In vitro characterization of PrismaLung+: a novel ECCO2R device

Extracorporeal CO2 removal (ECCO2R) can permit lung protective or noninvasive ventilation strategies in patients with chronic obstructive pulmonary disease (COPD) and acute respiratory distress syndrome (ARDS). With evidence supporting ECCO2R growing, investigating factors which affect CO2 removal is necessary. Multiple factors are known to affect the CO2 removal rate (vCO2) which can complicate the interpretation of changes in vCO2; however, the effect of hematocrit on the vCO2 of artificial lungs has not been investigated. This in vitro study evaluates the relationship between hematocrit level and vCO2 within an ECCO2R device. In vitro gas transfer was measured in bovine blood in accordance with the ISO 7199 standard. Plasma and saline were used to hemodilute the blood to hematocrits between 33% and 8%. The vCO2 significantly decreased as the blood was hemodiluted with saline and plasma by 42% and 32%, respectively, between a hematocrit of 33% and 8%. The hemodilution method did not significantly affect the vCO2. In conclusion, the hematocrit level significantly affects vCO2 and should be taken into account when interpreting changes in the vCO2 of an ECCO2R device.

Lung-protective ventilation (LPV) with low tidal volumes can significantly increase the survival of patients with acute respiratory distress syndrome (ARDS) by limiting ventilator-induced lung injuries. However, one of the main concerns regarding the use of LPV is the risk of developing hypercapnia and respiratory acidosis, which may limit the clinical application of this strategy. This is the reason why different extracorporeal CO2 removal (ECCO2R) techniques and devices have been developed. They include low-flow or high-flow systems that may be performed with dedicated platforms or, alternatively, combined with continuous renal replacement therapy (CRRT). ECCO2R has demonstrated effectiveness in controlling PaCO2 levels, thus allowing LPV in patients with ARDS from different causes, including those affected by Coronavirus disease 2019 (COVID-19). Similarly, the suitability and safety of combined ECCO2R and CRRT (ECCO2R-CRRT), which provides CO2 removal and kidney support simultaneously, have been reported in both retrospective and prospective studies. However, due to the complexity of ARDS patients and the limitations of current evidence, the actual impact of ECCO2R on patient outcome still remains to be defined. In this review, we discuss the main principles of ECCO2R and its clinical application in ARDS patients, in particular looking at clinical experiences of combined ECCO2R-CRRT treatments.

BackgroundExtracorporeal carbon dioxide removal (ECCO2R) is a promising yet limited researched therapy for hypercapnic respiratory failure in acute respiratory distress syndrome and exacerbated chronic obstructive pulmonary disease. Herein, we describe a new mock circuit that enables experimental ECCO2R research without animal models. In a second step, we use this model to investigate three experimental scenarios of ECCO2R: (I) the influence of hemoglobin concentration on CO2 removal. (II) a potentially portable ECCO2R that uses air instead of oxygen, (III) a low-flow ECCO2R that achieves effective CO2 clearance by recirculation and acidification of the limited blood volume of a small dual lumen cannula (such as a dialysis catheter).ResultsWith the presented ECCO2R mock, CO2 removal rates comparable to previous studies were obtained. The mock works with either fresh porcine blood or diluted expired human packed red blood cells. However, fresh porcine blood was preferred because of better handling and availability. In the second step of this work, hemoglobin concentration was identified as an important factor for CO2 removal. In the second scenario, an air-driven ECCO2R setup showed only a slightly lower CO2 wash-out than the same setup with pure oxygen as sweep gas. In the last scenario, the low-flow ECCO2R, the blood flow at the test membrane lung was successfully raised with a recirculation channel without the need to increase cannula flow. Low recirculation ratios resulted in increased efficiency, while high recirculation ratios caused slightly reduced CO2 removal rates. Acidification of the CO2 depleted blood in the recirculation channel caused an increase in CO2 removal rate.ConclusionsWe demonstrate a simple and cost effective, yet powerful, “in-vitro” ECCO2R model that can be used as an alternative to animal experiments for many research scenarios. Moreover, in our approach parameters such as hemoglobin level can be modified more easily than in animal models.

