests data from swine may not exactly predict gas dynamics for estimating DCS in humans.

Integrated method for quantitative morphometry and oxygen transport modeling in striated muscle.

Identifying structural limitations in O2 transport is primarily restricted by current methods employed to characterize the nature of physiological remodeling. Inadequate resolution or breadth of available data has impaired development of routine diagnostic protocols and effective therapeutic strategies. Understanding O2 transport within striated muscle faces major challenges, most notably in quantifying how well individual fibers are supplied by the microcirculation, which has necessitated exploring tissue O2 supply using theoretical modeling of diffusive exchange. With capillary domains identified as a suitable model for the description of local O2 supply and requiring less computation than numerically calculating the trapping regions that are supplied by each capillary via biophysical transport models, we sought to design a high-throughput method for histological analysis. We present an integrated package that identifies optimal protocols for identification of important input elements, processing of digitized images with semiautomated routines, and incorporation of these data into a mathematical modeling framework with computed output visualized as the tissue partial pressure of O2 (Po2) distribution across a biopsy sample. Worked examples are provided using muscle samples from experiments involving rats and humans. NEW & NOTEWORTHY Progress in quantitative morphometry and analytical modeling has tended to develop independently. Real diagnostic power lies in harnessing both disciplines within one user-friendly package. We present a semiautomated, high-throughput tool for determining muscle phenotype from biopsy material, which also provides anatomically relevant input to quantify tissue oxygenation, in a coherent package not previously available to nonspecialist investigators.

Novel Hemoglobin-Based Oxygen Carrier Bound With Albumin Shows Neuroprotection With Possible Antioxidant Effects

Background and Purpose- A hemoglobin-albumin cluster, 1 core of hemoglobin covalently bound with 3 shell albumins, designated as HemoAct was developed as a hemoglobin-based oxygen carrier. We aim to investigate neuroprotection by HemoAct in transient cerebral ischemia and elucidate its underlying mechanisms. Methods- Male rats were subjected to 2-hour transient middle cerebral artery occlusion and were then administered HemoAct transarterially at the onset of reperfusion. Neurological and pathological findings were examined after 24 hours of reperfusion to identify neuroprotection by HemoAct. Intermittent measurements of cortical blood flow and oxygen content were performed, and a histopathologic analysis was conducted on rats during the early phase of reperfusion to assess the therapeutic mechanism of HemoAct. In addition, the antioxidant effects of HemoAct were examined in hypoxia/reoxygenation-treated rat brain microvascular endothelial cells. Results- Neurological deterioration, infarct and edema development, and the activation of MMP-9 (matrix metalloprotease-9) and lipid peroxidation after 24 hours of reperfusion were significantly ameliorated by the HemoAct treatment. Reductions in blood flow and tissue partial oxygen pressure in the cortical penumbra after 6 hours of reperfusion were significantly ameliorated by the HemoAct treatment. The histopathologic analysis of the cortical penumbra revealed that HemoAct in HemoAct-treated rats showed superior microvascular perfusion with the mitigation of microvascular narrowing changes than autologous erythrocytes in nontreated rats. Although HemoAct extravasated into the ischemic core with serum protein, it did not induce an increase in serum extravasation or reactive oxygen species production in the ischemic core. In vitro experiments with rat brain microvascular endothelial cells revealed that HemoAct significantly suppressed cellular reactive oxygen species production in hypoxia/reoxygenation-treated cells, similar to albumin. Conclusions- HemoAct exerted robust neuroprotection in transient cerebral ischemia. Superior microvascular perfusion with an oxygen delivery capability and possible antioxidant effects appear to be the underlying neuroprotective mechanisms.

Dissociation between CSD-Evoked Metabolic Perturbations and Meningeal Afferent Activation and Sensitization: Implications for Mechanisms of Migraine Headache Onset.

