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Oxygen therapeutics has a range of applications in transfusion medicine and disease treatment. Synthetic molecules and all‐natural or semisynthetic hemoglobin‐based oxygen carriers (HBOCs) have seen success as potential circulating oxygen carriers. However, many early HBOC products stalled in development due to side effects from excess hemoglobin in the blood stream and hemoglobin entering the tissue. To overcome these issues, research has focused on increasing the molecular diameter of hemoglobin by polymerizing hemoglobin molecules or encapsulating hemoglobin in liposomal carriers. This work leverages the properties of silk fibroin, a cytocompatible and nonthrombogenic biopolymer, known to entrap protein‐based cargo, to engineer a fully protein‐based oxygen carrier. Herein, an all‐aqueous solvent evaporation technique is used to form silk particles via phase separation from a bulk polyvinyl alcohol phase. Particle size is tuned, and particles are formed with and without hemoglobin. The encapsulation efficiency and ferrous state of hemoglobin are analyzed, resulting in 60% encapsulation efficiency and a maximum of 20% ferric hemoglobin, yielding 100 μg mL −1 active hemoglobin in certain silk fibroin‐HBOCs formulations. The system does not elicit a strong inflammation response in vitro, demonstrating the potential for this particle system to serve as an injectable HBOC.

Tumour hypoxia limits the effectiveness of radiation therapy. Delivering normobaric or hyperbaric oxygen therapy elevates pO2 in both tumour and normal brain tissue. However, pO2 levels return to baseline within 15 minutes of stopping therapy. To investigate the effect of perfluorocarbon (PFC) emulsions on hypoxia in subcutaneous and intracranial mouse gliomas and their radiosensitising effect in orthotopic gliomas in mice breathing carbogen (95%O2 and 5%CO2). PFC emulsions completely abrogated hypoxia in both subcutaneous and intracranial GL261 models and conferred a significant survival advantage orthotopically (Mantel Cox: p = 0.048) in carbogen breathing mice injected intravenously (IV) with PFC emulsions before radiation versus mice receiving radiation alone. Carbogen alone decreased hypoxia levels substantially and conferred a smaller but not statistically significant survival advantage over and above radiation alone. IV injections of PFC emulsions followed by 1h carbogen breathing, radiosensitises GL261 intracranial tumors.

Hypoxia/hypoxia-inducible factor 1α-driven immunosuppressive transcription and cAMP-elevating signaling through A2A adenosine receptors (A2ARs) represent a major tumor-protecting pathway that enables immune evasion. Recent promising clinical outcomes due to the blockade of the adenosine-generating enzyme CD73 and A2AR in patients refractory to all other therapies have confirmed the importance of targeting hypoxia-adenosinergic signaling. We report a feasible approach to target the upstream stage of hypoxia-adenosinergic immunosuppression using an oxygen-carrying nanoemulsion (perfluorocarbon blood substitute). We show that oxygenation agent therapy (a) eliminates tumor hypoxia, (b) improves efficacy of endogenously developed and adoptively transferred T cells, and thereby (c) promotes regression of tumors in different anatomical locations. We show that both T cells and NK cells avoid hypoxic tumor areas and that reversal of hypoxia by oxygenation agent therapy increases intratumoral infiltration of activated T cells and NK cells due to reprogramming of the tumor microenvironment (TME). Thus, repurposing oxygenation agents in combination with supplemental oxygen may improve current cancer immunotherapies by preventing hypoxia-adenosinergic suppression, promoting immune cell infiltration and enhancing effector responses. These data also suggest that pretreating patients with oxygenation agent therapy may reprogram the TME from immunosuppressive to immune-permissive prior to adoptive cell therapy, or other forms of immunotherapy.

This case report demonstrates a small repetition of the case series carried out in Italy wherein inhaled adenosine was administered to patients experiencing severe and worsening coronavirus disease-2019 (COVID-19). The two cases are important not only because they were the first of their type in the United States, but also because both patients were DNR/DNI and were therefore expected to die. Study repetition is vitally important in medicine. New work in pharmacology hypothesizes that adenosine-regulator proteins may play a role in the pathogenesis of COVID-19 infection. Furthermore, adenosine, by interacting with cell receptor sites, has pluripotent effects upon inflammatory cells, is anti-inflammatory, and is important in tissue hypoxia signaling. Inhaled adenosine is potentially safe; thousands have received it for asthmatic challenge testing. The effects of adenosine in these two cases were rapid, positive, and fit the pharmacologic hypotheses (as seen in prior work in this journal) and support its role as a therapeutic nucleoside.

