Spinal Cord Infarction With Prolonged Femoral Venoarterial Extracorporeal Membrane Oxygenation.

OBJECTIVES: There have been sporadic reports of ischemic spinal cord injury (SCI) during venoarterial extracorporeal membrane oxygenation (VA-ECMO) support. The authors observed a troubling pattern of this catastrophic complication and evaluated the potential mechanisms of SCI related to ECMO. DESIGN: This study was a case series. SETTING: This study was performed at a single institution in a University setting. PARTICIPANTS: Patients requiring prolonged VA-ECMO were included. INTERVENTIONS: No interventions were done. This was an observational study. MEASUREMENTS AND MAIN RESULTS: Four hypotheses of etiology were considered: (1) hypercoagulable state/thromboembolism, (2) regional hypoxia/hypocarbia, (3) hyperperfusion and spinal cord edema, and (4) mechanical coverage of spinal arteries. The SCI involved the lower thoracic (T7-T12 level) spinal cord to the cauda equina in all patients. Seven out of 132 (5.3%) patients with prolonged VA-ECMO support developed SCI. The median time from ECMO cannulation to SCI was 7 (range: 6-17) days.There was no evidence of embolic SCI or extended regional hypoxia or hypocarbia. A unilateral, internal iliac artery was covered by the arterial cannula in 6/7 86%) patients, but flow into the internal iliac was demonstrated on imaging in all available patients. The median total flow (ECMO + intrinsic cardiac output) was 8.5 L/min (LPM), and indexed flow was 4.1 LPM/m2. The median central venous oxygen saturation was 88%, and intracranial pressure was measured at 30 mmHg in one patient, suggestive of hyperperfusion and spinal cord edema. CONCLUSIONS: An SCI is a serious complication of extended peripheral VA-ECMO support. Its etiology remains uncertain, but the authors' preliminary data suggested that spinal cord edema from hyperperfusion or venous congestion could contribute.

Body mass index does not impact survival in COVID-19 patients requiring veno-venous extracorporeal membrane oxygenation.

INTRODUCTION: With the increased demand for veno-venous extracorporeal membrane oxygenation (VV ECMO) during the COVID-19 pandemic, guidelines for patient candidacy have often limited this modality for patients with a body mass index (BMI) less than 40 kg/m2. We hypothesize that COVID-19 VV ECMO patients with at least class III obesity (BMI ≥ 40) have decreased in-hospital mortality when compared to non-COVID-19 and non-class III obese COVID-19 VV ECMO populations. METHODS: This is a single-center retrospective study of COVID-19 VV ECMO patients from January 1, 2014, to November 30, 2021. Our institution used BMI ≥ 40 as part of a multi-disciplinary VV ECMO candidate screening process in COVID-19 patients. BMI criteria were not considered for exclusion criteria in non-COVID-19 patients. Univariate and multivariable analyses were performed to assess in-hospital mortality differences. RESULTS: A total of 380 patients were included in our analysis: The COVID-19 group had a lower survival rate that was not statistically significant (65.7% vs.74.9%, p = .07). The median BMI between BMI ≥ 40 COVID-19 and non-COVID-19 patients was not different (44.5 vs 45.5, p = .2). There was no difference in survival between the groups (73.3% vs. 78.5%, p = .58), nor was there a difference in survival between the COVID-19 BMI ≥ 40 and BMI < 40 patients (73.3, 62.7, p= .29). Multivariable logistic regression with the outcome of in-hospital mortality was performed and BMI was not found to be significant (OR 0.99, 95% CI 0.89, 1.01; p = .92). CONCLUSION: BMI ≥ 40 was not an independent risk factor for decreased in-hospital survival in this cohort of VV ECMO patients at a high-volume center. BMI should not be the sole factor when deciding VV ECMO candidacy in patients with COVID-19.

A descriptive evaluation of causes of death in venovenous extracorporeal membrane oxygenation.