The onset of the headache phase during attacks of migraine with aura, which occur in ∼30% of migraineurs, is believed to involve cortical spreading depression (CSD) and the ensuing activation and sensitization of primary afferent neurons that innervate the intracranial meninges, and their related large vessels. The mechanism by which CSD enhances the activity and mechanosensitivity of meningeal afferents remains poorly understood, but may involve cortical metabolic perturbations. We used extracellular single-unit recording of meningeal afferent activity and monitored changes in cortical blood flow and tissue partial pressure of oxygen (tpO2) in anesthetized male rats to test whether the prolonged cortical hypoperfusion and reduction in tissue oxygenation that occur in the wake of CSD contribute to meningeal nociception. Suppression of CSD-evoked cortical hypoperfusion with the cyclooxygenase inhibitor naproxen blocked the reduction in cortical tpO2, but had no effect on the activation of meningeal afferents. Naproxen, however, distinctly prevented CSD-induced afferent mechanical sensitization. Counteracting the CSD-evoked persistent hypoperfusion and reduced tpO2 by preemptively increasing cortical blood flow using the ATP-sensitive potassium [K(ATP)] channel opener levcromakalim did not inhibit the sensitization of meningeal afferents, but prevented their activation. Our data show that the cortical hypoperfusion and reduction in tpO2 that occur in the wake of CSD can be dissociated from the activation and mechanical sensitization of meningeal afferent responses, suggesting that the metabolic changes do not contribute directly to these neuronal nociceptive responses.SIGNIFICANCE STATEMENT Cortical spreading depression (CSD)-evoked activation and mechanical sensitization of meningeal afferents is thought to mediate the headache phase in migraine with aura. We report that blocking the CSD-evoked cortical hypoperfusion and reduced tissue partial pressure of oxygen by cyclooxygenase inhibition is associated with the inhibition of the afferent sensitization, but not their activation. Normalization of these CSD-evoked metabolic perturbations by activating K(ATP) channels is, however, associated with the inhibition of afferent activation but not sensitization. These results question the contribution of cortical metabolic perturbations to the triggering mechanism underlying meningeal nociception and the ensuing headache in migraine with aura, further point to distinct mechanisms underlying the activation and sensitization of meningeal afferents in migraine, and highlight the need to target both processes for an effective migraine therapy.

The negative ultraslow potential, electrophysiological correlate of infarction in the human cortex.

Spreading depolarizations are characterized by abrupt, near-complete breakdown of the transmembrane ion gradients, neuronal oedema, mitochondrial depolarization, glutamate excitotoxicity and activity loss (depression). Spreading depolarization induces either transient hyperperfusion in normal tissue; or hypoperfusion (inverse coupling = spreading ischaemia) in tissue at risk for progressive injury. The concept of the spreading depolarization continuum is critical since many spreading depolarizations have intermediate characteristics, as opposed to the two extremes of spreading depolarization in either severely ischaemic or normal tissue. In animals, the spreading depolarization extreme in ischaemic tissue is characterized by prolonged depolarization durations, in addition to a slow baseline variation termed the negative ultraslow potential. The negative ultraslow potential is initiated by spreading depolarization and similar to the negative direct current (DC) shift of prolonged spreading depolarization, but specifically refers to a negative potential component during progressive recruitment of neurons into cell death in the wake of spreading depolarization. We here first quantified the spreading depolarization-initiated negative ultraslow potential in the electrocorticographic DC range and the activity depression in the alternate current range after middle cerebral artery occlusion in rats. Relevance of these variables to the injury was supported by significant correlations with the cortical infarct volume and neurological outcome after 72 h of survival. We then identified negative ultraslow potential-containing clusters of spreading depolarizations in 11 patients with aneurysmal subarachnoid haemorrhage. The human platinum/iridium-recorded negative ultraslow potential showed a tent-like shape. Its amplitude of 45.0 (39.0, 69.4) mV [median (first, third quartile)] was 6.6 times larger and its duration of 3.7 (3.3, 5.3) h was 34.9 times longer than the negative DC shift of spreading depolarizations in less compromised tissue. Using Generalized Estimating Equations applied to a logistic regression model, we found that negative ultraslow potential displaying electrodes were significantly more likely to overlie a developing ischaemic lesion (90.0%, 27/30) than those not displaying a negative ultraslow potential (0.0%, 0/20) (P = 0.004). Based on serial neuroimages, the lesions under the electrodes developed within a time window of 72 (56, 134) h. The negative ultraslow potential occurred in this time window in 9/10 patients. It was often preceded by a spreading depolarization cluster with increasingly persistent spreading depressions and progressively prolonged DC shifts and spreading ischaemias. During the negative ultraslow potential, spreading ischaemia lasted for 40.0 (28.0, 76.5) min, cerebral blood flow fell from 57 (53, 65) % to 26 (16, 42) % (n = 4) and tissue partial pressure of oxygen from 12.5 (9.2, 15.2) to 3.3 (2.4, 7.4) mmHg (n = 5). Our data suggest that the negative ultraslow potential is the electrophysiological correlate of infarction in human cerebral cortex and a neuromonitoring-detected medical emergency.awy102media15775596049001.

