A Role of Circuit Clotting and Strategies to Prevent It during Blood Purification Therapy with oXiris Membrane: An Observational Multicenter Study.

INTRODUCTION: Membrane fouling is a significant complication potentially reducing clinical effects of extracorporeal blood purification (EBP) in critically ill septic patients with acute kidney injury. Although fascinating, the effect of heparin coating in preventing membrane fouling is currently unknown. This multicenter prospective study aims to preliminary describe the incidence, associated factors, and clinical consequences of premature circuit clotting in a cohort of adult critically ill septic patients treated with EBP using a high biocompatible heparin-coated hemodiafilter characterized by advanced adsorption properties. METHODS: This study was a retrospective analysis of prospectively entered data in the oXirisNet Registry; overall, 97 septic patients undergoing EBP with oXiris between May 2019 and March 2020 were enrolled in this study. Patients were divided into two groups according to the occurrence of filter clotting (premature vs. nonpremature). Logistic regression analysis was used to identify factors associated with premature circuit clotting. RESULTS: Premature clotting occurred in 18 (18.6%) patients. Results of the multivariate logistic regression analysis demonstrated that hematocrit (p = 0.02, odds ratio [OR] 1.15 [1.05; 1.30]), serum procalcitonin (PCT) (p = 0.03, OR 1.1 [1.05; 1.2]), and anticoagulation strategy (p = 0.05 at Wald's test) were independent predictors of circuit clotting. Systemic anticoagulation (p = 0.02, OR 0.03 [0.01; 0.52]) and regional citrate anticoagulation (p = 0.10, OR 0.23 [0.04; 1.50]) were both protective factors if compared to no-anticoagulation strategy. Patients with nonpremature circuit clotting showed more rapid recovery from hemodynamic instability, pulmonary hypo-oxygenation, and electrolyte disorders and greater improvement of inflammatory markers and SOFA scores. CONCLUSION: Although in this study the incidence of premature circuit clotting was relatively low (18.6%) compared to previously reported values (54%), membrane clotting in adult critically ill septic patients could cause clinically relevant interferences with treatment performances. Prevention of clotting should be based on avoiding higher patients' hematocrit, high serum PCT, and no-anticoagulation strategy which resulted as independent predictors of circuit clotting.

Preoperative Left Ventricular Global Longitudinal Strain Identifies Aortic Stenosis Patients with Improved Postoperative Recovery of Left Ventricular Geometry: A Prospective Cohort Study

Abstract Introduction: The left ventricular ejection fraction (LVEF) is commonly used as a marker of aortic stenosis (AS) disease severity and to indicate surgical intervention. However, an LVEF <50% identifies mainly advanced disease. Hence, earlier detection of subclinical LV systolic dysfunction may improve clinical decision-making. The global longitudinal strain (GLS) can identify subclinical systolic dysfunction at earlier stages of AS progression even in the presence of preserved LVEF. To this end, we evaluated the preoperative prognostic significance of the LVGLS to identify patients who will undergo a more extensive postoperative LV reverse remodeling as a surrogate marker for clinical recovery. Methods: We performed a prospective observational study based on detailed pre- and postoperative 2D transthoracic echocardiographic examinations, including strain analysis with speckle tracking. We screened 60 consecutive patients with severe AS and a preoperative LVEF ≥50% indicated for surgery; 39 patients met the study entry criteria and consented to their participation. Results: The median age was 67 (range 30-79) years; 56.4% were female. At baseline, the GLS was 61.64±7.22%. Surgery led to an improvement in the GLS; the mean difference was 3.23% [95% CI=1.96 to 4.49%] during a median follow up time of 5 (interquartile range 4-6) months. The preoperative GLS correlated with the postoperative LV mass index (LVMI) r=0.526, P=0.001 and the intraventricular septal thickness in diastole (IVSd) r=0.462, P=0.003. Furthermore, patients with a normal GLS (≤-18.9%) at baseline experienced a better recovery of their LV morphology and systolic function during the postoperative course compared to those with an abnormal GLS (>-18.9%). The effect size, hedges g, was at least >0.75 for the LVMI, IVSd, intraventricular septal thickness in systole (IVSs), left ventricular posterior wall thickness in diastole (LVPWd) and LVEF, suggesting a clinically significant difference between subgroups at follow-up. Conclusion: A normal preoperative left ventricular global longitudinal strain is associated with an improved left ventricular reverse remodeling and systolic function following surgery to resolve aortic stenosis.

Preoperative Left Ventricular Global Longitudinal Strain Identifies Aortic Stenosis Patients with Improved Postoperative Recovery of Left Ventricular Geometry: A Prospective Cohort Study.