Veno-venous extracorporeal membrane oxygenation (VV ECMO) has become an important support modality for patients with acute respiratory failure refractory to optimal medical therapy, such as low tidal volume mechanical ventilator support, early paralytic infusion, and early prone positioning. The objective of this cohort study was to investigate the causes and timing of in-hospital mortality in patients on VV ECMO. All patients, excluding trauma and bridge to lung transplant, admitted 8/2014-6/2019 to a specialty ICU for VV ECMO were reviewed. Two hundred twenty-five patients were included. In-hospital mortality was 24.4% (n = 55). Most non-survivors (46/55, 84%) died prior to lung recovery and decannulation from VV ECMO. Most common cause of death (COD) for patients who died on VV ECMO was removal of life sustaining therapy (LST) in setting of multisystem organ failure (MSOF) (n = 24). Nine patients died a median of 9 days [6, 11] after decannulation. Most common COD in these patients was palliative withdrawal of LST due to poor prognosis (n = 3). Non-survivors were older and had worse predictive mortality scores than survivors. We found that death in patients supported with VV ECMO in our study most often occurs prior to decannulation and lung recovery. This study demonstrated that the most common cause of death in patients supported with VV ECMO was removal of LST due MSOF. Acute hemorrhage (systemic or intracranial) was not found to be a common cause of death in our patient population.

Decreased PRESET-Score corresponds with improved survival in COVID-19 veno-venous extracorporeal membrane oxygenation.

INTRODUCTION: The PREdiction of Survival on ECMO Therapy Score (PRESET-Score) predicts mortality while on veno-venous extracorporeal membrane oxygenation (VV ECMO) for acute respiratory distress syndrome. The aim of our study was to assess the association between PRESET-Score and survival in a large COVID-19 VV ECMO cohort. METHODS: This was a single-center retrospective study of COVID-19 VV ECMO patients from 15 March 2020, to 30 November 2021. Univariable and Multivariable analyses were performed to assess patient survival and score differences. RESULTS: A total of 105 patients were included in our analysis with a mean PRESET-Score of 6.74. Overall survival was 65.71%. The mean PRESET-Score was significantly lower in the survivor group (6.03 vs 8.11, p < 0.001). Patients with a PRESET-Score less than or equal to six had improved survival compared to those with a PRESET-Score greater than or equal to 8 (97.7% vs. 32.5%, p < 0.001). In a multivariable logistic regression, a lower PRESET-Score was also predictive of survival (OR 2.84, 95% CI 1.75, 4.63, p < 0.001). CONCLUSION: We demonstrate that lower PRESET scores are associated with improved survival. The utilization of this validated, quantifiable, and objective scoring system to help identify COVID-19 patients with the greatest potential to benefit from VV-ECMO appears feasible. The incorporation of the PRESET-Score into institutional ECMO candidacy guidelines can help insure and improve access of this limited healthcare resource to all critically ill patients.

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 >24 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 <1.5, INR 1.5 to 1.8, and INR >1.8. For all patients, demographics, comorbidities, and ECMO details were recorded. The study's 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 >1.8 v 42.3% INR 1.5-1.8 v 24.3% INR <1.5; p = 0.004). In a multivariate logistic regression model, precannulation INR >1.8 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 >1.8 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.

Peripheral cannulation for extracorporeal membrane oxygenation yields superior neurologic outcomes in adult patients who experienced cardiac arrest following cardiac surgery.

BACKGROUND: Extracorporeal cardiopulmonary resuscitation (ECPR) for refractory cardiac arrest has improved mortality in post-cardiac surgery patients; however, loss of neurologic function remains one of the main and devastating complications. We reviewed our experience with ECPR and investigated the effect of cannulation strategy on neurologic outcome in adult patients who experienced cardiac arrest following cardiac surgery that was managed with ECPR. METHODS: Patients were categorized by central versus percutaneous peripheral VA-extracorporeal membrane oxygenation (ECMO) cannulation strategy. We reviewed patient records and evaluated in-hospital mortality, cause of death, and neurologic status 72 hours after cannulation. RESULTS: From January 2010 to September 2019, 44 patients underwent post-cardiac surgery ECPR for cardiac arrest. Twenty-six patients received central cannulation; 18 patients received peripheral cannulation. Mean post-operative day of the cardiac arrest was 3 and 9 days (p = 0.006), and mean time between initiation of CPR and ECMO was 40 ± 24 and 28 ± 22 minutes for central and peripheral cannulation, respectively. After 72 hours of VA-ECMO support, 30% of centrally cannulated patients versus 72% of peripherally cannulated patients attained cerebral performance status 1-2 (p = 0.01). Anoxic brain injury was the cause of death in 26.9% of centrally cannulated and 11.1% of peripherally cannulated patients. Survival to discharge was 31% and 39% for central and peripheral cannulation, respectively. CONCLUSIONS: Peripheral VA-ECMO allows for continuous CPR and systemic perfusion while obtaining vascular access. Compared to central cannulation, a peripheral cannulation strategy is associated with improved neurologic outcomes and decreased likelihood of anoxic brain death.