Effects of Hypertonic Saline and Sodium Lactate on Cortical Cerebral Microcirculation and Brain Tissue Oxygenation.

Hyperosmolar solutions have been used in neurosurgery to modify brain bulk. The aim of this animal study was to compare the short-term effects of equivolemic, equiosmolar solutions of hypertonic saline (HTS) and sodium lactate (HTL) on cerebral cortical microcirculation and brain tissue oxygenation in a rabbit craniotomy model. Rabbits (weight, 1.5 to 2.0 kg) were anesthetized, ventilated mechanically, and subjected to a craniotomy. The animals were allocated randomly to receive a 3.75 mL/kg intravenous infusion of either 3.2% HTS (group HTS, n=9), half-molar sodium lactate (group HTL, n=10), or normal saline (group C, n=9). Brain tissue partial pressure of oxygen (PbtO2) and microcirculation in the cerebral cortex using sidestream dark-field imaging were evaluated before, 20 and 40 minutes after 15 minutes of hyperosmolar solution infusion. Global hemodynamic data were recorded, and blood samples for laboratory analysis were obtained at the time of sidestream dark-field image recording. No differences in the microcirculatory parameters were observed between the groups before and after the use of osmotherapy. Brain tissue oxygen deteriorated over time in groups C and HTL, this deterioration was not significant in the group HTS. Our findings suggest that equivolemic, equiosmolar HTS and HTL solutions equally preserve perfusion of cortical brain microcirculation in a rabbit craniotomy model. The use of HTS was better in preventing the worsening of brain tissue oxygen tension.

Allometric scaling of decompression sickness risk in terrestrial mammals; cardiac output explains risk of decompression sickness

A probabilistic model was used to predict decompression sickness (DCS) outcome in pig (70 and 20 kg), hamster (100 g), rat (220 g) and mouse (20 g) following air saturation dives. The data set included 179 pig, 200 hamster, 360 rat, and 224 mouse exposures to saturation pressures ranging from 1.9–15.2 ATA and with varying decompression rates (0.9–156 ATA • min−1). Single exponential kinetics described the tissue partial pressures (Ptiss) of N2: Ptiss = ∫(Pamb – Ptiss) • τ−1 dt, where Pamb is ambient N2 pressure and τ is a time constant. The probability of DCS [P(DCS)] was predicted from the risk function: P(DCS) = 1−e−r, where r = ∫(PtissN2 − Thr − Pamb) • Pamb–1 dt, and Thr is a threshold parameter. An equation that scaled τ with body mass included a constant (c) and an allometric scaling parameter (n), and the best model included n, Thr, and two c. The final model provided accurate predictions for 58 out of 61 dive profiles for pig, hamster, rat, and mouse. Thus, body mass helped improve the prediction of DCS risk in four mammalian species over a body mass range covering 3 orders of magnitude.

In vivo electron paramagnetic resonance oximetry and applications in the brain.

Molecular oxygen (O2) is essential to brain function and mechanisms necessary to regulate variations in delivery or utilization of O2 are crucial to support normal brain homeostasis, physiology and energy metabolism. Any imbalance in cerebral tissue partial pressure of O2 (pO2) levels may lead to pathophysiological complications including increased reactive O2 species generation leading to oxidative stress when tissue O2 level is too high or too low. Accordingly, the need for oximetry methods, which assess cerebral pO2 in vivo and in real time, is imperative to understand the role of O2 in various metabolic and disease states, including the effects of treatment and therapy options. In this review, we provide a brief overview of the common in vivo oximetry methodologies for measuring cerebral pO2. We discuss the advantages and limitations of oximetry methodologies to measure cerebral pO2 in vivo followed by a more in-depth review of electron paramagnetic resonance oximetry spectroscopy and imaging using several examples of current electron paramagnetic resonance oximetry applications in the brain.

Effect of amifostine, a radiation-protecting drug, on oxygen concentration in tissue measured by EPR oximetry and imaging.

Effect of amifostine, a radiation-protecting drug, on muscle tissue partial pressure of oxygen was investigated by electron paramagnetic resonance spectroscopy and imaging. When amifostine was administered intraperitoneally or intravenously to mice, the linewidth of the electron paramagnetic resonance spectra of the lithium octa-n-butoxy-substituted naphthalocyanine implanted in the mouse leg muscle decreased. Electron paramagnetic resonance oximetry using a lithium octa-n-butoxy-substituted naphthalocyanine probe and electron paramagnetic resonance oxygen mapping using a triarylmethyl radical paramagnetic probe was useful to quantify pressure of oxygen in the tissues of living mice. The result of electron paramagnetic resonance oximetric imaging showed that administration of amifostine could decrease pressure of oxygen in the muscle and also tumor tissues. This finding suggests that lowering pressure of oxygen in tissues might contribute in part to the radioprotection of amifostine.

