Lack Of Hypoxia Research Articles

Induction chemotherapy effects on very advanced (T3/T4) human papillomavirus-related oropharyngeal cancer for participation in hypoxia-directed major de-escalation (30 Gy) definitive treatment trial.

6076 Background: De-escalation trials in human papillomavirus associated oropharyngeal carcinoma (HPV+ OPC) often exclude patients with very locally advanced disease. We previously demonstrated in a Phase II study that for patients with T1-T2 HPV+OPC that de-escalation to 30Gy of definitive chemoradiation based on lack of hypoxia on 18F-FMISO (fluoromisonidazole) PET (ROC Study) is associated with excellent outcomes (JNCI 2021; JCO 2024). Here, we hypothesized that induction chemotherapy (ICT) could be used in locally advanced (T3-T4) HPV+OPC to down-stage patients and make them eligible for de-escalation and simultaneously improve tumor hypoxia. Methods: We conducted a pilot study in HPV+ OPC patients with AJCC v7 T3-T4 and/or large volume N2b-N2c-N3 disease (i.e. pts ineligible for ROC Study (NCT03323563)). ICT – carboplatin (AUC2), paclitaxel (90 mg/m2), and cetuximab (250 mg/m2 after 400 mg/m2 loading dose) weekly for 6 weeks. To be eligible for de-escalation (ROC), after ICT, patients needed to be down-staged (<=T2). 18F-FMISO PET scan done prior to ICT, after ICT, and, if eligible for ROC study, about 2 weeks after start of radiation therapy. If an 18F-FMISO PET scan showed no hypoxia at any time point, no further scans necessary and patients received 30Gy of radiation therapy with 2 cycles of chemotherapy concurrently. Primary outcome is 2-year local control rate in 20 evaluable patients (description only in this pilot study). This abstract reports only on the outcomes of the ICT portion of the study. Results: 20 patients were accrued 3/2023-12/2023. Median age - 70 years old (46-88); Male – 95%; ECOG PS 0 – 80%. Tumor stage – T3 (70%); T4a (30%); N2b (70%); N2c (30%). All 20 patients had pretreatment hypoxia by 18F-FMISO. Of the 17 evaluable patients post ICT, 14 (82%) had no hypoxia on post ICT scan (other 3 still receiving ICT). Of 3 patients with hypoxia after ICT, 2 had resolution 2 weeks into radiotherapy, and 1 patient is still pending intra-treatment scan. All 17 evaluable patients had a significant enough of a response anatomically to allow treatment on the ROC Study. All patients to date were able to receive 2 cycles of cisplatin (100 mg/m2) without dose or treatment adjustment. Conclusions: Preliminary results suggest that ICT can allow more advanced tumors (T3/T4), that are typically excluded from de-escalation studies, to be de-escalated and may eliminate tumor hypoxia in a large proportion of cases, but a larger study is needed to confirm these results. Further followup of outcomes (2 year local control rate) is still needed. Clinical trial information: NCT05491512 .

Comparative Study of Hemodynamic Infusion of Dexmedetomidine With Alternative Sufentanil-Midazolam Injection for Sedation of Patients Undergoing Cataract Surgery

