Combined extracorporeal CO2 removal and renal replacement therapy in a pregnant patient with COVID-19: a case report.

Background. Pregnant women are at high risk of Coronavirus disease 2019 (COVID-19) complications, including acute respiratory distress syndrome. Currently, one of the cornerstones in the treatment of this condition is lung-protective ventilation (LPV) with low tidal volumes. However, the occurrence of hypercapnia may limit this ventilatory strategy. So, different extracorporeal CO2 removal (ECCO2R) procedures have been developed. ECCO2R comprises a variety of techniques, including low-flow and high-flow systems, that may be performed with dedicated devices or combined with continuous renal replacement therapy (CRRT). Case description. Here, we report a unique case of a pregnant patient affected by COVID-19 who required extracorporeal support for multiorgan failure. While on LPV, because of the concomitant hypercapnia and acute kidney injury, the patient was treated with an ECCO2R membrane inserted in series after a hemofilter in a CRRT platform. This combined treatment reducing hypercapnia allowed LPV maintenance at the same time while providing kidney replacement and ensuring maternal and fetal hemodynamic stability. Adverse effects consisted of minor bleeding episodes due to the anticoagulation required to maintain the extracorporeal circuit patency. The patient's pulmonary and kidney function progressively recovered, permitting the withdrawal of any extracorporeal treatment. At the 25th gestational week, the patient underwent spontaneous premature vaginal delivery because of placental abruption. She gave birth to an 800-gram female baby, who three days later died because of multiorgan failure related to extreme prematurity. Conclusions. This case supports using ECCO2R-CRRT combined treatment as a suitable approach in the management of complex conditions, such as pregnancy, even in the case of severe COVID-19.

Evolving Characteristics of Heart Transplantation Donors and Recipients: JACC Focus Seminar.

Although the burden of end-stage heart failure continues to increase, the number of available organs for heart transplantation (HT) remains inadequate. The HT community has been challenged to find ways to expand the number of donor hearts available. Recent advances include use of hearts from donors infected with hepatitis C virus as well as other previously underutilized donors, including those with left ventricular dysfunction, of older age, and with a history of cocaine use. Concurrently, emerging trends in HT surgery include donation after circulatory death, ex vivo normothermic heart perfusion, and controlled hypothermic preservation, which may enable procurement of organs from farther distances and prevent early allograft dysfunction. Contemporary HT recipients have also evolved in light of the 2018 revision to the U.S. heart allocation policy. This focus seminar discusses recent trends in donor and recipient phenotypes and management strategies for successful HT, as well as evolving areas and future directions.

Xenogeneic support for the recovery of human donor organs.

VIDEO ABSTRACT.

Extracorporeal carbon dioxide removal with the Advanced Organ Support system in critically ill COVID-19 patients.

Disturbed oxygenation is foremost the leading clinical presentation in COVID-19 patients. However, a small proportion also develop carbon dioxide removal problems. The Advanced Organ Support (ADVOS) therapy (ADVITOS GmbH, Munich, Germany) uses a less invasive approach by combining extracorporeal CO2 -removal and multiple organ support for the liver and the kidneys in a single hemodialysis device. The aim of our study is to evaluate the ADVOS system as treatment option in-COVID-19 patients with multi-organ failure and carbon dioxide removal problems. COVID-19 patients suffering from severe respiratory insufficiency, receiving at least two treatments with the ADVOS multi system (ADVITOS GmbH, Munich, Germany), were eligible for study inclusion. Briefly, these included patients with acute kidney injury (AKI) according to KDIGO guidelines, and moderate or severe ARDS according to the Berlin definition, who were on invasive mechanical ventilation for more than 72 hours. In total, nine COVID-19 patients (137 ADVOS treatment sessions with a median of 10 treatments per patient) with moderate to severe ARDS and carbon dioxide removal problems were analyzed. During the ADVOS treatments, a rapid correction of acid-base balance and a continuous CO2 removal could be observed. We observed a median continuous CO2 removal of 49.2 mL/min (IQR: 26.9-72.3 mL/min) with some treatments achieving up to 160 mL/min. The CO2 removal significantly correlated with blood flow (Pearson 0.421; P < .001), PaCO2 (0.341, P < .001) and HCO 3 - levels (0.568, P < .001) at the start of the treatment. The continuous treatment led to a significant reduction in PaCO2 from baseline to the last ADVOS treatment. In conclusion, it was feasible to remove CO2 using the ADVOS system in our cohort of COVID-19 patients with acute respiratory distress syndrome and multiorgan failure. This efficient removal of CO2 was achieved at blood flows up to 300 mL/min using a conventional hemodialysis catheter and without a membrane lung or a gas phase.