Brain tissue partial pressure of oxygen predicts the outcome of severe traumatic brain injury under mild hypothermia treatment.

ObjectiveThe aim of this study was to investigate the clinical significance and changes of brain tissue partial pressure of oxygen (PbtO2) in the course of mild hypothermia treatment (MHT) for treating severe traumatic brain injury (sTBI).MethodsThere were 68 cases with sTBI undergoing MHT. PbtO2, intracranial pressure (ICP), jugular venous oxygen saturation (SjvO2), and cerebral perfusion pressure (CPP) were continuously monitored, and clinical outcomes were evaluated using the Glasgow Outcome Scale score.ResultsOf 68 patients with sTBI, PbtO2, SjvO2, and CPP were obviously increased, but decreased ICP level was observed throughout the MHT. PbtO2 and ICP were negatively linearly correlated, while there was a positive linear correlation between PbtO2 and SjvO2. Monitoring CPP and SjvO2 was performed under normal circumstances, and a large proportion of patients were detected with low PbtO2. Decreased PbtO2 was also found after MHT.ConclusionContinuous PbtO2 monitoring could be introduced to evaluate the condition of regional cerebral oxygen metabolism, thereby guiding the clinical treatment and predicting the outcome.

Oxygen availability and spreading depolarizations provide complementary prognostic information in neuromonitoring of aneurysmal subarachnoid hemorrhage patients

Multimodal neuromonitoring in neurocritical care increasingly includes electrocorticography to measure epileptic events and spreading depolarizations. Spreading depolarization causes spreading depression of activity (=isoelectricity) in electrically active tissue. If the depression is long-lasting, further spreading depolarizations occur in still isoelectric tissue where no activity can be suppressed. Such spreading depolarizations are termed isoelectric and are assumed to indicate energy compromise. However, experimental and clinical recordings suggest that long-lasting spreading depolarization-induced depression and isoelectric spreading depolarizations are often recorded outside of the actual ischemic zones, allowing the remote diagnosis of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage. Here, we analyzed simultaneous electrocorticography and tissue partial pressure of oxygen recording in 33 aneurysmal subarachnoid hemorrhage patients. Multiple regression showed that both peak total depression duration per recording day and mean baseline tissue partial pressure of oxygen were independent predictors of outcome. Moreover, tissue partial pressure of oxygen preceding spreading depolarization was similar and differences in tissue partial pressure of oxygen responses to spreading depolarization were only subtle between isoelectric spreading depolarizations and spreading depressions. This further supports that, similar to clustering of spreading depolarizations, long spreading depolarization-induced periods of isoelectricity are useful to detect energy compromise remotely, which is valuable because the exact location of future developing pathology is unknown at the time when the neurosurgeon implants recording devices.

The Effect of Norepinephrine and Dopamine on Radial Forearm Flap Partial Tissue Oxygen Pressure and Microdialysate Metabolite Measurements: A Randomized Controlled Trial.

Patients undergoing ablative and reconstructive head and neck surgery with a microvascular flap have multiple factors that potentially decrease postoperative mean arterial pressure, which may endanger flap survival. The safety of vasopressor use has long been a topic of discussion. The authors analyzed the effect of vasopressors on microvascular flap perfusion after head and neck cancer reconstruction. A total of 27 patients were enrolled in a randomized, controlled, clinical trial. A microvascular radial forearm flap was used for reconstruction. Patients were allocated into one of three groups: dopamine, norepinephrine, and control. The intervention groups received the vasoactive drug, aiming to maintain the mean arterial pressure between 80 and 90 mmHg. Normovolemia was maintained according to central venous pressure. Flap perfusion was monitored with continuous tissue partial pressure of oxygen and microdialysate metabolite (lactate-to-pyruvate ratio) measurements. No adverse effects were observed, and postoperative recovery was free of complications in all groups. Neither the lactate-to-pyruvate ratio nor continuous tissue partial pressure of oxygen values differed significantly between groups during the first 24 hours of the vasoactive drug infusion period or during the 72-hour follow-up. Norepinephrine and dopamine are safe and effective vasopressors for use during the postoperative period following head and neck cancer surgery with microvascular reconstruction. Dopamine should be used with caution, however, because of the risk of side effects. Therapeutic, II.