In order to induce sedation during cataract surgery, various medications with different side effects are used in separation or in combination. Dexmedetomidine has no effect on the respiratory system, but being dependent on dosage, it may cause cardiovascular disorders. The present study aims to compare the hemodynamic and sedative effects of dexmedetomidine and the combination of sufentanil-midazolam on patients undergoing cataract surgery. In a randomized clinical trial study, 60 patients were randomly divided into two dexmedetomidine and sufentanil-midazolam groups. In sufentanil-midazolam group, dexmedetomidine (DEX infusion at 0.5 μg/ kg for 10 minutes, then adjusted to 0.2 µg/kg/h) was prescribed. In the sufentanil-midazolam group, sufentanil (0.1 μg/kg for 5 minutes) and midazolam (0.2 µg/kg) were injected five minutes before the operation. Hemodynamic variables (Systolic blood pressure, diastolic blood pressure, heart rate), complications (nausea, vomiting, hypoxia), sedation level, and pain intensity were recorded (at the beginning of the study, 5, 10 minutes after anesthesia, at the start of surgery, 5, 10, 15 minutes after the surgery) as well as patient’s satisfaction, surgeon's satisfaction, and complications. Results suggest that apart from gender, other primary characteristics of patients, including age, history of blood pressure, diabetes history, ASA score, mean of systolic, diastolic blood pressure, heart rate, and SPO2 levels, were similar in both groups (P>0.05). Systolic blood pressure patients receiving dexmedetomidine declined significantly more than that of patients receiving sufentanil-midazolam (P>0.5). Diastolic blood pressure suddenly fell 5 minutes after the infusion of sufentanil-midazolam (P>0.05), but then a relative increase and finally a relative decrease occurred, while diastolic blood pressure in patients receiving dexmedetomidine decreased steadily. The mean heart rate in patients receiving dexmedetomidine and sufentanil-midazolam declined gently (P>0.05). SPO2 was reduced significantly in the sufentanil-midazolam group (P<0.05). Drugs used in both groups reduced pain intensity equally (P>0.05). From the beginning of the study, dexmedetomidine produced a relatively stable sedation level (score 2) based on Ramsay's criteria, while the combination of sufentanil-midazolam-medications causes deeper sedation (score 3) in patients (P<0.05). Despite this fact, 23.33% of the patient receiving sufentanil-midazolam could have movements during the surgery, which was 6.66% higher in patients receiving dexmedetomidine (P=0.071). The satisfaction of patients receiving dexmedetomidine was significantly higher (P=0.044), while the surgeon's satisfaction was almost identical in both anesthesia procedures (P=0.94). In the end, the results of the present study showed that although dexmedetomidine is associated with few respiratory problems and higher satisfaction of patients, it decreases blood pressure and heart rate progressively. However, it seems that this medicine is more effective than a combination of midazolam-sufentanil because of more patient satisfaction, lack of hypoxia, fewer complications, and more suitable immobility.

Implementation and Assessment of a Proning Protocol for Nonintubated Patients With COVID-19.

ABSTRACTIntroduction:The COVID-19 pandemic has caused over 1,250,000 deaths worldwide. With limited therapeutic options, proning nonintubated patients emerged as a safe and affordable intervention to manage hypoxemia.Methods:A proning protocol to identify and prone eligible patients was implemented. Patients were encouraged to self-prone for 2–3 hours, 3 times daily. Investigators created educational materials for nurses and patients and developed a COVID-19–specific proning order within the electronic health record (EHR). Investigators completed an 800-person retrospective chart review to study the implementation of this protocol.Results:From March 22, 2020, to June 5, 2020, 586 patients were admitted to the COVID-19 floor. Of these patients, 42.8% were eligible for proning. Common contraindications were lack of hypoxia, altered mental status, and fall risk. The proning protocol led to a significant improvement in provider awareness of patients appropriate for proning, increasing from 12% to 83%, as measured by placement of a proning order into the EHR. There was a significant improvement in all appropriate patients documented as proned, increasing from 18% to 45% of eligible patients.Conclusions:The creation of an effective hospital-wide proning protocol to address the exigencies of the COVID-19 pandemic is possible and may be accomplished in a short period of time.