Open-label randomized controlled trial of ultra-low tidal ventilation without extracorporeal circulation in patients with COVID-19 pneumonia and moderate to severe ARDS: study protocol for the VT4COVID trial.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a severe complication of COVID-19 pneumonia, with a mortality rate amounting to 34-50% in moderate and severe ARDS, and is associated with prolonged duration of invasive mechanical ventilation. Such as in non-COVID ARDS, harmful mechanical ventilation settings might be associated with worse outcomes. Reducing the tidal volume down to 4 mL kg-1 of predicted body weight (PBW) to provide ultra-low tidal volume ventilation (ULTV) is an appealing technique to minimize ventilator-inducted lung injury. Furthermore, in the context of a worldwide pandemic, it does not require any additional material and consumables and may be applied in low- to middle-income countries. We hypothesized that ULTV without extracorporeal circulation is a credible option to reduce COVID-19-related ARDS mortality and duration of mechanical ventilation. METHODS: The VT4COVID study is a randomized, multi-centric prospective open-labeled, controlled superiority trial. Adult patients admitted in the intensive care unit with COVID-19-related mild to severe ARDS defined by a PaO2/FiO2 ratio ≤ 150 mmHg under invasive mechanical ventilation for less than 48 h, and consent to participate to the study will be eligible. Patients will be randomized into two balanced parallels groups, at a 1:1 ratio. The control group will be ventilated with protective ventilation settings (tidal volume 6 mL kg-1 PBW), and the intervention group will be ventilated with ULTV (tidal volume 4 mL kg-1 PBW). The primary outcome is a composite score based on 90-day all-cause mortality as a prioritized criterion and the number of ventilator-free days at day 60 after inclusion. The randomization list will be stratified by site of recruitment and generated using random blocks of sizes 4 and 6. Data will be analyzed using intention-to-treat principles. DISCUSSION: The purpose of this manuscript is to provide primary publication of study protocol to prevent selective reporting of outcomes, data-driven analysis, and to increase transparency. Enrollment of patients in the study is ongoing. TRIAL REGISTRATION: ClinicalTrials.gov NCT04349618 . Registered on April 16, 2020.

Effect of Lower Tidal Volume Ventilation Facilitated by Extracorporeal Carbon Dioxide Removal vs Standard Care Ventilation on 90-Day Mortality in Patients With Acute Hypoxemic Respiratory Failure: The REST Randomized Clinical Trial.

