bims-heshmo 2021-08-15 papers

bims-heshmo

Biomed News

on Trauma hemorrhagic shock — molecular basis

Issue of 2021–08–15
fourteen papers selected by
Andreia Luís, Ludwig Boltzmann Institute

Predicting factors and incidence of preventable trauma induced mortality.
The Role of Tranexamic Acid in the Management of an Acutely Hemorrhaging Patient.
Soluble factors of mesenchimal stem cells (FS-MSC) as a potential tool to reduce inflammation in donor's lungs after hypovolemic shock.
Gut Microbiota and Probiotics/Synbiotics for Modulation of Immunity in Critically Ill Patients.
Differential Regulation of Damage-Associated Molecular Pattern Release in a Mouse Model of Skeletal Muscle Ischemia/Reperfusion Injury.
Autophagy-Related LC3 Accumulation Interacted Directly With LIR Containing RIPK1 and RIPK3, Stimulating Necroptosis in Hypoxic Cardiomyocytes.
κ Opioid Receptor Agonist Inhibits Myocardial Injury in Heart Failure Rats through Activating Nrf2/HO-1 Pathway and Regulating Ca2+-SERCA2a.
Reversing Rivaroxaban Anticoagulation as Part of a Multimodal Hemostatic Intervention in a Polytrauma Animal Model.
Efficacy and Safety of Low Molecular Weight Heparin Versus Unfractionated Heparin for Prevention of Venous Thromboembolism in Trauma Patients: A Systematic Review and Meta-Analysis.
Tranexamic acid for the prevention and treatment of bleeding in surgery, trauma and bleeding disorders: a narrative review.
A chitosan hydrogel sealant with self-contractile characteristic: From rapid and long-term hemorrhage control to wound closure and repair.
A performance comparison of the most commonly used minimally invasive monitors of cardiac output.
HO‑1 knockdown upregulates the expression of VCAM‑1 to induce neutrophil recruitment during renal ischemia‑reperfusion injury.
Myeloid-Derived Growth Factor Protects Against Pressure Overload-Induced Heart Failure by Preserving Sarco/Endoplasmic Reticulum Ca2+-ATPase Expression in Cardiomyocytes.

Ann Med Surg (Lond). 2021 Aug;68 102609

Predicting factors and incidence of preventable trauma induced mortality.

Abdoulhosein Davoodabadi, Esmail Abdorrahim Kashi, Mahdi Mohammadzadeh, Noushin Mousavi, Shima Shafagh, Leila Ghafoor, Mojtaba Sehat, Shahrzad Ale Mohammad, Abbas Hajian.

   Introduction: Trauma is one of the most common causes of morbidity and mortality worldwide. Since the definition of preventable death has been described many studies like current one were conducted to evaluate this issue.
Methods: This cohort retrospective study investigated archived medical files of trauma victims from 2017 to 2020 in a referral single-center trauma hospital. Registered demographic data, vital signs, Glasgow coma scale (GCS), timing of trauma and death, executed interventions, type and mechanism of trauma in addition to time errors, clinical mismanagements, and missed injuries were extracted. Injury severity score, revised trauma score, and probability of survival based on TRISS method for each case were calculated. Eventually preventable and non-preventable death were defined and compared.
Results: Finally from the all 413 trauma deaths 246(54.9 %) files were enrolled. Dead persons were from 18 to 95 years. Of all 189(76.8 %) were males. Analysis manifested 135(54.9 %) of all deaths were potentially preventable and the rest 49.1 % was non-preventable for expiration(p = 0.001). Data showed that from all variables systolic blood pressure ≥80 mmHg, respiratory rate >19 per minute, GCS>8, higher RTS, road traffic accidents and control of external bleeding were contributed to prediction of preventable trauma related mortality.
Conclusion: This study implied on that frequency of trauma related preventable death was regionally high and associating factors that could influence the number of these mortalities included systolic blood pressure, respiratory rate, GCS, revised trauma score, mechanism of trauma, and external bleeding of trauma patients.

Keywords:  Death; ISS; Preventable; Probability of survival; Trauma

DOI:  https://doi.org/10.1016/j.amsu.2021.102609
Hosp Pharm. 2021 Aug;56(4): 350-358

The Role of Tranexamic Acid in the Management of an Acutely Hemorrhaging Patient.

Steven Davis, Aria Nawab, Christiaan van Nispen, Ali Pourmand.