PurposeVasoplegia is a clinical syndrome marked by severe arteriolar vasodilatation, hypotension, and low systemic vascular resistance refractory to multiple vasopressor treatment. We report our experience with hydroxocobalamin (B12) infusion as a potential rescue adjunct for refractory vasoplegia during cardiopulmonary bypass (CPB).MethodsWe performed a retrospective chart review of 33 patients undergoing cardiac surgery between 1 January 2013 and 31 December 2015, who were given intravenous B12 for refractory hypotension during, or immediately following, CPB. We assessed mean arterial pressure (MAP) responses using semi-parametric group-based models (trajectory analysis). Vasopressor use was evaluated by norepinephrine-equivalent rates calculated five minutes prior, and up to 60 min following, B12 administration.ResultsPatients were mostly male (82%), had a mean (SD) age of 53 (13) yr, and median (IQR) EuroSCORE mortality index of 9 [4-40]. Four patterns of MAP responses to B12 were identified. In Group 1 (“poor responders”) nine of 33 patients (27%) had the highest median [IQR] mortality risk (EuroSCORE 40 [4-52]), lowest mean pre-B12 MAP (50 mmHg), and minimal hemodynamic response in spite of continued vasopressor support. In contrast, Group 2 “responders” (8/33, 24%) showed a brisk MAP response (> 15 mmHg) to B12, sustained for > 60 min post-infusion, with 50% vasopressor reduction. Groups 3 and 4 had the lowest median mortality risk (EuroSCORE 8) and highest pre-B12 MAP (72 mmHg). Although Group 3 patients (“sustainers”; 9/33, 27%) showed a sustained MAP improvement, those in Group 4 (“rebounders”; 7/33, 21%) were characterized by hypertensive overshoot followed by a decrease in MAP.ConclusionThese data indicate considerable heterogeneity in patient response to B12, potentially dependent on both patient preoperative condition and non-standardized time of administration. B12 may provide a useful alternative therapy for refractory hypotension and vasoplegia, but controlled clinical trials to assess efficacy are needed.

PurposeHydroxocobalamin, or vitamin B12 (V-B12), is frequently used to treat smoke inhalation and cyanide poisoning. Recent reports have also described its use to treat vasoplegia in cardiac surgery and liver transplantation. This narrative review discusses this “off-label” indication for V-B12, focusing on the potential biochemical mechanisms of its actions.SourcePubMed, Cochrane, and Web of Science databases were searched for clinical reports on the use of V-B12 for vasoplegia in cardiac surgery and liver transplantation, with the biochemical mechanisms discussed being based on a survey of the related biochemistry literature.Principal findingsForty-four patients have been treated with V-B12 for vasoplegia in various isolated case reports and one series. Although 75% of patients have increased blood pressure in response to V-B12, there were some “non-responders”. The true efficacy remains unknown because clinical trials have not been performed, and significant reporting bias likely exists. Plausible biochemical explanations exist for the potential beneficial effects of V-B12 in treating vasoplegia, including binding nitric oxide and other gasotransmitters. Additional research is required to clarify if and how these mechanisms are causally involved in effective clinical responders and non-responders.ConclusionsAlthough anecdotal reports utilizing V-B12 for vasoplegia are available, no higher-level evidence exists. Future work is necessary to further understand the dosing, timing, adverse events, and biochemical mechanisms of V-B12 compared with other therapies such as methylene blue.

ABSTRACT OBJECTIVE Perfluorocarbon emulsions have been shown to improve outcomes in stroke models. This study examined the effect of Oxycyte, a third-generation perfluorocarbon emulsion (04RD33; Synthetic Blood International, Inc., Costa Mesa, CA) treatment on cognitive recovery and mitochondrial oxygen consumption after a moderate lateral fluid percussion injury (LFPI). METHODS Adult male Sprague-Dawley rats (Harlan Bioproducts for Science, Indianapolis, IN) were allocated to 4 groups: 1) LFPI treated with a lower dose of Oxycyte (4.5 mL/kg); 2) LFPI with a higher dose of Oxycyte (9.0 mL/kg); 3) LFPI with saline infusion; and 4) sham animals treated with saline. Fifteen minutes after receiving moderate LFPI or sham surgery, animals were infused intravenously with Oxycyte or saline within 30 minutes while breathing 100% O2. Animals breathed 100% O2 continuously for a total of 4 hours after injury. At 11 to 15 days after LFPI, animals were assessed for cognitive deficits using the Morris water maze test. They were sacrificed at Day 15 after injury for histology to assess hippocampal neuronal cell loss. In a parallel study, mitochondrial oxygen consumption values were measured by the Cartesian diver microrespirometer method. RESULTS We found that injured animals treated with a lower or higher dose of Oxycyte had significant improvement in cognitive function when compared with injured saline-control animals (P < 0.05). Moreover, injured animals that received either dose of Oxycyte had significantly less neuronal cell loss in the hippocampal CA3 region compared with saline-treated animals (P < 0.05). Furthermore, a lower dose of Oxycyte significantly improved mitochondrial oxygen consumption levels (P < 0.05). CONCLUSION The current study demonstrates that Oxycyte can improve cognitive recovery and reduce CA3 neuronal cell loss after traumatic brain injury in rats.

