Plasma-Mediated Gut Protection After Hemorrhagic Shock is Lessened in Syndecan-1−/− MICE

Ban, Kechen; Peng, Zhanglong; Pati, Shibani; Witkov, Richard; Park, Pyong Woo; Kozar, Rosemary A.

doi:10.1097/shk.0000000000000452

Cited by 27 publications

(19 citation statements)

References 34 publications

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“…Plasma is an effective buffer of fibrinolytic activity (19) and effectively reverses hyperfibrinolysis and reduces mortality in hyperfibrinolytic rodents (20). This effective colloid also has been shown to enhance metabolic recovery (21) from hemorrhagic shock, restore the endothelial glycoalyx (22), reduce pulmonary injury (23) and reduce gastrointestinal damage (24). Additional blood products that impact fibrinolysis include cryoprecipitate, which has been found to have a similar survival advantage as TXA (25).…”

Section: Discussionmentioning

confidence: 99%

Tranexamic acid is associated with increased mortality in patients with physiological fibrinolysis

Moore

Huebner

et al. 2017

Journal of Surgical Research

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Introduction Tranexamic acid (TXA) administration following trauma has not been proven to improve survival in the US. Trauma patients present to the hospital with a spectrum of fibrinolytic activity, in which a physiologic levels of fibrinolysis are associated with the lowest mortality. We hypothesize that trauma patients who present to the hospital with physiologic levels of fibrinolysis will have increased mortality if they receive TXA. Material and Methods Severely injured trauma patients followed prospectively from 2014 to 2016 we included in the analysis. The patient’s first thrombelastography (TEG) was used to stratify patients into fibrinolysis phenotypes which included fibrinolysis shutdown, physiologic fibrinolysis, and systemic hyperfibrinolysis. The primary outcome was in hospital mortality. Results 232 patients were analyzed (11% received TXA) with an overall mortality rate of 20%. TXA administration was associated with a higher new injury severity score (NISS 49 vs 28 p=0.001) massive transfusion rate (69% vs 12% p<0.001) and mortality (52% vs 17% p<0.001). Hyperfibrinolysis and shutdown had higher mortality rates than physiologic (24% vs 30% vs 14% p=0.050). The effect of TXA within phenotypes, was not significant for shutdown (28% vs 38% p=0.604) but was significant in the physiologic group (11% vs 63% p<0.001) and systemic hyperfibrinolysis (19% vs 55% p=0.023). After adjusting for NISS, TXA remained a significant predictor of mortality for patients with physiologic fibrinolysis (p=0.018). Conclusion There was no clear benefit of receiving TXA in this study, and patients who present to the hospital with physiologic levels of fibrinolysis, who received TXA, had the highest mortality. The role of TXA in mature trauma systems remains unclear, and emerging data supports it may have adverse effects.

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Section: Discussionmentioning

confidence: 99%

Tranexamic acid is associated with increased mortality in patients with physiological fibrinolysis

Moore

Huebner

et al. 2017

Journal of Surgical Research

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“…We and others have shown that syndecan-1 is shed after hemorrhagic shock from both the lung and gut (14,15). Shedding of the cell surface ectodomain of syndecan-1 is regulated by multiple intracellular signaling pathways converging on a diverse group of proteases, referred to as sheddases.…”

Section: Introductionmentioning

confidence: 92%

Intraluminal tranexamic acid inhibits intestinal sheddases and mitigates gut and lung injury and inflammation in a rodent model of hemorrhagic shock