  Background: Acute hemorrhage, both traumatic and nontraumatic, leads to significant morbidity and mortality, both in the United States and globally. Traditional treatment of acute hemorrhage is focused on hemostasis and blood product replacement. Tranexamic acid is an antifibrinolytic agent that may reduce acute hemorrhage through inhibition of plasminogen. Newer research suggests that coagulopathy, specifically fibrinolysis, may contribute significantly to the pathology of acute hemorrhage. Methods: We searched the PubMed database for relevant articles from 2000 to 2018 for the terms "tranexamic acid," "TXA," "antifibrinolytic," "hyperfibrinolysis," and "coagulopathy." Our search was limited to studies published in the English language. Results: A total of 53 studies were included in this review. These articles suggest a potential role for tranexamic acid in the management of acute intracranial hemorrhage, epistaxis, hematuria, postpartum hemorrhage, gastrointestinal hemorrhage, and trauma-related hemorrhage. A theoretical risk of thrombotic events following tranexamic acid use exists, though large clinical trials suggest this risk remains exceedingly small. Conclusions: Recent studies suggest a mortality benefit with tranexamic acid following acute hemorrhage. First responders such as emergency medical technicians and emergency department clinicians should consider tranexamic acid as an adjunct therapy in the management of acute, severe traumatic and nontraumatic hemorrhage.

Keywords:  emergency department; epistaxis; hematuria; postpartum; review; tranexamic acid; trauma

DOI:  https://doi.org/10.1177/0018578720906613
J Bras Pneumol. 2021 ;pii: S1806-37132021000400202. [Epub ahead of print]47(4): e20200452

Soluble factors of mesenchimal stem cells (FS-MSC) as a potential tool to reduce inflammation in donor's lungs after hypovolemic shock.

Vinicius Luderer Dias, Karina Andrighetti de Oliveira Braga, Natalia Aparecida Nepomuceno, Liliane Moreira Ruiz, Juan David Ruiz Perez, Aristides Tadeu Correia, Luiz Carlos de Caires Junior, Ernesto Goulart, Mayana Zatz, Paulo Manuel Pêgo-Fernandes.

OBJECTIVE: The shortage of viable lungs is still a major obstacle for transplantation. Trauma victims who represent potential lung donors commonly present hypovolemic shock leading to pulmonary inflammation and deterioration and rejection after transplantation. Seeking to improve lung graft, new approaches to donor treatment have been tested. This study focuses on treatment with mesenchymal stem cells (MSCs) or soluble factors produced by MSCs (FS-MSC) using a rat model for lung donors after hemorrhagic shock.
METHODS: Forty-eight rats were divided into four groups: Sham (n=12), animals without induction of hypovolemic shock; Shock (n=12), animals submitted to hypovolemic shock (mean arterial pressure 40 mmHg); MSC (n=12), animals submitted to hypovolemic shock and treated with MSCs, and FS (n=12), animals submitted to hypovolemic shock and treated with FS-MSC. The animals were subjected to a 50-minute hypovolemic shock (40 mmHg) procedure. The treated animals were monitored for 115 minutes. We performed histopathology of lung tissue and quantification of inflammatory markers (TNF-α, IL-1β, IL-6, IL-10, iCAM and vCAM) in lung tissue and peripheral blood leukocytes (PBLs).
RESULTS: Hemorrhagic shock resulted in higher PBLs and neutrophil infiltrate in the lungs. FS animals had lower neutrophil density comparing with Shock and MSC animals (p<0.001). No differences in the cytokine levels in lung tissue were observed between the groups.
CONCLUSIONS: The lungs of rats submitted to hemorrhagic shock and treated with FS-MSC showed reduced inflammation indicated in a decrease in lung neutrophil infiltrate.

DOI: https://doi.org/10.36416/1806-3756/e20200452
Nutrients. 2021 Jul 16. pii: 2439. [Epub ahead of print]13(7):

Gut Microbiota and Probiotics/Synbiotics for Modulation of Immunity in Critically Ill Patients.

Kentaro Shimizu, Masahiro Ojima, Hiroshi Ogura.

  Patients suffering from critical illness have host inflammatory responses against injuries, such as infection and trauma, that can lead to tissue damage, organ failure, and death. Modulation of host immune response as well as infection and damage control are detrimental factors in the management of systemic inflammation. The gut is the motor of multiple organ failure following injury, and it is recognized that gut dysfunction is one of the causative factors of disease progression. The gut microbiota has a role in maintaining host immunity, and disruption of the gut microbiota might induce an immunosuppressive condition in critically ill patients. Treatment with probiotics and synbiotics has been reported to attenuate systemic inflammation by maintaining gut microbiota and to reduce postoperative infectious complications and ventilator-associated pneumonia. The administration of prophylactic probiotics/synbiotics could be an important treatment option for preventing infectious complications and modulating immunity. Further basic and clinical research is needed to promote intestinal therapies for critically ill patients.