INTRODUCTION: The left ventricular ejection fraction (LVEF) is commonly used as a marker of aortic stenosis (AS) disease severity and to indicate surgical intervention. However, an LVEF <50% identifies mainly advanced disease. Hence, earlier detection of subclinical LV systolic dysfunction may improve clinical decision-making. The global longitudinal strain (GLS) can identify subclinical systolic dysfunction at earlier stages of AS progression even in the presence of preserved LVEF. To this end, we evaluated the preoperative prognostic significance of the LVGLS to identify patients who will undergo a more extensive postoperative LV reverse remodeling as a surrogate marker for clinical recovery. METHODS: We performed a prospective observational study based on detailed pre- and postoperative 2D transthoracic echocardiographic examinations, including strain analysis with speckle tracking. We screened 60 consecutive patients with severe AS and a preoperative LVEF ≥50% indicated for surgery; 39 patients met the study entry criteria and consented to their participation. RESULTS: The median age was 67 (range 30-79) years; 56.4% were female. At baseline, the GLS was 61.64±7.22%. Surgery led to an improvement in the GLS; the mean difference was 3.23% [95% CI=1.96 to 4.49%] during a median follow up time of 5 (interquartile range 4-6) months. The preoperative GLS correlated with the postoperative LV mass index (LVMI) r=0.526, P=0.001 and the intraventricular septal thickness in diastole (IVSd) r=0.462, P=0.003. Furthermore, patients with a normal GLS (≤-18.9%) at baseline experienced a better recovery of their LV morphology and systolic function during the postoperative course compared to those with an abnormal GLS (>-18.9%). The effect size, hedges g, was at least >0.75 for the LVMI, IVSd, intraventricular septal thickness in systole (IVSs), left ventricular posterior wall thickness in diastole (LVPWd) and LVEF, suggesting a clinically significant difference between subgroups at follow-up. CONCLUSION: A normal preoperative left ventricular global longitudinal strain is associated with an improved left ventricular reverse remodeling and systolic function following surgery to resolve aortic stenosis.

Early Initiation of Extracorporeal Blood Purification Using the AN69ST (oXiris®) Hemofilter as a Treatment Modality for COVID-19 Patients: a Single-Centre Case Series

Abstract Introduction: Severe coronavirus disease 2019 (COVID-19) is characterised by hyperinflammatory state, systemic coagulopathies, and multiorgan involvement, especially acute respiratory distress syndrome (ARDS). We here describe our preliminary clinical experience with COVID-19 patients treated via an early initiation of extracorporeal blood purification combined with systemic heparinisation and respiratory support. Methods: Fifteen patients were included; several biomarkers associated with COVID-19 severity were monitored. Personalised treatment was tailored according to the levels of interleukin (IL)-6, IL-8, tumour necrosis factor alpha, C-reactive protein (CRP), neutrophil-to-lymphocyte ratio, thrombocyte counts, D-dimers, and fibrinogen. Treatment consisted of respiratory support, extracorporeal blood purification using the AN69ST (oXiris®) hemofilter, and 300 U/kg heparin to maintain activation clotting time ≥ 180 seconds. Results: Ten patients presented with severe to critical disease (dyspnoea, hypoxia, respiratory rate > 30/min, peripheral oxygen saturation < 90%, or > 50% lung involvement on X-ray imaging). The median intensive care unit length of stay was 9.3 days (interquartile range 5.3-10.1); two patients developed ARDS and died after 5 and 26 days. Clinical improvement was associated with normalisation (increase) of thrombocytes and white blood cells, stable levels of IL-6 (< 50 ng/mL), and a decrease of CRP and fibrinogen. Conclusion: Continuous monitoring of COVID-19 severity biomarkers and radiological imaging is crucial to assess disease progression, uncontrolled inflammation, and to avert irreversible multiorgan failure. The combination of systemic heparin anticoagulation regimens and extracorporeal blood purification using cytokine-adsorbing hemofilters may reduce hyperinflammation, prevent coagulopathy, and support clinical recovery.

Early Initiation of Extracorporeal Blood Purification Using the AN69ST (oXiris®) Hemofilter as a Treatment Modality for COVID-19 Patients: a Single-Centre Case Series.