Monitoring intracranial pressure utilizing a novel pattern of brain multiparameters in the treatment of severe traumatic brain injury.

The aim of the study was to evaluate the clinical value of multiple brain parameters on monitoring intracranial pressure (ICP) procedures in the therapy of severe traumatic brain injury (sTBI) utilizing mild hypothermia treatment (MHT) alone or a combination strategy with other therapeutic techniques. A total of 62 patients with sTBI (Glasgow Coma Scale score <8) were treated using mild hypothermia alone or mild hypothermia combined with conventional ICP procedures such as dehydration using mannitol, hyperventilation, and decompressive craniectomy. The multiple brain parameters, which included ICP, cerebral perfusion pressure, transcranial Doppler, brain tissue partial pressure of oxygen, and jugular venous oxygen saturation, were detected and analyzed. All of these measures can control the ICP of sTBI patients to a certain extent, but multiparameters associated with brain environment and functions have to be critically monitored simultaneously because some procedures of reducing ICP can cause side effects for long-term recovery in sTBI patients. The result suggested that multimodality monitoring must be performed during the process of mild hypothermia combined with conventional ICP procedures in order to safely target different clinical methods to specific patients who may benefit from an individual therapy.

Renal Blood Oxygenation Level–dependent Imaging in Longitudinal Follow-up of Donated and Remaining Kidneys

Purpose To determine renal oxygenation changes associated with uninephrectomy and transplantation in both native donor kidneys and transplanted kidneys by using blood oxygenation level-dependent (BOLD) MR imaging. Materials and Methods The study protocol was approved by the local ethics committee. Thirteen healthy kidney donors and their corresponding recipients underwent kidney BOLD MR imaging with a 3-T imager. Written informed consent was obtained from each subject. BOLD MR imaging was performed in donors before uninephrectomy and in donors and recipients 8 days, 3 months, and 12 months after transplantation. R2* values, which are inversely related to tissue partial pressure of oxygen, were determined in the cortex and medulla. Longitudinal R2* changes were statistically analyzed by using repeated measures one-way analysis of variance with post hoc pair-wise comparisons. Results R2* values in the remaining kidneys significantly decreased early after uninephrectomy in both the medulla and cortex (P < .003), from 28.9 sec(-1) ± 2.3 to 26.4 sec(-1) ± 2.5 in the medulla and from 18.3 sec(-1) ± 1.5 to 16.3 sec(-1) ± 1.0 in the cortex, indicating increased oxygen content. In donors, R2* remained significantly decreased in both the medulla and cortex at 3 (P < .01) and 12 (P < .01) months. In transplanted kidneys, R2* remained stable during the first year after transplantation, with no significant change. Among donors, cortical R2* was found to be negatively correlated with estimated glomerular filtration rate (R = -0.47, P < .001). Conclusion The results suggest that BOLD MR imaging may potentially be used to monitor renal functional changes in both remaining and corresponding transplanted kidneys. (©) RSNA, 2016.

Abstract 10826: GBT1118, a Potent Allosteric Modifier of Hemoglobin Oxygen Affinity Increases Tolerance to Hypoxia in Mice

Introduction: Adaptation to hypoxia involves several mechanisms that influence oxygen (O2) transport and utilization, including a reduction in hemoglobin (Hb) O2 affinity to favor the release of O2 to tissues. Paradoxically, increased Hb O2 affinity has been observed to have beneficial effects during severe hypoxia. Hypothesis: This study was designed to test the hypothesis that pharmacologically increasing Hb O2 affinity with GBT1118 can augment O2 transport during severe hypoxia (10 and 5% O2). Method: Mice were orally dosed with GBT1118 (70 or 140 mg/kg) or only vehicle (Control), and Hb O2 affinity was determined by hemoximetry. During hypoxia, changes in systemic and microvascular hemodynamics, tissue partial pressure of O2 (PO2) and tissue hypoxia were evaluated. At each timepoint, mice with adequate systolic blood pressure (BP) were counted as survived and mice with severe hypotension (BP ≤60 mmHg) were counted as non-survived and were euthanized. Results: Similar trends were observed at 10 and 5% O2 hypoxia. GBT1118 at 70 and 140 mg/kg decreased the P50 (PO2 at which blood is 50% saturated with O2) by 29 and 35 mmHg, respectively. During 5% O2 hypoxia, GBT1118 at 70 and 140 mg/kg increased SaO2 from 40% (Control) to 57% (70mg/kg) and 80% (140mg/kg), respectively. Moreover, mean BP and heart rate (HR) decreased to 50 mmHg and 375 bpm in control mice, whereas GBT1118-dosed mice sustained higher mean BP and HR in a dose-dependent fashion and improved survival (Figure 1). In addition, GBT1118 preserved microvascular blood flow and tissue oxygenation; consequently, GBT1118 reduced heart and brain hypoxic areas compared with control groups during hypoxia. Conclusion: Under severe hypoxia, GBT1118-mediated increase in Hb O2 affinity increases SaO2. At the tissue level, local milieu allows for efficient O2 extraction leading to improved oxygenation as measured by decreased lactic acidosis, improved cardiovascular function and ultimately, survival.