Keywords:  ICU; critically; gut; immune; inflammation; microbiota; prebiotics; probiotics; synbiotics; ventilator

DOI:  https://doi.org/10.3390/nu13072439
Front Immunol. 2021 ;12 628822

Differential Regulation of Damage-Associated Molecular Pattern Release in a Mouse Model of Skeletal Muscle Ischemia/Reperfusion Injury.

Hiroaki Furubeppu, Takashi Ito, Midori Kakuuchi, Tomotsugu Yasuda, Chinatsu Kamikokuryo, Shingo Yamada, Ikuro Maruyama, Yasuyuki Kakihana.

   Background: Skeletal muscle ischemia/reperfusion (I/R) injury is an important clinical issue that can cause remote organ injury. Although its pathogenesis has not been fully elucidated, recent studies have suggested that damage-associated molecular patterns (DAMPs) are mediators of remote organ injury in sterile inflammation. The purpose of this study was to investigate the possible involvement of DAMPs, including the nuclear proteins high-mobility group box 1 (HMGB1) and histone H3, in the pathogenesis of skeletal muscle I/R injury in mice.
Methods: Hindlimb ischemia was induced in mice through bilateral ligation of inguinal regions using rubber grommets. Reperfusion was induced by cutting the rubber grommets after 2-12 h of ischemic period. Survival rates, localization of HMGB1 and histone H3 in the gastrocnemius muscle, and circulating HMGB1 and histone H3 levels were analyzed. The effect of anti-HMGB1 and anti-histone H3 antibodies on survival was analyzed in mice with I/R injury.
Results: All mice with hindlimb ischemia survived for at least 36 h, while all mice died within 24 h if the hindlimbs were reperfused after ischemia for 4-12 h. Immunohistochemical analysis revealed that HMGB1 translocated from the nucleus to the cytoplasm in the ischemic gastrocnemius muscle, while histone H3 was confined to the nucleus. Accordingly, serum HMGB1 levels were significantly elevated in mice with hindlimb I/R compared with normal mice or mice with hindlimb ischemia (P < 0.05). Serum histone H3 levels were not elevated after I/R. Treatment with anti-HMGB1 antibodies significantly improved survival of mice with hindlimb I/R injury compared with control antibodies (P < 0.05).
Conclusions: HMGB1, but not histone H3, translocated to the cytoplasm during skeletal muscle ischemia, and was released into the systemic circulation after reperfusion in mice with I/R injury. Treatment with anti-HMGB1 antibodies partially improved survival.

Keywords:  damage-associated molecular patterns; extracellular histones; high mobility group box 1; ischemia reperfusion injury; skeletal muscle

DOI:  https://doi.org/10.3389/fimmu.2021.628822
Front Cell Dev Biol. 2021 ;9 679637

Autophagy-Related LC3 Accumulation Interacted Directly With LIR Containing RIPK1 and RIPK3, Stimulating Necroptosis in Hypoxic Cardiomyocytes.

Yao Huang, Yanhai Feng, Lin Cui, Lei Yang, Qiong Zhang, Junhui Zhang, Xupin Jiang, Xingyue Zhang, Yanling Lv, Jie-Zhi Jia, Dong-Xia Zhang, Yue-Sheng Huang.