BackgroundExtracorporeal carbon dioxide removal (ECCO2R) systems have gained clinical appeal as supplemental therapy in the treatment of acute and chronic respiratory injuries with low tidal volume or non-invasive ventilation. We have developed an ultra-low-flow ECCO2R device (ULFED) capable of operating at blood flows comparable to renal hemodialysis (250 mL/min). Comparable operating conditions allow use of minimally invasive dialysis cannulation strategies with potential for direct integration to existing dialysis circuitry.MethodsA carbon dioxide (CO2) removal device was fabricated with rotating impellers inside an annular hollow fiber membrane bundle to disrupt blood flow patterns and enhance gas exchange. In vitro gas exchange and hemolysis testing was conducted at hemodialysis blood flows (250 mL/min).ResultsIn vitro carbon dioxide removal rates up to 75 mL/min were achieved in blood at normocapnia (pCO2 = 45 mmHg). In vitro hemolysis (including cannula and blood pump) was comparable to a Medtronic Minimax oxygenator control loop using a time-of-therapy normalized index of hemolysis (0.19 ± 0.04 g/100 min versus 0.12 ± 0.01 g/100 min, p = 0.169).ConclusionsIn vitro performance suggests a new ultra-low-flow extracorporeal CO2 removal device could be utilized for safe and effective CO2 removal at hemodialysis flow rates using simplified and minimally invasive connection strategies.

Introduction: Hypercapnic respiratory failure is associated with high morbidity and mortality. Low-flow extracorporeal CO2 removal (ECCO2R) has been shown to facilitate lung-protective ventilation or spontaneous breathing. However, three multicenter randomized trials have failed to show benefit which could potentially be a result of patient selection. In this study, we aimed to characterize prognostic scores developed for extracorporeal membrane oxygenation therapy which could potentially assist with the selection of patients for ECCO2R. Methods: A total of 70 patients admitted to the intensive care unit at the University Hospital of Zurich between 10/2009 and 02/2017 with hypercapnic respiratory failure were treated with ECCO2R if pH ≤7.25 and/or PaCO2 ≥ 9 kPa experiencing respiratory exhaustion during spontaneous breathing in obstructive lung disease or reaching the limits of lung protective ventilation (n = 22 and n = 48) in patients with restrictive lung pathologies. Data including baseline characteristics and respiratory parameters were collected prospectively. Scores were calculated retrospectively. Results: The underlying diseases were acute respiratory distress syndrome (n = 27), chronic-obstructive pulmonary disease (n = 12), bronchiolitis obliterans syndrome (BOS; n = 9), cystic fibrosis (n = 10), pulmonary fibrosis (n = 8), and other causes (n = 4). The 180-day mortality was 45.7% with the highest rate observed in PF and BOS patients as well as in patients who had been mechanically ventilated >6 days before initiation of ECCO2R. The modified PRedicting dEath for SEvere hypercapnic respiratory failure on vv-ECCO2R (PRESERVE-CO2) score differentiated well between survivors and non-survivors (4.3 ± 2.2 vs. 6.9 ± 2.6, p < 0.01), whereas the modified Respiratory ECMO Survival Prediction (RESP-CO2) score showed no significant distinction. Receiver operating characteristics analysis of the PRESERVE-CO2 score revealed an area under the curve of 0.78, suggesting a cut-off of 7 points. Conclusion: Careful selection of patients for ECCO2R therapy may help to improve outcomes. The proposed PRESERVE-CO2 score may serve as a guide. A score of 7 points or higher is associated with an unfavorable outcome regarding the 180-day mortality in the specific patient cohort of this study, but future studies to externally validate this score are required.

Lung-protective mechanical ventilation with low tidal volumes (V(T)) is often associated with hypercapnia (HC), which may be unacceptable in patients with brain injury. CO2 removal using a percutaneous extracorporeal lung assist (pECLA) enables normocapnia despite low V(T), but its effects on regional cerebral blood flow (rCBF) remain ambiguous. We hypothesized that reversal of HC by pECLA impairs rCBF in a porcine lung injury model. Lung injury was induced in 9 anesthetized pigs by hydrochloric acid aspiration. rCBF and systemic hemodynamics were measured by colored microsphere technique and transpulmonary-thermodilution during a randomized sequence of 4 experimental situations: pECLA shunt-on (1) with HC and (2) without HC, pECLA shunt-off (3) with HC and (4) without HC. HC increased rCBF (P<0.05). CO2 removal with pECLA resulting in normocapnia, decreased rCBF to levels comparable to those without pECLA and normocapnia. HC resulted in increased cardiac output (+25.5%). Cardiac output was highest during HC with pECLA shunt (+44.9%). During pECLA with CO2 removal, cardiac output (+38.1%) decreased compared with pECLA without CO2 removal, but stayed higher than during normocapnia/no pECLA shunt (P<0.05). In this animal model, mechanical ventilation with low V(T) was associated with HC and increased rCBF. CO2 removal by pECLA restored normocapnia, reduced rCBF to levels of normocapnia, but required a higher systemic blood flow for the perfusion of the pECLA device. If these results could be transferred to patients, extracorporeal CO2 removal might be an option for treatment of combined lung and brain injury in condition of a sufficient cardiac flow reserve.

