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Acute respiratory distress syndrome (ARDS) is a complication of pulmonary disease that produces life-threatening hypoxaemia. Despite ventilation and hyperoxic therapies, undetected hypoxia can manifest in capillary beds leading to multi-organ failure. Ox66™ is an ingestible, solid-state form of oxygen designed to supplement oxygen deficits. Twenty-four anaesthetized rats underwent a two-hit model of respiratory distress (ARDS), where a single dose (5 mg/kg) of lipopolysaccharide (LPS) was given intratracheally, and then the respiratory tidal volume was reduced by 40%. After 60 min, animals were randomized to receive Ox66™, or normal saline (NS; vehicle control) via gavage or supplemental inspired oxygen (40% FiO2). A second gavage was administered at 120 min. Cardiovascular function and blood oximetry/chemistry were measured alongside the peripheral spinotrapezius muscle's interstitial oxygenation (PISFO2). ARDS reduced mean arterial pressure (MAP) and PISFO2 compared to baseline (BL) for all treatment groups. Treatment with Ox66 or NS did not improve MAP, but 40% FiO2 caused a rapid return to BL. PISFO2 improved after treatment with Ox66™ and 40% FiO2 and remained elevated for both groups against NS until study conclusion. Both oxygen treatments also suppressed the inflammatory response to LPS, suggesting that Ox66™ can deliver therapeutically-impactful levels of oxygen in situations of pulmonary dysfunction. [ABSTRACT FROM AUTHOR]

Sepsis is a devastating complication of infection and injury that, through widespread endothelial dysfunction, can cause perfusion deficits and multi-organ failure. To address the recognised need for therapeutics targetting the endothelial barrier, a topical formulation (CUR; VASCEPTORTM; Vascarta Inc, Summit, NJ) was developed to transdermally deliver bio-active concentrations of curcumin--an antiinflammatory and nitric oxide promoter. Male, Sprague Dawley rats were treated daily with lipopolysaccharide (LPS, 10mg/kg, IP) to induce endotoxemia, and topical applications of Vehicle Control (LPSþVC; N=7) or Curcumin (LPSþCUR; N=7). A third group received neither LPS nor treatment (No-LPS; N=8). After 72 h, animals were surgically prepared for measurements of physiology and endothelial dysfunction in the exteriorised spinotrapezius muscle through the extravasation of 67 kDa TRITCBSA (albumin) and 500 kDa FITC-dextran (dextran). At 72 h, LPSþVC saw weight loss, and increases to pulse pressure, lactate, pCO2, CXCL5 (vs No-LPS) and IL-6 (vs 0 h; p<0.05). LPSþCUR was similar to No-LPS, but with hypotension. Phenylephrine response was increased in LPSþCUR. Regarding endothelial function, LPSþCUR albumin and dextran extravasation were significantly reduced versus LPSþVC suggesting that Curcumin mitigated endotoxemic endothelial dysfunction. The speculated mechanisms are nitric oxide modulation of the endothelium and/or an indirect anti-inflammatory effect. [ABSTRACT FROM AUTHOR]

This study examined changes in interstitial PO2, which allowed calculation of VO2 during periods of rest, muscle contraction and recovery using an in situ rat spinotrapezius muscle preparation. The PO2 was measured using phosphorescence quenching microscopy and the muscle VO2 was calculated as the rate of O2 disappearance during brief periods of muscle compression to stop blood flow with a supra-systolic pressure. The PO2 and VO2 measurements were made during "5 s compression and 15 s recovery" (CR) cycles. With all three stimulation frequencies, 1, 2 and 4 Hz, the fall in interstitial PO2 and rise in VO2 fromresting values occurred within the first 20 s of contraction. The PO2 during contraction became lower as stimulation frequency increased from 1 to 4 Hz. VO2 was higher at 2 Hz than at 1 Hz contraction. With cessation of stimulation, PO2 began increasing exponentially towards baseline values. After 1 and 2 Hz contraction, the fall in muscleVO2 was delayed by oneCR cycle and then exponentially decreased towards resting values. After 4 Hz stimulation, VO2 increased for 2 cycles and then decreased. The post-contraction transients of PO2 and VO2 were not synchronous and had different time constants. With further analysis two distinct functional responses were identified across all stimulation frequencies having PO2 during contraction above or below 30 mmHg. The corresponding VO2 responses were different - for "high" PO2,muscleVO2 reachedhigh levels, while for the "low" PO2 data setmuscle VO2 remained low. Recovery patterns were similar to those described above. In summary, local microscopic PO2 and VO2 were measured in resting and contractingmuscle in situ and the post-contraction transients of PO2 and VO2 were all much slower than the onset transients. [ABSTRACT FROM AUTHOR]