  The exact relationships and detailed mechanisms between autophagy and necroptosis remain obscure. Here, we demonstrated the link between accumulated autophagosome and necroptosis by intervening with autophagic flux. We first confirmed that the LC3 interacting region (LIR) domain is present in the protein sequences of RIPK1 and RIPK3. Mutual effects among LC3, RIPK1, and RIPK3 have been identified in myocardium and cardiomyocytes. Direct LC3-RIPK1 and LC3-RIPK3 interactions were confirmed by pull-down assays, and their interactions were deleted after LIR domain mutation. Moreover, after disrupting autophagic flux under normoxia with bafilomycin A1 treatment, or with LC3 or ATG5 overexpression adenovirus, RIPK1, RIPK3, p-RIPK3, and p-MLKL levels increased, suggesting necroptosis activation. Severe disruptions in autophagic flux were observed under hypoxia and bafilomycin A1 co-treated cardiomyocytes and myocardium and led to more significant activation of necroptosis. Conversely, after alleviating hypoxia-induced autophagic flux impairment with LC3 or ATG5 knockdown adenovirus, the effects of hypoxia on RIPK1 and RIPK3 levels were reduced, which resulted in decreased p-RIPK3 and p-MLKL. Furthermore, necroptosis was inhibited by siRNAs against RIPK1 and RIPK3 under hypoxia or normoxia. Based on our results, LIR domain mediated LC3-RIPK1 and LC3-RIPK3 interaction. Besides, autophagosome accumulation under hypoxia lead to necrosome formation and, in turn, necroptosis, while when autophagic flux was uninterrupted, RIPK1 and RIPK3 were cleared through an autophagy-related pathway which inhibited necroptosis. These findings provide novel insights for the role of LC3 in regulating cardiomyocyte necroptosis, indicating its therapeutic potential in the prevention and treatment of hypoxic myocardial injury and other hypoxia-related diseases.

Keywords:  LC3; autophagosome; autophagy; myocardial hypoxia; necroptosis

DOI:  https://doi.org/10.3389/fcell.2021.679637
Oxid Med Cell Longev. 2021 ;2021 7328437

κ Opioid Receptor Agonist Inhibits Myocardial Injury in Heart Failure Rats through Activating Nrf2/HO-1 Pathway and Regulating Ca2+-SERCA2a.

Tengfei Wu, Hui Yao, Binghua Zhang, Shenglai Zhou, Ping Hou, Keyan Chen.

Objectives: We aimed to observe the protective effect of κ opioid receptor (κ-OR) agonist on myocardial injury in heart failure (HF) rats and its effect on Ca2+-SERCA2a and to explore the regulatory mechanism with the Nrf2/HO-1 signaling pathway.
Methods: 50 Sprague-Dawley rats were randomly divided into the following groups: the sham operation group (sham group), HF model group (HF group), HF+κ-OR agonist U50488 group (HU group), HF+U50488H+novel calmodulin-dependent protein kinase II (CaMKII) agonist (oleic acid) (HUO group), and HF+U50488H+Nrf2 inhibitor (HUM group). The HF rat's model was established through surgical ligation of the left anterior descending coronary artery and the exhausting swimming exercise. After that, rat's cardiac function was monitored by echocardiography. HE and MASSON staining was used to detect the myocardial injury, and TUNEL staining was used to detect the myocardial apoptosis. ELISA was performed to detect the biomarkers of oxidative stress. Moreover, the distribution of reactive oxygen species (ROS) and Nrf2 was detected under immunofluorescence. The expression of sarco/endoplasmic reticulum calcium (Ca2+) ATPase (SERCA) 2a, calmodulin, endoplasmic reticulum stress- (ERS-) related proteins, and Nrf2/HO-1 signaling pathway-related proteins were detected by Western Blotting.
Results: κ-OR agonist U50488H can significantly enhance rat's cardiac function, reduce the injury and apoptosis of myocardial cells, and alleviate endoplasmic reticulum stress injury in HF rats via upregulating the SERCA2a expression and inhibiting the Ca2+ influx. Furthermore, U50488H could also inhibit the phosphorylation of CaMKII and cAMP-response element binding protein (CREB). Additionally, administration of CaMKII-specific agonist could partially block the therapeutic effect of κ-OR agonist on the myocardium of HF rats. Interestingly, the antagonist of Nrf2 could also significantly reverse the therapeutic effect of κ-OR agonist. Therefore, these results suggested that the effect of U50488H on HF rats is dependent on regulating CaMKII phosphorylation and activating the Nrf2/HO-1 pathway.
Conclusion: κ-OR agonists U50488H can improve ERS in cardiomyocytes and relieve myocardial injury in HF rats through activating the Nrf2/HO-1 pathway and regulating Ca2+-SERCA2a to inhibit Ca2+ influx.

DOI: https://doi.org/10.1155/2021/7328437
Anesthesiology. 2021 Aug 09.

Reversing Rivaroxaban Anticoagulation as Part of a Multimodal Hemostatic Intervention in a Polytrauma Animal Model.

Farahnaz Rayatdoost, Till Braunschweig, Benjamin Maron, Herbert Schöchl, Necib Akman, Rolf Rossaint, Eva Herzog, Stefan Heitmeier, Oliver Grottke.