Ultrasound-assisted catheter directed thrombolysis for pulmonary embolus during extracorporeal membrane oxygenation.

BACKGROUND: Acute pulmonary embolism (PE) is the third most common cause of cardiovascular death. For patients who are hemodynamically unstable, veno-arterial extracorporeal membrane oxygenation (VA-ECMO) support has been shown to provide hemodynamic stability, and allow time for definitive treatment and recovery. Ultrasound-assisted catheter directed thrombolysis (USAT) has the potential to be a safe adjunct and expedite right ventricular (RV) recovery for patients requiring VA-ECMO for PE. METHODS: A review of all VA-ECMO patients from January 2017 to September 2019 was performed. A total of 49 of these patients were cannulated due to a PE. USAT therapy was used as an adjunct in 6 (12%) of these patients. These 6 patients were given standardized USAT therapy with EKOs catheters at 1 mg/h of tissue plasminogen activator with an unfractionated heparin infusion for additional systemic anticoagulation. Outcomes, including in-hospital death, 90-day survival, RV recovery, and complications, were examined in the cohort of patients that received USAT as an adjunct to ECMO. RESULTS: Median age was 54 years old. Five of the six patients presented with a massive PE and had a PE severity score of Class V. One patient presented with a submassive PE with a Bova score of 2, but was cannulated to VA-ECMO in the setting of worsening RV function. All patients demonstrated recovery of RV function, were free from in-hospital death, and were alive at 90-day follow-up. CONCLUSION: Ekosonic endovascular system therapy may be a safe and feasible adjunct for patients on VA-ECMO for PE, and allow for survival with RV recovery with minimal complications.

Stem Cell Therapy for Hypoplastic Left Heart Syndrome: Mechanism, Clinical Application, and Future Directions.

Hypoplastic left heart syndrome is a type of congenital heart disease characterized by underdevelopment of the left ventricle, outflow tract, and aorta. The condition is fatal if aggressive palliative operations are not undertaken, but even after the complete 3-staged surgical palliation, there is significant morbidity because of progressive and ultimately intractable right ventricular failure. For this reason, there is interest in developing novel therapies for the management of right ventricular dysfunction in patients with hypoplastic left heart syndrome. Stem cell therapy may represent one such innovative approach. The field has identified numerous stem cell populations from different tissues (cardiac or bone marrow or umbilical cord blood), different age groups (adult versus neonate-derived), and different donors (autologous versus allogeneic), with preclinical and clinical experience demonstrating the potential utility of each cell type. Preclinical trials in small and large animal models have elucidated several mechanisms by which stem cells affect the injured myocardium. Our current understanding of stem cell activity is undergoing a shift from a paradigm based on cellular engraftment and differentiation to one recognizing a primarily paracrine effect. Recent studies have comprehensively evaluated the individual components of the stem cells' secretomes, shedding new light on the intracellular and extracellular pathways at the center of their therapeutic effects. This research has laid the groundwork for clinical application, and there are now several trials of stem cell therapies in pediatric populations that will provide important insights into the value of this therapeutic strategy in the management of hypoplastic left heart syndrome and other forms of congenital heart disease. This article reviews the many stem cell types applied to congenital heart disease, their preclinical investigation and the mechanisms by which they might affect right ventricular dysfunction in patients with hypoplastic left heart syndrome, and finally, the completed and ongoing clinical trials of stem cell therapy in patients with congenital heart disease.