Importance: In patients who require mechanical ventilation for acute hypoxemic respiratory failure, further reduction in tidal volumes, compared with conventional low tidal volume ventilation, may improve outcomes. Objective: To determine whether lower tidal volume mechanical ventilation using extracorporeal carbon dioxide removal improves outcomes in patients with acute hypoxemic respiratory failure. Design, Setting, and Participants: This multicenter, randomized, allocation-concealed, open-label, pragmatic clinical trial enrolled 412 adult patients receiving mechanical ventilation for acute hypoxemic respiratory failure, of a planned sample size of 1120, between May 2016 and December 2019 from 51 intensive care units in the UK. Follow-up ended on March 11, 2020. Interventions: Participants were randomized to receive lower tidal volume ventilation facilitated by extracorporeal carbon dioxide removal for at least 48 hours (n = 202) or standard care with conventional low tidal volume ventilation (n = 210). Main Outcomes and Measures: The primary outcome was all-cause mortality 90 days after randomization. Prespecified secondary outcomes included ventilator-free days at day 28 and adverse event rates. Results: Among 412 patients who were randomized (mean age, 59 years; 143 [35%] women), 405 (98%) completed the trial. The trial was stopped early because of futility and feasibility following recommendations from the data monitoring and ethics committee. The 90-day mortality rate was 41.5% in the lower tidal volume ventilation with extracorporeal carbon dioxide removal group vs 39.5% in the standard care group (risk ratio, 1.05 [95% CI, 0.83-1.33]; difference, 2.0% [95% CI, -7.6% to 11.5%]; P = .68). There were significantly fewer mean ventilator-free days in the extracorporeal carbon dioxide removal group compared with the standard care group (7.1 [95% CI, 5.9-8.3] vs 9.2 [95% CI, 7.9-10.4] days; mean difference, -2.1 [95% CI, -3.8 to -0.3]; P = .02). Serious adverse events were reported for 62 patients (31%) in the extracorporeal carbon dioxide removal group and 18 (9%) in the standard care group, including intracranial hemorrhage in 9 patients (4.5%) vs 0 (0%) and bleeding at other sites in 6 (3.0%) vs 1 (0.5%) in the extracorporeal carbon dioxide removal group vs the control group. Overall, 21 patients experienced 22 serious adverse events related to the study device. Conclusions and Relevance: Among patients with acute hypoxemic respiratory failure, the use of extracorporeal carbon dioxide removal to facilitate lower tidal volume mechanical ventilation, compared with conventional low tidal volume mechanical ventilation, did not significantly reduce 90-day mortality. However, due to early termination, the study may have been underpowered to detect a clinically important difference. Trial Registration: ClinicalTrials.gov Identifier: NCT02654327.

Application of extracorporeal therapies in critically ill COVID-19 patients.

The coronavirus disease 2019 (COVID-19) pandemic is a major public health event caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 has spread widely all over the world. A high proportion of patients become severely or critically ill, and suffer high mortality due to respiratory failure and multiple organ dysfunction. Therefore, providing timely and effective treatment for critically ill patients is essential to reduce overall mortality. Convalescent plasma therapy and pharmacological treatments, such as aerosol inhalation of interferon-α (IFN-α), corticosteroids, and tocilizumab, have all been applied in clinical practice; however, their effects remain controversial. Recent studies have shown that extracorporeal therapies might have a potential role in treating critically ill COVID-19 patients. In this review, we examine the application of continuous renal replacement therapy (CRRT), therapeutic plasma exchange (TPE), hemoadsorption (HA), extracorporeal membrane oxygenation (ECMO), and extracorporeal carbon dioxide removal (ECCO2R) in critically ill COVID-19 patients to provide support for the further diagnosis and treatment of COVID-19.

Application of extracorporeal carbon dioxide removal combined with continuous blood purification therapy in ARDS with hypercapnia in patients with critical COVID-19.

