The effect of matrix metalloproteinase 2 and matrix metalloproteinase 2/9 deletion in experimental post-thrombotic vein wall remodeling

BackgroundVein wall fibrotic injury following deep venous thrombosis (VT) is associated with elevated matrix metalloproteinases (MMPs). Whether and by what mechanism MMP2 contributes to vein wall remodeling after VT is unknown.MethodsStasis VT was produced by ligation of the inferior vena cava and tissue was harvested at 2, 8, and 21 days in MMP2 -/- and genetic wild type (WT) mice. Tissue analysis by immunohistochemistry, enzyme-linked immunosorbent assay, real-time polymerase chain reaction, and zymography was performed.ResultsThrombus resolution was less at 8 days in MMP2 -/- compared with WT, evidenced by a 51% increase in VT size (P < .01), and threefold fewer von Willebrand's factor positive channels (P < .05). In MMP2 -/- mice, the main phenotypic fibrotic differences occurred at 8 days post-VT, with significantly less vein wall collagen content (P = .013), fourfold lower procollagen III gene expression (P < .01), but no difference in procollagen I compared with WT. Decreased inflammation in MMP2 -/- vein walls was suggested by ∼ threefold reduced TNFα and IL-1β at 2 days and 8 days post-VT (P < .05). A fourfold increase in vein wall monocytes (P = .03) with threefold decreased apoptosis (P < .05), but no difference in cellular proliferation at 8 days was found in MMP2 -/- compared with WT. As increased compensatory MMP9 activity was observed in the MMP2 -/-mice, MMP2/9 double null mice had thrombus induced with VT harvest at 8 days. Consistently, twofold larger VT, a threefold decrease in vein wall collagen, and a threefold increase in monocytes were found (all P < .05). Similar findings were observed in MMP9 -/- mice administered an exogenous MMP2 inhibitor.ConclusionsIn stasis VT, deletion of MMP2 was associated with less midterm vein wall fibrosis and inflammation, despite an increase in monocytes. Consideration that VT resolution was impaired with MMP2 (and MMP2/9) deletion suggests direct inhibition will likely also require anticoagulant therapy.Clinical RelevancePost-thrombotic syndrome has no direct therapies and causes significant morbidity. Anticoagulation limits thrombosis but does not clinically impact directly the vein wall response to injury as well as has bleeding risks. In this experimental study, we show that matrix metalloproteinase 2 genetic deletion lessens fibrotic injury and inflammation at the midterm timepoint, yet is also important for thrombus resolution. Future therapies that positively impact vein wall remodeling will need to account for how the thrombus responds as well

Normoxic re-oxygenation ameliorates end-organ injury after cardiopulmonary bypass

Abstract Background In a rabbit model of cardiopulmonary bypass (CPB) and cardioplegic arrest, we previously showed that hyperoxic myocardial reperfusion was associated with increased left ventricular (LV) systolic dysfunction and myocardial injury compared with normoxic reperfusion. The aim of this study was to evaluate in our experimental model the impact of post-CPB reperfusion conditions on other organs potentially vulnerable to ischemic injury such as the brain and kidney. Methods After 60 min of CPB, aortic cross-clamp, and cold cardioplegic arrest, rabbits were reperfused under hyperoxic or normoxic conditions for 120 min. Left ventricular systolic contractility (LV + dP/dt) and diastolic relaxation (LV –dP/dt) were continuously recorded, and end-organ injury was assessed by measuring circulating biomarkers specific for kidney (cystatin C and creatinine) and brain injury [S100B and neuron specific enolase (NSE)]. At completion of the protocol, kidney and brain tissues were harvested for measuring oxidant stress (OS), inflammation and apoptosis. Results Following aortic cross-clamp removal, rabbits exposed to normoxic reperfusion demonstrated preserved LV systolic and diastolic function compared with hyperoxic reperfusion (LV + dP/dt: 70 ± 14% of pre-CPB vs. 36 ± 21%, p = 0.018; LV -dP/dt: 72 ± 36% of pre-CPB vs. 33 ± 20%, p = 0.023). Similarly, CPB increased plasma creatinine, S100B and NSE that were significantly attenuated by normoxic reperfusion compared with hyperoxic reperfusion (creatinine: 4.0 ± 0.5 vs. 7.1 ± 0.8 mg/dL, p = 0.004; S100B: 4.0 ± 0.8 vs. 6.7 ± 1.0 ng/mL, p = 0.047; NSE: 57.7 ± 6.8 vs. 101.3 ± 16.1 pg/mL, p = 0.040). Furthermore, both kidney and brain tissues showed increased mRNA expression and activation of pathways for OS, inflammation, and apoptosis, that were reduced under normoxic compared with hyperoxic conditions. Conclusions Normoxic reperfusion ameliorates cardiac, renal and neural injury compared with hyperoxic reperfusion in an in vivo animal model of CPB and cardioplegic arrest. This protective effect of normoxic reperfusion may be due to a reduction in signaling pathways for OS, inflammation, and apoptosis.http://deepblue.lib.umich.edu/bitstream/2027.42/173806/1/13019_2020_Article_1173.pd