Oxygen (O2) exchange between capillaries and muscle cells in exercising muscles is of great interest for physiology and kinesiology. However, methodical limitations prevent O2 measurements on the millisecond scale. To bypass the constraints of quasi-continuous recording, progressive measurements of O2 partial pressure (PO2) in rhythmically contracting skeletal muscle were compiled to describe the O2 kinetics surrounding and including a single muscle contraction. Phosphorescence quenching microscopy measured PO2 in the interstitium of the rat spinotrapezius muscle. Measurements were triggered by contraction-inducing electrical pulses. For the first 60 seconds, measurement preceeded stimulation. After 60, measurement followed with a progressive 20 ms increment. Thus, the first 60 measurements describe the overall PO2 response to electrical stimulation initiated after a 10 second rest period, while 61--100 (stroboscopic mode) were compiled into a single 800 ms profile of the PO2 transient surrounding muscle contraction. Thirty seconds of stimulated contractions decreased interstitial PO2 from a baseline of 71 ± 1.4 mmHg to an "active" steady-state of 43 ± 1.5 mmHg. The stroboscopic mode compilation revealed an unexpected post-contractile rise in PO2 as a 205 ms spike with a maximum amplitude of 58 ± 3.8 mmHg at 68 ms, which restored 58% of the PO2 drop from baseline. Interpretation of this phenomenon is based on classical experiments by G.V. Anrep (1935), who discovered the rapid thrust of blood flow associated with muscle contraction. In addition to the metabolic implications during exercise, the physiological impact of these PO2 spikes may grow with an increased rate of rhythmical contractions in muscle or heart. New&Noteworthy: The principal finding is a spike of interstitial PO2, produced by a twitch in a rhythmically contracting muscle. A possible mechanism is flushing capillaries with arterial blood by mechanical forces. A technical novelty is the PO2 measurement with a "stroboscopic mode" and progressively increasing delay between stimulator pulse and PO2 measuring. That permitted a 20 ms time resolution for a 205 ms spike duration, using an excitation flash rate one per second. [ABSTRACT FROM AUTHOR]

The O2 disappearance curve (ODC) recorded in an arteriole after the rapid arrest of blood flow reflects the complex interaction among the dissociation of O2 from hemoglobin, O2 diffusivity, and rate of respiration in the vascular wall and surrounding tissue. In this study, the analysis of experimental ODCs allowed the estimation of parameters of O2 transport and O2 consumption in the microcirculation of the mesentery. We collected ODCs from rapidly arrested blood inside rat mesenteric arterioles using scanning phosphorescence quenching microscopy (PQM). The technique was used to prevent the artifact of accumulated O2 photoconsumption in stationary media. The observed ODC signatures were close to linear, in contrast to the reported exponential decline of intra-arteriolar Po2. The rate of Po2 decrease was 0.43 mmHg/s in 20-μm-diameter arterioles. The duration of the ODC was 290 s, much longer than the 12.8 s reported by other investigators. The arterioles associated with lymphatic microvessels had a higher O2 disappearance rate of 0.73 mmHg/s. The O2 flux from arterioles, calculated from the average O2 disappearance rate, was 0.21 nl O2·cm-2·s-1, two orders of magnitude lower than reported in the literature. The physical upper limit of the O2 consumption rate by the arteriolar wall, calculated from the condition that all O2 is consumed by the wall, was 452 nl O2·cm-3·s-1. From consideration of the microvascular tissue volume fraction in the rat mesentery of 6%, the estimated respiration rate of the vessel wall was ∼30 nl O2·cm-3·s-1. This result was three orders of magnitude lower than the respiration rate in rat mesenteric arterioles reported by other investigators. Our results demonstrate that O2 loss from mesenteric arterioles is small and that the O2 consumption by the arteriolar wall is not unusually large. [ABSTRACT FROM AUTHOR]