INTRODUCTION: Coronavirus disease-19 (COVID-19) is a new type of epidemic pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The population is generally susceptible to COVID-19, which mainly causes lung injury. Some cases may develop severe acute respiratory distress syndrome (ARDS). Currently, ARDS treatment is mainly mechanical ventilation, but mechanical ventilation often causes ventilator-induced lung injury (VILI) accompanied by hypercapnia in 14% of patients. Extracorporeal carbon dioxide removal (ECCO2R) can remove carbon dioxide from the blood of patients with ARDS, correct the respiratory acidosis, reduce the tidal volume and airway pressure, and reduce the incidence of VILI. CASE REPORT: Two patients with critical COVID-19 combined with multiple organ failure undertook mechanical ventilation and suffered from hypercapnia. ECCO2R, combined with continuous renal replacement therapy (CRRT), was conducted concomitantly. In both cases (No. 1 and 2), the tidal volume and positive end-expiratory pressure (PEEP) were down-regulated before the treatment and at 1.5 hours, one day, three days, five days, eight days, and ten days after the treatment, together with a noticeable decrease in PCO2 and clear increase in PO2, while FiO2 decreased to approximately 40%. In case No 2, compared with the condition before treatment, the PCO2 decreased significantly with down-regulation in the tidal volume and PEEP and improvement in the pulmonary edema and ARDS after the treatment. CONCLUSION: ECCO2R combined with continuous blood purification therapy in patients with COVID-19 who are criti-cally ill and have ARDS and hypercapnia might gain both time and opportunity in the treatment, down-regulate the ventilator parameters, reduce the incidence of VILI and achieve favorable therapeutic outcomes.

Vascular activation is a strong predictor of mortality in coronavirus disease 2019 patients on the ICU.

Respiratory failure in coronavirus disease 2019 (COVID-19) patients is one of the most frequent causes for referral to the ICU. A significant percentage of these patients does not survive the infection due to thromboembolic complications. Furthermore, the vascular system seems also to be involved in the pathogenesis. To investigate the role of hemostasis and endothelium on the outcome of COVID-19 patients admitted to the ICU. Blood was drawn from 16 ICU COVID-19 patients for hemostatic analysis. Patients were followed-up till discharge (n = 11) or death (n = 5). Parameters related to both coagulation and fibrinolysis, though disturbed, were not associated with mortality. Contrarily, activated Von Willebrand factor was increased and ADAMTS13 levels were decreased by two-fold in nonsurvivors compared with survivors. Our data established the involvement of the Von Willebrand factor-ADAMTS13 axis in the COVID-19 pathogenesis, thereby demonstrating that these plasma proteins seem to be strong predictors for ICU mortality.

Extracorporeal multiorgan support including CO2-removal with the ADVanced Organ Support (ADVOS) system for COVID-19: A case report.

A substantial part of COVID-19-patients suffers from multi-organ failure (MOF). We report on an 80-year old patient with pulmonary, renal, circulatory, and hepatic failure. We decided against the use of extracorporeal membrane oxygenation (ECMO) due to old age and a SOFA-score of 13. However, the patient was continuously treated with the extracorporeal multi-organ- "ADVanced Organ Support" (ADVOS) device (ADVITOS GmbH, Munich, Germany). During eight 24h-treatment-sessions blood flow (100-300 mL/min), dialysate flow (160-320 mL/min) and dialysate pH (7.6-9.0) were adapted to optimize arterial PaCO2 and pH. Effective CO2 removal and correction of acidosis could be demonstrated by mean arterial- versus post-dialyzer values of pCO2 (68.7 ± 13.8 vs. 26.9 ± 11.6 mmHg; p < 0.001). The CO2-elimination rate was 48 ± 23mL/min. The initial vasopressor requirement could be reduced in parallel to pH-normalization. Interruptions of ADVOS-treatment repeatedly resulted in reversible deteriorations of paCO2 and pH. After 95 h of continuous extracorporeal decarboxylating therapy the patient had markedly improved circulatory parameters compared to baseline. In the context of secondary pulmonary infection and progressive liver failure, the patient had a sudden cardiac arrest. In accordance with the presumed patient will, we decided against mechanical resuscitation. Irrespective of the outcome we conclude that extracorporeal CO2 removal and multiorgan-support were feasible in this COVID-19-patient. Combined and less invasive approaches such as ADVOS might be considered in old-age-COVID-19 patients with MOF.

Effectiveness of extracorporeal blood purification (hemoadsorption) in patients with severe coronavirus disease 2019 (COVID-19).