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 <18 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/m (33-42 kg/m) 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.

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.

High-efficiency, high-flux in-line hemofiltration using a high blood flow extracorporeal circuit.

The ability of current renal replacement therapy modalities to achieve rapid solute removal is limited by membrane surface area and blood flow rate. Extracorporeal membrane oxygenation offers high blood flow and hemodynamic support that may be harnessed to overcome limitations in traditional renal replacement therapy. Using an extracorporeal membrane oxygenation circuit, we describe a high blood flow, high-efficiency hemofiltration technique using in-line hemofilters (hemoconcentrators) and standard replacement fluid to enhance solute clearance. Using this approach and a total of 5 L of replacement volume per treatment, creatinine (Cr) clearances of 8.3 L/hour and 11.2 L/hour using one and two hemoconcentrators, respectively, were achieved. With use of a high blood flow rate of up to 5 L/min, this hemofiltration technique can potentially offer clearance of 30 times that of continuous renal replacement therapy and of 6 times that of hemodialysis which may expand the ability to remove substances traditionally not considered removable via existing extracorporeal therapies.

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 < 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.

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 < 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.

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.

Study design and rationale for ELPIS: A phase I/IIb randomized pilot study of allogeneic human mesenchymal stem cell injection in patients with hypoplastic left heart syndrome.

Despite advances in surgical technique and postoperative care, long-term survival of children born with hypoplastic left heart syndrome (HLHS) remains limited, with cardiac transplantation as the only alternative for patients with failing single ventricle circulations. Maintenance of systemic right ventricular function is crucial for long-term survival, and interventions that improve ventricular function and avoid or defer transplantation in patients with HLHS are urgently needed. We hypothesize that the young myocardium of the HLHS patient is responsive to the biological cues delivered by bone marrow-derived mesenchymal stem cells (MSCs) to improve and preserve right ventricle function. The ELPIS trial (Allogeneic Human MEsenchymal Stem Cell Injection in Patients with Hypoplastic Left Heart Syndrome: An Open Label Pilot Study) is a phase I/IIb trial designed to test whether MSC injection will be both safe and feasible by monitoring the first 10 HLHS patients for new major adverse cardiac events. If our toxicity stopping rule is not activated, we will proceed to the phase IIb component of our study where we will test our efficacy hypothesis that MSC injection improves cardiac function compared with surgery alone. Twenty patients will be enrolled in a randomized phase II trial with a uniform allocation to MSC injection versus standard surgical care (no injection). The 2 trial arms will be compared with respect to improvement of right ventricular function, tricuspid valve annulus size, and regurgitation determined by cardiac magnetic resonance and reduced mortality, morbidity, and need for transplantation. This study will establish the safety and feasibility of allogeneic mesenchymal stem cell injection in HLHS patients and provide important insights in the emerging field of stem cell-based therapy for congenital heart disease patients.

Current and future status of extracorporeal life support for respiratory failure in adults.

PURPOSE OF REVIEW: The purpose is to review the development and current application of extracorporeal life support [ECLS, extracorporeal membrane oxygenation (ECMO)] in acute severe respiratory failure. RECENT FINDINGS: Extracorporeal support (ECMO) is used for acute severe respiratory failure in advanced ICUs. The current survival rate is 60-70%. Three controlled trials all demonstrated 20-30% improvement in survival compared to conventional care. Patients may now be maintained awake and ambulatory with spontaneous breathing. SUMMARY: ECMO is the next step in the algorithm for management of severe respiratory failure unresponsive to conventional care.

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

BACKGROUND: Vein 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. METHODS: Stasis 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. RESULTS: Thrombus 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-1ß 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. CONCLUSIONS: In 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.

Contralateral Lower Extremity Ischemia on Femoral Veno-Arterial Extracorporeal Membrane Oxygenation.

Ipsilateral lower extremity ischemia is a common and morbid complication during veno-arterial extracorporeal membrane oxygenation (VA-ECMO). The cannula can impede ipsilateral distal arterial flow leading to critical limb ischemia. Cannula size, placement, and utilization of distal perfusion catheters are strategies that have been used to prevent this complication. We report the novel case of a 19-year-old female on VA-ECMO complicated by contralateral lower extremity ischemia. Diagnosis was made by computed tomography, and with repositioning of the femoral arterial cannula, she had a complete resolution of symptoms.