BACKGROUND: Life-threatening bleeding requires prompt reversal of the anticoagulant effects of factor Xa inhibitors. This study investigated the effectiveness of four-factor prothrombin complex concentrate in treating trauma-related hemorrhage with rivaroxaban-anticoagulation in a pig polytrauma model. This study also tested the hypothesis that the combined use of a low dose of prothrombin complex concentrate plus tranexamic acid and fibrinogen concentrate could improve its subtherapeutic effects.
METHODS: Trauma (blunt liver injury and bilateral femur fractures) was induced in 48 anesthetized male pigs after 30 min of rivaroxaban infusion (1 mg/kg). Animals in the first part of the study received prothrombin complex concentrate (12.5, 25, and 50 U/kg). In the second part, animals were treated with 12.5 U/kg prothrombin complex concentrate plus tranexamic acid or plus tranexamic acid and fibrinogen concentrate. The primary endpoint was total blood loss postinjury. The secondary endpoints (panel of coagulation parameters and thrombin generation) were monitored for 240 min posttrauma or until death.
RESULTS: The first part of the study showed that blood loss was significantly lower in the 25 U/kg prothrombin complex concentrate (1,541 ± 269 ml) and 50 U/kg prothrombin complex concentrate (1,464 ± 108 ml) compared with control (3,313 ± 634 ml), and 12.5 U/kg prothrombin complex concentrate (2,671 ± 334 ml, all P < 0.0001). In the second part of the study, blood loss was significantly less in the 12.5 U/kg prothrombin complex concentrate plus tranexamic acid and fibrinogen concentrate (1,836 ± 556 ml, P < 0.001) compared with 12.5 U/kg prothrombin complex concentrate plus tranexamic acid (2,910 ± 856 ml), and there were no early deaths in the 25 U/kg prothrombin complex concentrate, 50 U/kg prothrombin complex concentrate, and 12.5 U/kg prothrombin complex concentrate plus tranexamic acid and fibrinogen concentrate groups. Histopathologic analyses postmortem showed no adverse events.
CONCLUSIONS: Prothrombin complex concentrate effectively reduced blood loss, restored hemostasis, and balanced thrombin generation. A multimodal hemostatic approach using tranexamic acid plus fibrinogen concentrate enhanced the effect of low doses of prothrombin complex concentrate, potentially reducing the prothrombin complex concentrate doses required for effective bleeding control.
EDITOR’S PERSPECTIVE:

DOI: https://doi.org/10.1097/ALN.0000000000003899
Ann Surg. 2021 Aug 13.

Efficacy and Safety of Low Molecular Weight Heparin Versus Unfractionated Heparin for Prevention of Venous Thromboembolism in Trauma Patients: A Systematic Review and Meta-Analysis.

Alexandre Tran, Shannon M Fernando, Marc Carrier, Deborah M Siegal, Kenji Inaba, Kelly Vogt, Paul T Engels, Shane W English, Salmaan Kanji, Kwadwo Kyeremanteng, Jacinthe Lampron, Dennis Kim, Bram Rochwerg.

PURPOSE: Trauma patients are at high risk of venous thromboembolism (VTE). We summarize the efficacy and safety of low molecular weight heparin (LMWH) versus unfractionated heparin (UFH) for the prevention of VTE in trauma patients.
METHODS: We searched six databases from inception through March 12th, 2021. We included randomized controlled trials (RCTs) or observational studies comparing LMWH vs UFH for thromboprophylaxis in adult trauma patients. We pooled effect estimates across RCTs and observational studies separately, using random-effects model and inverse variance weighting. We assessed risk of bias using the Cochrane tool for RCTs and the ROBINS-I tool for observational studies and assessed certainty of findings using GRADE methodology.
RESULTS: We included 4 RCTs (879 patients) and 8 observational studies (306,747 patients). Based on pooled RCT data, compared to UFH, LMWH reduces deep vein thrombosis (DVT) (relative risk [RR] 0.67, 95% confidence interval [CI] 0.50 to 0.88, moderate certainty) and VTE (RR 0.68, 95% CI 0.51 to 0.90, moderate certainty). As compared to UFH, LMWH may reduce pulmonary embolism (adjusted odds ratio from pooled observational studies (aOR) 0.56 (95% CI 0.50 to 0.62) and mortality (aOR from pooled observational studies 0.54, 95% CI 0.45 to 0.65), though based on low certainty evidence. There was an uncertain effect on adverse events (RR from pooled RCTs 0.80, 95% CI 0.48 to 1.33, very low certainty) and heparin induced thrombocytopenia (RR from pooled RCTs 0.26 (95% CI 0.03 to 2.38, very low certainty).
CONCLUSION: Among adult trauma patients, LMWH is superior to UFH for DVT and VTE prevention and may additionally reduce pulmonary embolism and mortality. The impact on adverse events and heparin induced thrombocytopenia is uncertain.