Peng

Ban

LeBlanc

et al. 2016

Journal of Trauma and Acute Care Surgery

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Background Intravenous tranexamic acid (TXA) is an effective adjunct after hemorrhagic shock (HS) due to its antifibrinolytic properties. TXA is also a serine protease inhibitor and recent laboratory data demonstrated that intraluminal TXA into the small bowel inhibited digestive proteases and protected the gut. .ADAM-17 and TNFα are effective sheddases of intestinal syndecan-1 which when shed, exposes the underlying intestinal epithelium to digestive proteases and subsequent systemic insult. We therefore hypothesized that intraluminal TXA as a serine protease inhibitor would reduce intestinal sheddases and syndecan-1 shedding, mitigating gut and distant organ (lung) damage. Methods Mice underwent 90 minutes of hemorrhagic shock to a mean arterial pressure of 35±5 mm Hg following by the intraluminal administration of TXA or vehicle. After 3 hours, small intestine, lung, and blood were collected for analysis. Results Intraluminal TXA significantly reduced gut and lung histopathologic injury and inflammation compared to hemorrhagic shock alone. Gut, lung, and systemic ADAM-17 and TNFα were significantly increased by hemorrhagic shock but lessened by TXA. Additionally, gut and lung syndecan-1 immunostaining were preserved and systemic shedding lessened after TXA. TXA reduced ADAM-17 and TNFα, but not syndecan-1, in TXA-sham animals compared to sham vehicles. Conclusions Results of the present study demonstrate a beneficial effect of intraluminal TXA in the gut and lung after experimental hemorrhagic shock in part due to inhibition of the syndecan-1 shedding by ADAM-17 and TNFα. Further studies are needed to determine if orally administered TXA could provide similar intestinal protection and thus be of potential benefit to patients with survivable hemorrhage at risk for organ injury. This is particularly relevant in patients or soldiers who may not have access to timely medical care. Level of evidence NA

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“…Laboratory data suggest that plasma has benefits beyond the coagulation system, including restoration of endothelial glycocalyx 11 and reduction of intestinal permeability, 12 metabolic derangements, 13 and hyper-fibrinolysis. 14 Prehospital plasma infusion has been shown to be feasible during helicopter transport, 15 but the logistics of storage and thawing in fast ground transport have been challenging.…”

Section: Introductionmentioning

confidence: 99%

Plasma-first resuscitation to treat haemorrhagic shock during emergency ground transportation in an urban area: a randomised trial

et al. 2018

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Summary Background Plasma is integral to haemostatic resuscitation after injury, but the timing of administration remains controversial. Anticipating approval of lyophilised plasma by the US Food and Drug Administration, the US Department of Defense funded trials of prehospital plasma resuscitation. We investigated use of prehospital plasma during rapid ground rescue of patients with haemorrhagic shock before arrival at an urban level 1 trauma centre. Methods The Control of Major Bleeding After Trauma Trial was a pragmatic, randomised, single-centre trial done at the Denver Health Medical Center (DHMC), which houses the paramedic division for Denver city. Consecutive trauma patients in haemorrhagic shock (defined as systolic blood pressure [SBP] ≤70 mm Hg or 71–90 mm Hg plus heart rate ≥108 beats per min) were assessed for eligibility at the scene of the injury by trained paramedics. Eligible patients were randomly assigned to receive plasma or normal saline (control). Randomisation was achieved by preloading all ambulances with sealed coolers at the start of each shift. Coolers were randomly assigned to groups 1:1 in blocks of 20 according to a schedule generated by the research coordinators. If the coolers contained two units of frozen plasma, they were defrosted in the ambulance and the infusion started. If the coolers contained a dummy load of frozen water, this indicated allocation to the control group and saline was infused. The primary endpoint was mortality within 28 days of injury. Analyses were done in the as-treated population and by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01838863. Findings From April 1, 2014, to March 31, 2017, paramedics randomly assigned 144 patients to study groups. The as-treated analysis included 125 eligible patients, 65 received plasma and 60 received saline. Median age was 33 years (IQR 25–47) and median New Injury Severity Score was 27 (10–38). 70 (56%) patients required blood transfusions within 6 h of injury. The groups were similar at baseline and had similar transport times (plasma group median 19 min [IQR 16–23] vs control 16 min [14–22]). The groups did not differ in mortality at 28 days (15% in the plasma group vs 10% in the control group, p=0∙37). In the intention-to-treat analysis, we saw no significant differences between the groups in safety outcomes and adverse events. Due to the consistent lack of differences in the analyses, the study was stopped for futility after 144 of 150 planned enrolments. Interpretation During rapid ground rescue to an urban level 1 trauma centre, use of prehospital plasma was not associated with survival benefit. Blood products might be beneficial in settings with longer transport times, but the financial burden would not be justified in an urban environment with short distances to mature trauma centres.

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Plasma-Mediated Gut Protection After Hemorrhagic Shock is Lessened in Syndecan-1−/− MICE

Cited by 27 publications

References 34 publications

Tranexamic acid is associated with increased mortality in patients with physiological fibrinolysis

Tranexamic acid is associated with increased mortality in patients with physiological fibrinolysis

Intraluminal tranexamic acid inhibits intestinal sheddases and mitigates gut and lung injury and inflammation in a rodent model of hemorrhagic shock

Plasma-first resuscitation to treat haemorrhagic shock during emergency ground transportation in an urban area: a randomised trial

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