Gradually Increased Oxygen Administration Improved Oxygenation and Mitigated Oxidative Stress after Resuscitation from Severe Hemorrhagic Shock.

The optimal oxygen administration strategy during resuscitation from hemorrhagic shock (HS) is still controversial. Improving oxygenation and mitigating oxidative stress simultaneously seem to be contradictory goals. To maximize oxygen delivery while minimizing oxidative damage, the authors proposed the notion of gradually increased oxygen administration (GIOA), which entails making the arterial blood hypoxemic early in resuscitation and subsequently gradually increasing to hyperoxic, and compared its effects with normoxic resuscitation, hyperoxic resuscitation, and hypoxemic resuscitation in severe HS. Rats were subjected to HS, and on resuscitation, the rats were randomly assigned to four groups (n = 8): the normoxic, the hyperoxic, the hypoxemic, and the GIOA groups. Rats were observed for an additional 1 h. Hemodynamics, acid-base status, oxygenation, and oxidative injury were observed and evaluated. Central venous oxygen saturation promptly recovered only in the hyperoxic and the GIOA groups, and the liver tissue partial pressure of oxygen was highest in the GIOA group after resuscitation. Oxidative stress in GIOA group was significantly reduced compared with the hyperoxic group as indicated by the reduced malondialdehyde content, increased catalase activity, and the lower histologic injury scores in the liver. In addition, the tumor necrosis factor-α and interleukin-6 expressions in the liver were markedly decreased in the GIOA group than in the hyperoxic and normoxic groups as shown by the immunohistochemical staining. GIOA improved systemic/tissue oxygenation and mitigated oxidative stress simultaneously after resuscitation from severe HS. GIOA may be a promising strategy to improve resuscitation from HS and deserves further investigation.

Dynamic oxygenation measurements using a phosphorescent coating within a mammary window chamber mouse model.

Phosphorescent lifetime imaging was employed to measure the spatial and temporal distribution of oxygen partial pressure in tissue under the coverslip of a mammary window chamber breast cancer mouse model. A thin platinum-porphyrin coating, whose phosphorescent lifetime varies monotonically with oxygen partial pressure, was applied to the coverslip surface. Dynamic temporal responses to induced modulations in oxygenation levels were measured using this approach.

Decompression sickness in breath-hold diving, and its probable connection to the growth and dissolution of small arterial gas emboli

We solved the Laplace equation for the radius of an arterial gas embolism (AGE), during and after breath-hold diving. We used a simple three-region diffusion model for the AGE, and applied our results to two types of breath-hold dives: single, very deep competitive-level dives and repetitive shallower breath-hold dives similar to those carried out by indigenous commercial pearl divers in the South Pacific. Because of the effect of surface tension, AGEs tend to dissolve in arterial blood when arteries remote from supersaturated tissue. However if, before fully dissolving, they reach the capillary beds that perfuse the brain and the inner ear, they may become inflated with inert gas that is transferred into them from these contiguous temporarily supersaturated tissues. By using simple kinetic models of cerebral and inner ear tissue, the nitrogen tissue partial pressures during and after the dive(s) were determined. These were used to theoretically calculate AGE growth and dissolution curves for AGEs lodged in capillaries of the brain and inner ear. From these curves it was found that both cerebral and inner ear decompression sickness are expected to occur occasionally in single competitive-level dives. It was also determined from these curves that for the commercial repetitive dives considered, the duration of the surface interval (the time interval separating individual repetitive dives from one another) was a key determinant, as to whether inner ear and/or cerebral decompression sickness arose. Our predictions both for single competitive-level and repetitive commercial breath-hold diving were consistent with what is known about the incidence of cerebral and inner ear decompression sickness in these forms of diving.