INTRODUCTION: Severe coronavirus disease 2019 (COVID-19) is characterised by hyperinflammatory state, systemic coagulopathies, and multiorgan involvement, especially acute respiratory distress syndrome (ARDS). We here describe our preliminary clinical experience with COVID-19 patients treated via an early initiation of extracorporeal blood purification combined with systemic heparinisation and respiratory support. METHODS: Fifteen patients were included; several biomarkers associated with COVID-19 severity were monitored. Personalised treatment was tailored according to the levels of interleukin (IL)-6, IL-8, tumour necrosis factor alpha, C-reactive protein (CRP), neutrophil-to-lymphocyte ratio, thrombocyte counts, D-dimers, and fibrinogen. Treatment consisted of respiratory support, extracorporeal blood purification using the AN69ST (oXiris®) hemofilter, and 300 U/kg heparin to maintain activation clotting time ≥ 180 seconds. RESULTS: Ten patients presented with severe to critical disease (dyspnoea, hypoxia, respiratory rate > 30/min, peripheral oxygen saturation < 90%, or > 50% lung involvement on X-ray imaging). The median intensive care unit length of stay was 9.3 days (interquartile range 5.3-10.1); two patients developed ARDS and died after 5 and 26 days. Clinical improvement was associated with normalisation (increase) of thrombocytes and white blood cells, stable levels of IL-6 (< 50 ng/mL), and a decrease of CRP and fibrinogen. CONCLUSION: Continuous monitoring of COVID-19 severity biomarkers and radiological imaging is crucial to assess disease progression, uncontrolled inflammation, and to avert irreversible multiorgan failure. The combination of systemic heparin anticoagulation regimens and extracorporeal blood purification using cytokine-adsorbing hemofilters may reduce hyperinflammation, prevent coagulopathy, and support clinical recovery.

Extracorporeal Blood Purification in Moderate and Severe COVID-19 Patients: A Prospective Cohort Study.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) is characterized by hyperinflammation and coagulopathy. Severe cases often develop respiratory distress, requiring mechanical ventilation and with critical cases progressing to acute respiratory distress syndrome. Control of hyperinflammation has been proposed as a possible therapeutic avenue for COVID-19; extracorporeal blood purification (EBP) modalities offer an attractive mean to ameliorate maladaptive inflammation. With this work, we evaluated the longitudinal changes of systemic inflammatory markers in critically ill COVID-19 patients treated with blood purification using AN69ST (oXiris®) haemofilter. METHODS: We performed a time-series analysis of 44 consecutive COVID-19 cases treated with the AN69ST (oXiris®) cytokine adsorbing haemofilter (CAH) according to local practice; we visualize longitudinal results of biochemical, inflammatory, blood gas, and vital sign parameters focussing on systemic levels of interleukin-6 (IL-6), C-reactive protein (CRP), and procalcitonin. RESULTS: All patients were treated with ≥1 cycle extracorporeal continuous venovenous haemofiltration (CVVH) with CAH; of these, 30 severe patients received CVVH-CAH within 4-12 h of admission after recognizing a hyper-inflammatory state. Another 14 patients admitted with mild-to-moderate symptoms progressed to severe disease and were placed on EBP during hospitalization. The treatment was associated with a reduction of ferritin, CRP, fibrinogen, several inflammatory markers, and a resolution of numerous cytopenias. The observed mortality across the cohort was 36.3%. CONCLUSION: EBP with CAH was associated with a decrease in CRP, and control of IL-6 and procalcitonin.

Minimally Invasive Surgical Repair of Vertebral Artery Ostium Stenosis in Patients with Ischemic Stroke: A Single-Center Case Series.

BACKGROUND: Ischemic stroke is the second leading cause of death in North Macedonia. Posterior circulation disease, caused by vertebral artery (VA) ostium (VAo) stenosis, is a common cause of ischemic stroke. We established a treatment approach using surgical revascularization of posterior circulation disease. In the present observational study, we assessed the outcome after surgical revascularization of the posterior circulation ischemia caused by VAo stenosis. METHODS: A retrospective analysis of 20 consecutive patients who had undergone surgery from January 2017 to December 2019. The VA was accessed through a 3-cm incision in the upper medial clavicle. The corrective procedures consisted of resection and anastomosis (15 of 20), VA to subclavian artery transposition (16 of 20), endarterectomy (10 of 20), vein graft interposition techniques (4 of 20), and vein graft bypass (1 of 20). RESULTS: The cohort included 9 acute cases. The mean patient age was 66.5 years (range 46-77). Of the 20 patients, 8 were women and 12 were men. Left-sided VA pathology was present in 75% of the cases. We observed rapid clinical improvement in 19 patients (95%). The total study period was 321 patient-months, with a median follow-up of 18 months (interquartile range, 5-24 months). One patient had died of an unknown cause after 12 months. During the follow-up period, 15 patients (75%) had reported permanent clinical improvement with no significant relapse of symptoms. CONCLUSIONS: Minimally invasive surgical revascularization of the posterior brain circulation is a clinically effective therapeutic approach to manage ischemia caused by VAo stenosis. It can be performed safely, promote long-lasting symptom relief, and prevent recurrent strokes.