Long term veno-venous extracorporeal life support without intravenous anticoagulation for diffuse alveolar hemorrhage

Introduction: Diffuse alveolar damage is the histologic hallmark for the acute phase of acute respiratory distress syndrome and can occasionally present as diffuse alveolar hemorrhage. Case report: We report a patient with diffuse alveolar hemorrhage and acute respiratory distress syndrome requiring veno-venous extracorporeal life support for 210 days, who was successfully treated for a period of 130 consecutive days without intravenous anticoagulation. Discussion: Although there are a few brief reports detailing long extracorporeal life support runs, the literature is largely devoid of data regarding long-term extracorporeal life support without full systemic anticoagulation. Regular inspection of the extracorporeal membrane oxygenation circuit is critical because externally visible thrombi may predict internal thrombus generation with the potential for systemic embolization or abrupt oxygenator failure. In our case, multiple circuit and oxygenators changes were required. Conclusion: We have demonstrated that a patient with a contraindication for systemic anticoagulation can safely have veno-venous extracorporeal life support for prolonged periods without catastrophic thrombotic complications

Does weight matter? Outcomes in adult patients on venovenous extracorporeal membrane oxygenation when stratified by obesity class

BACKGROUND: Many believe obesity is associated with higher rates of mortality in the critically ill. The purpose of this retrospective observational study is to evaluate the association between body mass index (BMI) and survival in patients receiving venovenous (VV) extracorporeal membrane oxygenation (ECMO) for acute hypoxic or hypercarbic respiratory failure. METHODS: All of the patients admitted to a dedicated VV ECMO unit were included. Patients \u3c18 years of age, listed for lung transplant, or underweight were excluded. ECMO outcomes, including hospital length of stay and survival to discharge, were analyzed after stratification according to BMI. Multivariate logistic and linear regression techniques were used to assess variables associated with the outcomes of death and length of stay, respectively. RESULTS: One hundred ninety-four patients with a median BMI of 35.7 kg/m2(33-42 kg/m2) were included. Obese patients were older, had higher creatinine levels, and required higher levels of positive end-expiratory pressure and mean airway pressure at time of cannulation. Survival to discharge in any group did not differ when stratified by BMI classification (P =.36). Multivariable regression did not reveal any association with greater odds of death or longer length of stay when controlling for BMI and other variables. CONCLUSIONS: We did not detect an association between obesity and increased mortality in patients requiring VV ECMO for acute hypoxic or hypercarbic respiratory failure. These data suggest that obesity alone should not exclude candidacy for VV ECMO. Evidence for the obesity paradox in this population of VV ECMO patients may be supported by these data

Bleeding, Thrombosis, and Transfusion With Two Heparin Anticoagulation Protocols in Venoarterial ECMO Patients