Abstract: Blood products are the current standard for resuscitation of hemorrhagic shock. However, logistical constraints of perishable blood limit availability and prehospital use, meaning alternatives that provide blood-like responses remain an area of active investigation and development. VS-101 is a new PEGylated human hemoglobin-based oxygen carrier that avoids the logistical hurdles of traditional blood transfusion. This study sought to determine the safety and ability of VS -101 to maintain circulatory function and capillary oxygen delivery in a severe (50%) exchange transfusion (ET) model. Anesthetized, male Sprague Dawley rats were prepared for cardiovascular monitoring and phosphorescence quenching microscopy of interstitial fluid oxygen tension (P ISFo2 ) in the spinotrapezius muscle. Fifty-percent isovolemic ET of estimated total blood volume with either lactated Ringer's solution (LRS, n = 8) or VS -101 (n = 8) at 1 mL/kg/min was performed, and animals were observed for 240 min. VS -101 maintained P ISFo2 at baseline with a transient 18 ± 4 mm Hg decrease ( P < 0.05) in mean arterial pressure (MAP). In contrast, ET with LRS decreased P ISFo2 by approximately 50% ( P < 0.05) and MAP by 74 ± 10 mm Hg ( P < 0.05). All VS -101 animals survived 240 min, the experimental endpoint, while 100% of LRS animals expired by 142 min. VS -101 animals maintained normal tissue oxygenation through 210 min, decreasing by 25% ( P < 0.05 vs. baseline) thereafter, likely from VS -101 vascular clearance. No arteriolar vasoconstriction was observed following VS -101 treatment. In this model of severe ET, VS -101 effectively maintained blood pressure, perfusion, and P ISFo2 with no vasoconstrictive effects. Further elucidation of these beneficial resuscitation effects of VS -101 is warranted to support future clinical trials., Competing Interests: The study was funded by Vivosang, Inc., manufacturer of VS-101 and patent holder of another PEG-Hb product, MP4. AM, KV, and WMS are employed by Vivosang, Inc. Manuscript preparation was funded and executed by Song Biotechnologies, LLC. WHN and BKS are employees of Song Biotechnologies. FRS reports no conflicts of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Shock Society.)

This study examined changes in interstitial PO 2 , which allowed calculation of VO 2 during periods of rest, muscle contraction and recovery using an in situ rat spinotrapezius muscle preparation. The PO 2 was measured using phosphorescence quenching microscopy and the muscle VO 2 was calculated as the rate of O 2 disappearance during brief periods of muscle compression to stop blood flow with a supra-systolic pressure. The PO 2 and VO 2 measurements were made during "5 s compression and 15 s recovery" (CR) cycles. With all three stimulation frequencies, 1, 2 and 4 Hz, the fall in interstitial PO 2 and rise in VO 2 from resting values occurred within the first 20 s of contraction. The PO 2 during contraction became lower as stimulation frequency increased from 1 to 4 Hz. VO 2 was higher at 2 Hz than at 1 Hz contraction. With cessation of stimulation, PO 2 began increasing exponentially towards baseline values. After 1 and 2 Hz contraction, the fall in muscle VO 2 was delayed by one CR cycle and then exponentially decreased towards resting values. After 4 Hz stimulation, VO 2 increased for 2 cycles and then decreased. The post-contraction transients of PO 2 and VO 2 were not synchronous and had different time constants. With further analysis two distinct functional responses were identified across all stimulation frequencies having PO 2 during contraction above or below 30 mmHg. The corresponding VO 2 responses were different - for "high" PO 2 , muscle VO 2 reached high levels, while for the "low" PO 2 data set muscle VO 2 remained low. Recovery patterns were similar to those described above. In summary, local microscopic PO 2 and VO 2 were measured in resting and contracting muscle in situ and the post-contraction transients of PO 2 and VO 2 were all much slower than the onset transients., Competing Interests: Authors AG, BS, and WN were employed by Song Biotechnologies LLC. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Golub, Song, Nugent and Pittman.)