We congratulate you on a quality review of the article on hemostasis in end-stage liver disease by Saner FH et al [...].We congratulate you on a quality review of the article on hemostasis in end-stage liver disease by Saner FH et al [...].

Background Severe traumatic injury and haemorrhagic shock are frequently associated with disruptions of coagulation function (such as trauma-induced coagulopathy TIC) and activation of inflammatory cascades. These pathologies may be exacerbated by current standard of care resuscitation protocols. Observational studies suggest early administration of plasma to severely-injured haemorrhaging patients may correct TIC, minimise inflammation, and improve survival. The proposed randomised clinical trial will evaluate the clinical effectiveness of pre-hospital plasma administration compared with standard- of-care crystalloid resuscitation in severely-injured patients with major traumatic haemorrhage. Methods/design This is a prospective, randomized, open-label, non-blinded trial to determine the effect of pre-hospital administration of thawed plasma (TP) on mortality, morbidity, transfusion requirements, coagulation, and inflammatory response in severely-injured bleeding trauma patients. Two hundred and ten eligible adult trauma patients will be randomised to receive either two units of plasma, to be administered in-field, vs standard of care normal saline (NS). Main analyses will compare subjects allocated to TP to those allocated to NS, on an intention-to-treat basis. Primary outcome measure is all-cause 30-day mortality. Secondary outcome measures include coagulation and lipidomic/pro-inflammatory marker responses, volume of resuscitation fluids (crystalloid, colloid) and blood products administered, and major hospital outcomes (e.g. incidence of MSOF, length of ICU stay, length of hospital stay). Discussion This study is part of a US Department of Defense (DoD)-funded multi-institutional investigation, conducted independently of, but in parallel with, the University of Pittsburgh and University of Denver. Demonstration of significant reductions in mortality and coagulopathic/inflammatory-related morbidities as a result of pre-hospital plasma administration would be of considerable clinical importance for the management of haemorrhagic shock in both civilian and military populations. Trial registration ClinicalTrials.gov: NCT02303964 on 28 November 2014

Background Clinical trial success depends on appropriate management, but practical guidance to trial organisation and planning is lacking. The Incident Command System (ICS) is the ‘gold standard’ management system developed for managing diverse operations in major incident and public health arenas. It enables effective and flexible management through integration of personnel, procedures, resources, and communications within a common hierarchical organisational structure. Conventional ICS organisation consists of five function modules: Command, Planning, Operations, Logistics, and Finance/Administration. Large clinical trials will require a separate Regulatory Administrative arm, and an Information arm, consisting of dedicated data management and information technology staff. We applied ICS principles to organisation and management of the Prehospital Use of Plasma in Traumatic Haemorrhage (PUPTH) trial. This trial was a multidepartmental, multiagency, randomised clinical trial investigating prehospital administration of thawed plasma on mortality and coagulation response in severely injured trauma patients. We describe the ICS system as it would apply to large clinical trials in general, and the benefits, barriers, and lessons learned in utilising ICS principles to reorganise and coordinate the PUPTH trial. Results Without a formal trial management structure, early stages of the trial were characterised by inertia and organisational confusion. Implementing ICS improved organisation, coordination, and communication between multiple agencies and service groups, and greatly streamlined regulatory compliance administration. However, unfamiliarity of clinicians with ICS culture, conflicting resource allocation priorities, and communication bottlenecks were significant barriers. Conclusions ICS is a flexible and powerful organisational tool for managing large complex clinical trials. However, for successful implementation the cultural, psychological, and social environment of trial participants must be accounted for, and personnel need to be educated in the basics of ICS. Trial registration ClinicalTrials.gov, NCT02303964 . Registered on 28 November 2014.