DOI: https://doi.org/10.1097/SLA.0000000000005157
Thromb J. 2021 Aug 11. 19(1): 54

Tranexamic acid for the prevention and treatment of bleeding in surgery, trauma and bleeding disorders: a narrative review.

Anna Ockerman, Thomas Vanassche, Melisa Garip, Christophe Vandenbriele, Matthias M Engelen, Jeroen Martens, Constantinus Politis, Reinhilde Jacobs, Peter Verhamme.

OBJECTIVES: We review the evidence for tranexamic acid (TXA) for the treatment and prevention of bleeding caused by surgery, trauma and bleeding disorders. We highlight therapeutic areas where evidence is lacking and discuss safety issues, particularly the concern regarding thrombotic complications.
METHODS: An electronic search was performed in PubMed and the Cochrane Library to identify clinical trials, safety reports and review articles.
FINDINGS: TXA reduces bleeding in patients with menorrhagia, and in patients undergoing caesarian section, myomectomy, hysterectomy, orthopedic surgery, cardiac surgery, orthognathic surgery, rhinoplasty, and prostate surgery. For dental extractions in patients with bleeding disorders or taking antithrombotic drugs, as well as in cases of idiopathic epistaxis, tonsillectomy, liver transplantation and resection, nephrolithotomy, skin cancer surgery, burn wounds and skin grafting, there is moderate evidence that TXA is effective for reducing bleeding. TXA was not effective in reducing bleeding in traumatic brain injury and upper and lower gastrointestinal bleeding. TXA reduces mortality in patients suffering from trauma and postpartum hemorrhage. For many of these indications, there is no consensus about the optimal TXA dose. With certain dosages and with certain indications TXA can cause harm, such as an increased risk of seizures after high TXA doses with brain injury and cardiac surgery, and an increased mortality after delayed administration of TXA for trauma events or postpartum hemorrhage. Whereas most trials did not signal an increased risk for thrombotic events, some trials reported an increased rate of thrombotic complications with the use of TXA for gastro-intestinal bleeding and trauma.
CONCLUSIONS: TXA has well-documented beneficial effects in many clinical indications. Identifying these indications and the optimal dose and timing to minimize risk of seizures or thromboembolic events is work in progress.

DOI: https://doi.org/10.1186/s12959-021-00303-9
Carbohydr Polym. 2021 Nov 01. pii: S0144-8617(21)00815-8. [Epub ahead of print]271 118428

A chitosan hydrogel sealant with self-contractile characteristic: From rapid and long-term hemorrhage control to wound closure and repair.

Wen Fang, Ling Yang, Liangjie Hong, Qiaoling Hu.

  Emergent and long-term hemorrhage control is requisite and beneficial for reducing global mortality and postoperative complications (e.g., second bleeding and adverse tissue adhesion). Despite recent advance in injectable hydrogels for hemostasis, achieving rapid gelation, strong tissue-adhesive property and stable mechanical strength under fluid physiological environment is still challenging. Herein, we developed a novel chitosan hydrogel (CCS@gel) via dynamic Schiff base reaction and mussel-inspired catechol chemistry. The hydrogel possessed high gelation rate (<10 s), strong wet adhesiveness, excellent self-healing performance and biocompatibility. More importantly, the CCS@gel exhibited saline-induced contractile performance and mechanical enhancement, promoting its mechanical property in moist internal conditions. In vivo studies demonstrated its superior hemostatic efficacy for diverse anticoagulated visceral and carotid bleeding scenarios, compared to commercialized fibrin glue. The hydrogel-treated rats survived for 8 weeks with minimal inflammation and postoperative adhesion. These results revealed that the promising CCS@gel would be a facile, efficient and safe sealant for clinical hemorrhage control.

Keywords:  Hemorrhage control; Hydrogel; Self-contraction; Wet adhesiveness; Wound closure and repair

DOI:  https://doi.org/10.1016/j.carbpol.2021.118428
Can J Anaesth. 2021 Aug 09.

A performance comparison of the most commonly used minimally invasive monitors of cardiac output.