Impact of inflammation on brain subcellular energetics in anesthetized rats

BackgroundEmerging data suggests that volatile anesthetic agents may have organ protection properties in the setting of critical illness. The purpose of this study was to better understand the effect of inflammation on cerebral subcellular energetics in animals exposed to two different anesthetic agents—a GABA agonist (propofol) and a volatile agent (isoflurane).ResultsForty-eight Sprague–Dawley rats were anesthetized with isoflurane or propofol. In each group, rats were randomized to celiotomy and closure (sham) or cecal ligation and puncture (inflammation [sepsis model]) for 8 h. Brain tissue oxygen saturation and the oxidation state of cytochrome aa3 were measured. Brain tissue was extracted using the freeze-blow technique. All rats experienced progressive increases in tissue oxygenation and cytochrome aa3 reduction over time. Inflammation had no impact on cytochrome aa3, but isoflurane caused significant cytochrome aa3 reduction. During isoflurane (not propofol) anesthesia, inflammation led to an increase in lactate (+ 0.64 vs. − 0.80 mEq/L, p = 0.0061). There were no differences in ADP:ATP ratios between groups. In the isoflurane (not propofol) group, inflammation increased the expression of hypoxia-inducible factor-1α (62%, p = 0.0012), heme oxygenase-1 (67%, p = 0.0011), and inducible nitric oxide synthase (31%, p = 0.023) in the brain. Animals exposed to inflammation and isoflurane (but not propofol) exhibited increased expression of protein carbonyls (9.2 vs. 7.0 nM/mg protein, p = 0.0050) and S-nitrosylation (49%, p = 0.045) in the brain. RNA sequencing identified an increase in heat shock protein 90 and NF-κβ inhibitor mRNA in the inflammation/isoflurane group.ConclusionsIn the setting of inflammation, rats exposed to isoflurane show increased hypoxia-inducible factor-1α expression despite a lack of hypoxia, increased oxidative stress in the brain, and increased serum lactate, all of which suggest a relative increase in anaerobic metabolism compared to propofol. Differences in oxidative stress as well as heat shock protein 90 and NF-κβ inhibitor may account for the differential expression of cerebral hypoxia-inducible factor-1α during inflammation.

Glioma FMISO PET/MR Imaging Concurrent with Antiangiogenic Therapy: Molecular Imaging as a Clinical Tool in the Burgeoning Era of Personalized Medicine.

The purpose of this article is to provide a focused overview of the current use of positron emission tomography (PET) molecular imaging in the burgeoning era of personalized medicine in the treatment of patients with glioma. Specifically, we demonstrate the utility of PET imaging as a tool for personalized diagnosis and therapy by highlighting a case series of four patients with recurrent high grade glioma who underwent 18F-fluoromisonidazole (FMISO) PET/MR (magnetic resonance) imaging through the course of antiangiogenic therapy. Three distinct features were observed from this small cohort of patients. First, the presence of pseudoprogression was retrospectively associated with the absence of hypoxia. Second, a subgroup of patients with recurrent high grade glioma undergoing bevacizumab therapy demonstrated disease progression characterized by an enlarging nonenhancing mass with newly developed reduced diffusion, lack of hypoxia, and preserved cerebral blood volume. Finally, a reduction in hypoxic volume was observed concurrent with therapy in all patients with recurrent tumor, and markedly so in two patients that developed a nonenhancing reduced diffusion mass. This case series demonstrates how medical imaging has the potential to influence personalized medicine in several key aspects, especially involving molecular PET imaging for personalized diagnosis, patient specific disease prognosis, and therapeutic monitoring.

Retinal oxygen: the good, the bad and the unknown?

AbstractIschemia is suspected in the pathophysiology of several eye diseases including glaucoma. The most direct way to study ischemia is through blood flow and circulatory studies and these have shown abnormalities in glaucoma and other eye diseases. However, blood flow changes per se do not necessarily indicate an unhealthy situation; blood flow indeed varies substantially in healthy tissues. The main metabolic consequence of ischemia is hypoxia and any harmful consequence of ischemia must include hypoxia at some point in time. Therefore, oxygen measurements are a direct way to study pathogenesis in ischemic diseases. Tissue damage would involve hypoxia and lack of hypoxia is not fully consistent with ischemic pathophysiology. The fact that hypoxia has to date not been found in glaucoma patients, suggests that ischemia may not be involved in the pathophysiology of glaucoma. The abnormalities in blood flow and oxygenation seen in glaucoma may be secondary to tissue atrophy, rather than the cause of the disease. Further studies, especially in patients with progressive glaucoma and high intraocular pressure will clarify the issue.