Cytokine storm and COVID-19: a chronicle of pro-inflammatory cytokines.

Coronavirus disease 2019 (COVID-19) has swept the world, unlike any other pandemic in the last 50 years. Our understanding of the disease has evolved rapidly since the outbreak; disease prognosis is influenced mainly by multi-organ involvement. Acute respiratory distress syndrome, heart failure, renal failure, liver damage, shock and multi-organ failure are strongly associated with morbidity and mortality. The COVID-19 disease pathology is plausibly linked to the hyperinflammatory response of the body characterized by pathological cytokine levels. The term 'cytokine storm syndrome' is perhaps one of the critical hallmarks of COVID-19 disease severity. In this review, we highlight prominent cytokine families and their potential role in COVID-19, the type I and II interferons, tumour necrosis factor and members of the Interleukin family. We address various changes in cellular components of the immune response corroborating with changes in cytokine levels while discussing cytokine sources and biological functions. Finally, we discuss in brief potential therapies attempting to modulate the cytokine storm.

Cardiac autotransplantation and ex vivo surgical repair of giant left atrium: a case presentation.

BACKGROUND: Chronic Mitral Valve disease is strongly associated with Left atrial enlargement; the condition has a high mortality risk. Clinical manifestations include atrial fibrillation, pulmonary hypertension, thromboembolic events, and in cases of Giant Left Atrium (GLA) and a distorted cardiac silhouette. Full sternotomy, conventional open-heart surgery, reductive atrioplasty and atrioventricular valve repair are required to resolve symptoms. However, these procedures can be complicated due to the posterior location of the GLA and concomitant right lateral protrusion. Cardiac autotransplantation is superior under these conditions; it provides improved visual access to the posterior atrial wall and mitral valve, hence, facilitates corrective surgical procedures. We aimed to assess the clinical outcome of patients undergoing cardiac autotransplantation as the primary treatment modality to resolve GLA. Moreover, we evaluated the procedural safety profile and technical feasibility. CASE PRESENTATION: Four patients, mean EuroSCORE II of 23.7% ± 7.7%, presented with heart failure, atrial fibrillation, left atrial diameter > 6.5 cm and a severe distorted cardiac silhouette; X-ray showed prominent right lateral protrusion. We performed cardiac autotransplantation using continuous retrograde perfusion with warm blood supplemented with glucose followed by atrioplasty, atrial plication, valve annuloplasty and valve repair on the explanted beating heart. The surgical approach reduced the left atrial area, mean reduction was - 90.71 cm2 [CI95% -153.3 cm2 to - 28.8 cm2, p = 0.02], and normalized pulmonary arterial pressure, mean decrease - 11.25 mmHg [CI95% -15.23 mmHg to - 7.272 mmHg, p = 0.003]. 3 out of 4 patients experienced an uneventful postoperative course; 2 out of 4 patients experienced a transient return to sinus rhythm following surgery. One was operated on in 2017 and is still in good condition; two other patients survived for more than 10 years; Kaplan-Meier determined median survival is 10.5 years. CONCLUSIONS: Cardiac autotransplantation is an elegant surgical procedure that facilitates the surgical remodelling of Giant Left Atrium. Surgical repair on the ex vivo beating heart, under continuous warm blood perfusion, is a safe procedure applicable also to high-risk patients.

Depletion of T(reg) cells inhibits minimal residual disease after surgery of HPV16-associated tumours.

It is generally accepted that T regulatory cells (T(reg) CD4(+)CD25(+)Foxp3(+)) play an important role in the suppression of tumour immunity. We examined the impact of T(reg) cell depletion with anti-CD25 antibody as adjuvant therapy in the treatment of minimal residual disease after excision of murine HPV16-associated tumours. We found that the depletion of T(reg) cells inhibited growth of the recurrences after surgery of HPV16-associated MHC class I+ as well as MHC class I-deficient tumours transplanted in syngeneic mice. These results demonstrate that depletion of CD25(+)CD4(+) T(reg) cells can be used as an efficient adjuvant treatment improving the results of surgery in the experimental systems mimicking human MHC class I+ and MHC class I-deficient, HPV16-associated neoplasms. Therefore, this therapeutic modality is worth being examined in patients with minimal residual HPV16-associated tumour disease after surgery.