Jonathan J Gamble, William P McKay, Barbara Ambros, Grant G Miller, Andrea Vasquez Camargo, Jonathan Norton, Jayden Cowan, Jean du Rand, Erick D McNair, Kris Milbrandt, Martin Gérard, Maria Valentina Carrozzo.

   BACKGROUND: Shock is common in critically ill and injured patients. Survival during shock is highly dependent on rapid restoration of tissue oxygenation with therapeutic goals based on cardiac output (CO) optimization. Despite the clinical availability of numerous minimally invasive monitors of CO, limited supporting performance data are available.
METHODS: Following approval of the University of Saskatchewan Animal Research Ethics Board, we assessed the performance and trending ability of PiCCOplus™, FloTrac™, and CardioQ-ODM™ across a range of CO states in pigs. In addition, we assessed the ability of invasive mean arterial blood pressure (iMAP) to follow changes in CO using a periaortic transit-time flow probe as the reference method. Statistical analysis was performed with function-fail, bias and precision, percent error, and linear regression at all flow, low-flow (> 1 standard deviation [SD] below the mean), and high-flow (> 1 SD above the mean) CO conditions.
RESULTS: We made a total of 116,957 paired CO measurements. The non-invasive CO monitors often failed to provide a CO value (CardioQ-ODM: 40.6% failed measurements; 99% confidence interval [CI], 38.5 to 42.6; FloTrac: 9.6% failed measurements; 99% CI, 8.7 to 10.5; PiCCOplus: 4.7% failed measurements; 99% CI, 4.5 to 4.9; all comparisons, P < 0.001). The invasive mean arterial pressure provided zero failures, failing less often than any of the tested CO monitors (all comparisons, P < 0.001). The PiCCOplus was most interchangeable with the flow probe at all flow states: PiCCOplus (20% error; 99% CI, 19 to 22), CardioQ-ODM (25% error; 99% CI, 23 to 27), FloTrac (34% error; 99% CI, 32 to 38) (all comparisons, P < 0.001). At low-flow states, CardioQ-ODM (43% error; 99% CI, 32 to 63) and Flotrac (45% error; 99% CI, 33 to 70) had similar interchangeability (P = 0.07), both superior to PiCCOplus (48% error; 99% CI, 42 to 60) (P < 0.001). Regarding CO trending, the CardioQ-ODM (correlation coefficient, 0.82; 99% CI, 0.81 to 0.83) was statistically superior to other monitors including iMAP, but at low flows iMAP (correlation coefficient, 0.58; 99% CI, 0.58 to 0.60) was superior to all minimally invasive CO monitors (all comparisons P < 0.001).
CONCLUSIONS: None of the minimally invasive monitors of CO performed well at all tested flows. Invasive mean arterial blood pressure most closely tracked CO change at critical flow states.

Keywords:  Anesthesia and analgesia; Arterial pressure; Cardiac output; Hemodynamics; Monitoring; physiologic

DOI:  https://doi.org/10.1007/s12630-021-02085-0
Int J Mol Med. 2021 Oct;pii: 185. [Epub ahead of print]48(4):

HO‑1 knockdown upregulates the expression of VCAM‑1 to induce neutrophil recruitment during renal ischemia‑reperfusion injury.

Yecheng He, Huadong Li, Juan Yao, Hua Zhong, Yanbin Kuang, Xin Li, Weihua Bian.

  Heme oxygenase‑1 (HO‑1) has been reported to be upregulated following renal ischemia‑reperfusion injury (IRI) and plays a key cytoprotective role; however, the underlying molecular mechanisms of its protective effects remain poorly understood. In the present study, in order to further elucidate the molecular mechanisms underlying the cytoprotective role of HO‑1 in renal IRI, HO‑1+/+ and HO‑1+/‑ mice were subjected to renal ischemia and subsequent reperfusion followed by the analysis of blood urea nitrogen (BUN) and serum creatinine (SCr) levels, the severity of histological changes, HO‑1 and vascular cell adhesion molecule‑1 (VCAM‑1) protein expression, the mRNA expression of inflammatory factors and the effects of VCAM‑1 blockade. The results of the present study demonstrated that the upregulated expression levels of VCAM‑1 in HO‑1+/‑ mice during IRI increased the extent of renal tissue damage and activated the inflammatory response. These effects were subsequently reversed following infusion with an anti‑VCAM‑1 antibody. In addition, the upregulated expression of VCAM‑1 in mouse glomerulus vascular endothelial cells isolated from HO‑1+/‑ mice increased the adhesion and migration of neutrophils, effects which were also reversed upon incubation with an anti‑VCAM‑1 antibody. These results indicated that HO‑1 knockdown may upregulate the expression of VCAM‑1 during renal IRI, resulting in increased neutrophil recruitment and the activation of the inflammatory response, thereby exacerbating renal IRI. The present study thus highlights the regulatory mechanisms of HO‑1 in renal IRI and provides a potential target for the clinical treatment of IRI following renal transplantation.