Objective: To compare the incidence of bleeding and thrombosis between adult venoarterial (VA) extracorporeal membrane oxygenation (ECMO) patients managed with an activated clotting time (ACT)-guided heparin anticoagulation protocol and activated partial thromboplastin time (aPTT) protocol. Design: Retrospective cohort study. Setting: Tertiary care, academic medical center. Participants: Consecutive adult VA ECMO patients during a 6-year period. Interventions: None. Measurements and Main Results: Demographic, medical, transfusion, and ECMO data were collected for all patients. Primary study outcomes were bleeding and thrombosis. Secondary outcomes were stroke and in-hospital mortality. One hundred twenty-one patients were included in the cohort. Fifty patients had ACT monitoring, and 71 had aPTT monitoring. There was no difference in the incidence of bleeding or thrombosis between the 2 groups (78.0% v 67.6% for bleeding [p = 0.21] and 16.0% v 19.7% for thrombosis [p = 1.0]). After adjusting for age and total ECMO days, patients managed with ACT received approximately 30% more red blood cell, fresh frozen plasma, and platelet transfusion (all p \u3c 0.05). Conclusion: There is no apparent difference in the incidence rate of bleeding or thrombosis between VA ECMO patients managed with an ACT- or aPTT-guided heparin anticoagulation protocol. Patients managed with an ACT-guided protocol received more blood transfusion, which could reflect greater total bleeding. Future randomized controlled trials would help to elucidate optimal anticoagulation strategies for VA ECMO patients

Outcomes of Venovenous Extracorporeal Membrane Oxygenation When Stratified by Age: How Old Is Too Old?

The purpose of this study was to evaluate survival to hospital discharge for patients on venovenous extracorporeal membrane oxygenation (VV ECMO) when stratified by age. We performed a retrospective study at single, academic, tertiary care center intensive care unit for VV ECMO. All patients, older than 17 years of age, on VV ECMO admitted to a specialized intensive care unit for the management of VV ECMO between August 2014 and May 2018 were included in the study. Trauma and bridge-to-lung transplant patients were excluded for this analysis. Demographics, pre-ECMO and ECMO data were collected. Primary outcome was survival to hospital discharge when stratified by age. Secondary outcomes included time on VV ECMO and hospital length of stay (HLOS). One hundred eighty-two patients were included. Median P/F ratio at time of cannulation was 69 [56-85], and respiratory ECMO survival prediction (RESP) score was 3 [1-5]. Median time on ECMO was 319 [180-567] hours. Overall survival to hospital discharge was 75.8%. Lowess and cubic spline curves demonstrated an inflection point associated with increased mortality at age \u3e45 years. Kaplan-Meier analysis demonstrated significantly greater survival in patients \u3c45 years of age (p = 0.0001). Survival to hospital discharge for thos

Precannulation International Normalized Ratio is Independently Associated With Mortality in Veno-Arterial Extracorporeal Membrane Oxygenation

Objectives: To explore whether precannulation international normalized ratio (INR) is associated with in-hospital mortality in venoarterial extracorporeal membrane oxygenation (VA-ECMO) patients. Design: A retrospective, observational cohort study. Setting: A quaternary care academic medical center. Participants: Patients with cardiogenic shock on VA-ECMO for \u3e24 hours. Interventions: None, observational study. Measurements and Main Results: A total of 188 patients who were on VA-ECMO were included over three years. Patients were stratified into three groups based on their pre-ECMO INR: INR \u3c1.5, INR 1.5 to 1.8, and INR \u3e1.8. For all patients, demographics, comorbidities, and ECMO details were recorded. The study\u27s primary outcome was in-hospital mortality and secondary outcomes included major bleeding, minor bleeding, allogeneic transfusion, ischemic stroke, intracranial hemorrhage, acute renal failure, acute liver failure, gastrointestinal bleeding, intensive care unit and hospital lengths of stay. A multivariate logistic regression was used to determine whether precannulation INR was associated independently with in-hospital mortality. In-hospital mortality differed significantly by INR group (51.6% INR \u3e1.8 v 42.3% INR 1.5-1.8 v 24.3% INR \u3c1.5; p = 0.004). In a multivariate logistic regression model, precannulation INR \u3e1.8 was associated independently with an increased odds of mortality (odds ratio, 2.48; 95% confidence interval, 1.05-6.04) after controlling for sex, Survival after VA- ECMO score, and ECMO indication. An INR within 1.5 to 1.8 did not confer an increased mortality risk. Conclusions: An INR \u3e1.8 before VA-ECMO cannulation is associated independently with in-hospital mortality. Precannulation INR should be considered by clinicians so that ECMO resources can be better allocated and risks of organ failure and intracranial hemorrhage can be better understood