Maternal transfer of IgA and IgG SARS-CoV-2 specific antibodies transplacentally and via breast milk feeding.

BACKGROUND: Although there have been many studies on antibody responses to SARS-CoV-2 in breast milk, very few have looked at the fate of these in the infant, and whether they are delivered to immunologically relevant sites in infants. METHODS: Mother/infant pairs (mothers who breast milk fed and who were SARS-CoV-2 vaccinated before or after delivery) were recruited for this cross-sectional study. Mother blood, mother breast milk, infant blood, infant nasal specimen, and infant stool was tested for IgA and IgG antibodies against SARS-CoV-2 spike trimer. RESULTS: Thirty-one mother/infant pairs were recruited. Breast milk fed infants acquired systemic anti-spike IgG antibodies only if their mothers were vaccinated antepartum (100% Antepartum; 0% Postpartum; P<0.0001). Breast milk fed infants acquired mucosal anti-spike IgG antibodies (in the nose) only if their mothers were vaccinated antepartum (89% Antepartum; 0% Postpartum; P<0.0001). None of the infants in either group had anti-spike IgA in the blood. Surprisingly, 33% of the infants whose mothers were vaccinated antepartum had high titer anti-spike IgA in the nose (33% Antepartum; 0% Postpartum; P = 0.03). Half-life of maternally transferred plasma IgG antibodies in the Antepartum infant cohort was ~70 days. CONCLUSION: Vaccination antepartum followed by breast milk feeding appears to be the best way to provide systemic and local anti-SARS-CoV-2 antibodies for infants. The presence of high titer SARS-CoV-2-specific IgA in the nose of infants points to the potential importance of breast milk feeding early in life for maternal transfer of mucosal IgA antibodies. Expectant mothers should consider becoming vaccinated antepartum and consider breast milk feeding for optimal transfer of systemic and mucosal antibodies to their infants.

Nicorandil attenuates ventricular dysfunction and organ injury after cardiopulmonary bypass.

BACKGROUND: Nicorandil, an adenosine triphosphate-sensitive potassium channel agonist and nitric oxide donor, is a coronary vasodilator used to treat ischemia-induced chest pain, but it's potential cardioprotective benefits during open heart surgery have not been thoroughly investigated. The study objective was to assess the impact of nicorandil on postoperative ventricular dysfunction and end-organ injury in an established experimental model of open-heart surgery with cardiopulmonary bypass (CPB) and cardioplegic arrest. We hypothesized that nicorandil would attenuate myocardial ischemia-reperfusion (IR) injury, preserve ventricular function, and reduce end-organ injury. METHODS: Rabbits were cannulated for CPB, followed by 60 min of aortic cross-clamp (ACC) with cold cardioplegic arrest, and 120 min of recovery after ACC removal. Nicorandil (or normal saline vehicle) was given intravenously 5 min before ACC and continued throughout the recovery period. Left ventricular developed pressure (LVDP), systolic contractility (LV + dP/dt), and diastolic relaxation (LV -dP/dt) were continuously recorded, and blood and tissue samples were collected for measurement of oxidant stress (OS), inflammation, apoptosis, and organ injury. RESULTS: Nicorandil significantly attenuated IR-induced LV dysfunction compared to saline control (R-120: LV + dP/dt: 1596 ± 397 vs. 514 ± 269 mmHg/s, p = 0.010; LV -dP/dt: -1524 ± 432 vs. -432 ± 243 mmHg/s, p < 0.001; LVDP: 55 ± 11 vs. 22 ± 5 mmHg, p = 0.046). Furthermore, nicorandil inhibited IR-induced increases in OS, inflammation, apoptosis, and organ injury. CONCLUSIONS: Nicorandil exhibits myocardial protection by attenuation of IR-induced LV dysfunction associated with OS, inflammation, apoptosis, and organ injury. Nicorandil should be explored further as a potential therapeutic strategy for limiting global IR injury during open-heart surgery in humans.