BACKGROUND: Extracorporeal blood purification has been proposed as one of the therapeutic approaches in patients with coronavirus infection, because of its beneficial impact on elimination of inflammatory cytokines. METHODS: This controlled trial has been conducted on critically ill COVID-19 patients admitted in the state hospital affiliated to Babol University of Medical Sciences, Iran who received different antiviral and antibacterial drugs, and different modalities of respiratory treatments and did not have positive clinical improvement. No randomization and blindness was considered. All of the participants underwent three sessions of resin-directed hemoperfusion using continuous renal replacement therapy with a mode of continuous venovenous hemofiltration (CVVH). RESULTS: Five men and five women with a mean age of 57.30 ± 18.07 years have been enrolled in the study; and six of them have improved after the intervention. Peripheral capillary oxygen saturation (SpO2) changed after each session. Mean SpO2 before the three sessions of hemoperfusion was 89.60% ± 3.94% and increased to 92.13% ± 3.28% after them (p < 0.001). Serum IL-6 showed a reduction from 139.70 ± 105.62 to 72.06 ± 65.87 pg/mL (p = 0.073); and c-reactive protein decreased from 136.25 ± 84.39 to 78.25 ± 38.67 mg/L (P = 0.016). CONCLUSIONS: Extracorporeal hemoadsorption could improve the general condition in most of recruited patients with severe coronavirus disease; however, large prospective multicenter trials in carefully selected patients are needed to definitely evaluate the efficacy of hemoperfusion in COVID-19 patients. TRIAL REGISTRATION: The research protocol has been registered in the website of Iranian Registry of Clinical Trials with the reference number IRCT20150704023055N2 .

Opportunities for biomaterials to address the challenges of COVID-19.

The coronavirus disease 2019 (COVID-19) pandemic has revealed major shortcomings in our ability to mitigate transmission of infectious viral disease and provide treatment to patients, resulting in a public health crisis. Within months of the first reported case in China, the virus has spread worldwide at an unprecedented rate. COVID-19 illustrates that the biomaterials community was engaged in significant research efforts against bacteria and fungi with relatively little effort devoted to viruses. Accordingly, biomaterials scientists and engineers will have to participate in multidisciplinary antiviral research over the coming years. Although tissue engineering and regenerative medicine have historically dominated the field of biomaterials, current research holds promise for providing transformative solutions to viral outbreaks. To facilitate collaboration, it is imperative to establish a mutual language and adequate understanding between clinicians, industry partners, and research scientists. In this article, clinical perspectives are shared to clearly define emerging healthcare needs that can be met by biomaterials solutions. Strategies and opportunities for novel biomaterials intervention spanning diagnostics, treatment strategies, vaccines, and virus-deactivating surface coatings are discussed. Ultimately this review serves as a call for the biomaterials community to become a leading contributor to the prevention and management of the current and future viral outbreaks.

Extracorporeal blood purification treatment options for COVID-19: The role of immunoadsorption.

The activation of the innate and adaptive immune systems by SARS-CoV-2 causes the release of several inflammatory cytokines, including IL-6. The inflammatory hypercytokinemia causes immunopathological changes in the lungs including vascular leakage, and alveolar edema. As a result of these changes in the lungs, hypoxia and acute respiratory distress syndrome occur in patients with COVID-19. Even though there are clinical trials on the development of therapeutics and vaccines, there are currently no licensed vaccines or therapeutics for COVID-19. Pharmacological approaches have shown poor results in sepsis-like syndromes caused by the hypercytokinemia. Suppressing the cytokine storm is an important way to prevent the organ damage in patients with COVID-19. Extracorporeal blood purification could be proposed as an adjunctive therapy for sepsis, aiming to control the associated dysregulation of the immune system, which is known to protect organ functions. Several extracorporeal blood purification therapies are now available, and most of them target endotoxins and/or the cytokines and aim improving the immune response. For this purpose, plasmapheresis and immunoadsorption may be an important adjunctive treatment option to manage the complications caused by cytokine storm in critically ill patients with COVID-19.