Pilot study evaluating a non-titrating, weight-based anticoagulation scheme for patients on veno-venous extracorporeal membrane oxygenation

Objective: There is no universally accepted algorithm for anticoagulation in patients on veno-venous extracorporeal membrane oxygenation. The purpose of this pilot study was to compare a non-titrating weight-based heparin infusion to that of a standard titration algorithm. Methods: We performed a prospective randomized non-blinded study of patients: Arm 1—standard practice of titrating heparin to activated partial thromboplastin times goal of 45-55 seconds, and Arm 2—a non-titrating weight-based (10 units/kg/h) infusion. Primary outcome was need for oxygenator/circuit changes. Secondary outcomes included differences in hemolysis and bleeding episodes. Descriptive statistics were performed for the continuous data, and primary and secondary outcomes were compared using Fisher’s exact test as appropriate. Results: Six patients were randomized to Arm 1 and four to Arm 2. There was no difference in age, pH, PaO2/FiO2 ratio, peak inspiratory pressure, positive end expiratory pressure, mean airway pressure at time of cannulation, time on extracorporeal membrane oxygenation, or survival to hospital discharge in the two arms. Arm 1 had a statistically higher median activated partial thromboplastin times (48 (43, 52) vs 38 (35, 42), p \u3c 0.008) and lower LDH (808 units/L (727, 1112) vs 940 units/L (809, 1137), p = 0.02) than Arm 2. There was no difference in plasma hemoglobin (4.3 (2.5, 8.7) vs 4.3 (3.0, 7.3), p = 0.65) between the two arms. There was no difference in mean oxygenator/circuit change, transfused packed red blood cell, or documented bleeding complications per patient in each arm (p = 0.56, 0.43, 0.77, respectively). Conclusion: In this pilot study, a non-titrating, weight-based heparin infusion appears safe and as effective in preventing veno-venous extracorporeal membrane oxygenation circuit thrombotic complications as compared to a titration algorithm. Larger studies are needed to confirm these preliminary findings

Early tracheostomy after initiation of venovenous extracorporeal membrane oxygenation is associated with decreased duration of extracorporeal membrane oxygenation support

Timing of tracheostomy placement for patients with respiratory failure requiring venovenous extracorporeal membrane oxygenation support is variable and continues to depend on surgeon preference. We retrospectively reviewed all consecutive adult patients supported with peripheral venovenous extracorporeal membrane oxygenation for acute respiratory distress syndrome at a single institution with the hypothesis that early tracheostomy (within 7 days of extracorporeal membrane oxygenation initiation) decreases the duration of extracorporeal membrane oxygenation support. The primary endpoint was duration of extracorporeal membrane oxygenation support. Secondary endpoints included mortality, overall and intensive care unit length of stay, duration of mechanical ventilation, and time from extracorporeal membrane oxygenation initiation to liberation from ventilator, intensive care unit discharge, and hospital discharge. Overall and extracorporeal membrane oxygenation–associated hospital costs were compared. A total of 50 patients were identified for inclusion (early n = 21; late n = 29). Baseline characteristics including indices of disease severity were similar between groups. Duration of extracorporeal membrane oxygenation support was significantly shorter in the early tracheostomy group (12 vs. 21 days; p = 0.005). Median extracorporeal membrane oxygenation–related costs were significantly decreased in the early tracheostomy group ($3,624 vs.$5,603, p = 0.03). Early tracheostomy placement is associated with decreased time on extracorporeal membrane oxygenation support and reduced extracorporeal membrane oxygenation–related costs in this cohort. Validation in a prospective cohort or a clinical trial is indicated