Keywords:  adhesion; heme oxygenase‑1; migration; neutrophil recruitment; renal ischemia‑reperfusion injury; vascular cell adhesion molecule‑1

DOI:  https://doi.org/10.3892/ijmm.2021.5018
Circulation. 2021 Aug 10.

Myeloid-Derived Growth Factor Protects Against Pressure Overload-Induced Heart Failure by Preserving Sarco/Endoplasmic Reticulum Ca2+-ATPase Expression in Cardiomyocytes.

Mortimer Korf-Klingebiel, Marc R Reboll, Felix Polten, Natalie Weber, Felix Jäckle, Xuekun Wu, Marinos Kallikourdis, Paolo Kunderfranco, Gianluigi Condorelli, Evangelos Giannitsis, Olga S Kustikova, Axel Schambach, Andreas Pich, Julian D Widder, Johann Bauersachs, Joop van den Heuvel, Theresia Kraft, Yong Wang, Kai C Wollert.

  Background: Inflammation contributes to the pathogenesis of heart failure, but there is limited understanding of inflammation's potential benefits. Inflammatory cells secrete myeloid-derived growth factor (MYDGF) to promote tissue repair after acute myocardial infarction. We hypothesized that MYDGF has a role in cardiac adaptation to persistent pressure overload. Methods: We defined the cellular sources and function of MYDGF in wild-type, Mydgf-deficient (Mydgf-/-), and Mydgf bone marrow-chimeric or bone marrow-conditional transgenic mice with pressure overload-induced heart failure after transverse aortic constriction surgery. We measured MYDGF plasma concentrations by targeted liquid chromatography-mass spectrometry. We identified MYDGF signaling targets by phosphoproteomics and substrate-based kinase activity inference. We recorded Ca2+ transients and sarcomere contractions in isolated cardiomyocytes. Additionally, we explored the therapeutic potential of recombinant MYDGF. Results: MYDGF protein abundance increased in the left ventricular (LV) myocardium and in blood plasma of pressure-overloaded mice. Patients with severe aortic stenosis also had elevated MYDGF plasma concentrations, which declined after transcatheter aortic valve implantation. Monocytes and macrophages emerged as the main MYDGF sources in the pressure-overloaded murine heart. While Mydgf-/- mice had no apparent phenotype at baseline, they developed more severe LV hypertrophy and contractile dysfunction during pressure overload than wild-type mice. Conversely, conditional transgenic overexpression of MYDGF in bone marrow-derived inflammatory cells attenuated pressure overload-induced hypertrophy and dysfunction. Mechanistically, MYDGF inhibited G protein coupled receptor agonist-induced hypertrophy and augmented sarco/endoplasmic reticulum Ca2+ ATPase 2a (SERCA2a) expression in cultured neonatal rat cardiomyocytes by enhancing PIM1 serine/threonine kinase expression and activity. Along this line, cardiomyocytes from pressure-overloaded Mydgf-/- mice displayed reduced PIM1 and SERCA2a expression, greater hypertrophy, and impaired Ca2+ cycling and sarcomere function compared to cardiomyocytes from pressure-overloaded wild-type mice. Transplanting Mydgf-/- mice with wild-type bone marrow cells augmented cardiac PIM1 and SERCA2a levels and ameliorated pressure overload-induced hypertrophy and dysfunction. Pressure-overloaded Mydgf-/- mice were similarly rescued by adenoviral Serca2a gene transfer. Treating pressure-overloaded wild-type mice subcutaneously with recombinant MYDGF enhanced SERCA2a expression, attenuated LV hypertrophy and dysfunction, and improved survival. Conclusions: These findings establish a MYDGF-based adaptive crosstalk between inflammatory cells and cardiomyocytes that protects against pressure overload-induced heart failure.

Keywords:  cardiomyocytes; inflammation; myeloid-derived growth factor; sarco/endoplasmic reticulum Ca2+ ATPase 2a

DOI:  https://doi.org/10.1161/CIRCULATIONAHA.120.053365