Physiological responses to temperature and haeme synthesis modifiers in earthworm Lumbricus terrestris (Annelida: Oligochaeta)

Earthworms (Lumbricus terrestris) acclimated at 2° and 6°C above their average habitat temperature (10°C) had respectively 15 and 40% higher rate of respiration than those at habitat temperature. At 14°C, the rate of respiration and blood hemoglobin (Hb) concentration both increased by ∼60 and 50%, respectively, of the values at habitat temperature. At higher temperatures the rate of respiration and Hb synthesis started decreasing. At 20-23°C, the respiration and Hb concentration decreased respectively by about 85% and 35% of that at 14°C. Decrease in blood Hb concentration at higher temperatures appeared to be due to the lowering of the activity of blood enzyme δ-aminolaevulinic acid dehydratase (ALAD). Exposure of 20-23°C-acclimated pale worms to ALAD inhibitor (lead), lowered the already compromised rate of respiration and blood Hb concentration; while exposure to hexachlorobenzene (HCB, inducer of haeme synthesis) and ferric chloride (enhancer of haeme synthesis) did not overcome the inhibitory effect of high temperature on Hb synthesis. At 20-23°C the affinity of Hb for oxygen also decreased as indicated by the lowering of oxy-Hb (HbO) concentration in blood. The lowering of concentration of blood Hb and its affinity for oxygen may lower the amount of oxygen delivered to cells, which may limit the level of aerobic metabolism (glycolysis, oxidative phosphorylation), as indicated by an increase in blood glucose concentration and a decrease in in vitro activities of mitochondrial electron transport system components (ETS) namely NADH-cytochrome c reductase, succinate dehydrogenase, cytochrome c oxidase, and ATPases. Although the oxygen concentration in air, at sea level, does not decrease significantly from 6° to 20-23°C (lack of hypoxia), lowering of both Hb and HbO concentrations by high temperature may cause significant hypoxemia. The latter may lead to inhibition of the activity of muscle mitochondrial respiratory enzymes (ETS). The resulting inhibition of ATP synthesis and hydrolysis may cause deficit of energy needed for peristalsis/fictive locomotion of body and heart muscles (as indicated by a decrease in heart rate) to facilitate diffusion and transport of gases. The upper critical temperature (20-23°C) also slows down the heart rate and causes hyperosmotic stress (hypovolemia). Thus, a rise in soil temperature above 18°C, which inhibits Hb synthesis, Hb oxygenation, and mitochondrial ETS activity, and slows down the heart rate and causes hyperosmotic stress, can make this and higher temperatures lethal to populations of these earthworms, especially in the presence of metabolic inhibitors and respiratory poisons.

Zonal redox changes as a cause of selective perivenular hepatotoxicity of alcohol

Alcohol-induced lesions predominate in perivenular zones of the liver. To test the hypothesis that ethanol aggravates hypoxia in this zone by stimulating oxygen consumption, we measured hepatic venous pO 2 after ethanol-administration to both alcohol-fed baboons (with perivenular lesions) and their controls, and found no changes: the stimulation of oxygen consumption was fully offset by a parallel increase in blood flow. Despite the lack of hypoxia, ehtanol increased lactate/pyruvate (L/P) 15-fold in hepatic venous blood and only 3-fold in liver tissue. Addition of lactate to increase arterial L/P several-fold produced no changes in the hepatic venous ratio, indicating that the equilibrium between this ratio and the cytosolic redox state was reached in one passage through the liver. Thus, the higher L/P in hepatic venous blood most likely reflects an enhanced redox shift in perivenular zones. In isolated hepatocytes, a pO 2 comparable to that normally prevailing in perivenular zones mimicked the exaggeration of the ethanol-induced redox shift and aggravated inhibition of protein synthesis. We therefore propose an alternate mechanism for the selective perivenular injury; namely, that the low pO 2 normally prevailing at this site aggravates the redox-linked toxicity of ethanol.