In the conventional treatment of acute respiratory distress syndrome (ARDS), high O2 concentrations and mechanical ventilation may damage the lung tissue. Extracorporeal membrane oxygenation limits damage, provides the needed O2 supply and improves survival of ARDS neonates, but not of adults. Hydrophilic membranes used in hemodialysis are more non-thrombogenic and biocompatible than those used in blood oxygenation, but their O2 transport capacity is not as high. In recent years, CO2 removal at low blood flow rates combined with apneic oxygenation and low frequency ventilation has proved promising in the treatment of ARDS. This approach makes O2 supply across ECMO membranes unnecessary; it also makes hydrophilic membranes candidates for extracorporeal CO2 removal to minimize anticoagulation and immune system activation. This paper reports on the in vitro capacity of hydrophilic polysulphone membranes to remove CO2 from carbonated pig blood into an oxygen-rich gas stream. Experiments were performed on clinical-size dialysis modules and their capacity to remove CO2 as a function of blood flow rate and membrane surface area was investigated. Membranes effectively removed CO2 , more so at increasing blood flow rates and membrane surface areas, at rates of up to 15% of the CO2 metabolic production rate. The specific CO2 removal rate was comparable to that of blood oxygenators equipped with microporous hydrophobic membranes. It is concluded that CO2 removal from slowly flowing blood with hydrophilic membranes is feasible.

Extracorporeal CO2 removal (ECCO2R) is becoming an increasingly established treatment option for patients with acute severe hypercapnic respiratory failure. Technically, pumpless arterio-venous systems using the natural arterio-venous pressure gradient and also pump-driven veno-venous systems are available. Here, veno-venous ECCO2R has become the preferred technique, as settings for arterio-venous ECCO2R are restricted and side effects are more common with arterio-venous ECCO2R. Using veno-venous ECCO2R with blood flow rates up to 450 ml/min 60 to 80 ml CO2 can be removed per minute corresponding to 20 to 30 % of the total amount of CO2 production. However, in case of very severe hypercapnic respiratory failure with severe respiratory acidosis (pH 7.1 or less) blood flow rates of around 1000 ml/min are required for compensating severe respiratory acidosis corresponding to the elimination of 50 to 60 % of the total amount of CO2 production. Relevant side effects include the activation of blood coagulation and associated bleeding complications. Two recent case-control studies in severely exacerbated COPD patients could demonstrate that intubation rates can be reduced by the application of ECCO2R, but this was associated with non-ignorable side effects. Therefore, randomized controlled trials are urgently needed to more precisely establish the risks and benefits of ECCO2R when aimed at avoiding intubation.

Conventional extracorporeal CO2 removal systems require blood flow rates of 1 to 2.5 L/min in the extracorporeal circuit. We hypothesized that standard hemofiltration equipment can be combined with a high-performance extracorporeal lung to achieve high rates of CO2 removal at lower blood flow rates. To test this hypothesis, we performed experiments on nine sheep to examine the extent to which CO2 elimination can be achieved at blood flow rates less than 600 mL/min using a 5-m2 hollow fiber membrane lung with countercurrent gas flow, combined with a hemofiltration blood pump, and connected to femoral arterial and venous hemodialysis catheters. CO2 eliminations of 130 to 180 mL/min at standard temperature and pressure were achieved with blood flow rates in the range 470 to 600 mL/min. With a pumpless artery-to-vein shunt, up to 90 mL/min of CO2 at standard temperature and pressure was eliminated. However, in this mode, the resistance of the access catheters and tubing was the main factor limiting CO2 elimination. Standard hemofiltration equipment may be combined with a hollow fiber membrane lung to remove the equivalent of a high proportion of the basal metabolic CO2 production of an adult human at low blood flow rates. Use of this technology would bring extracorporeal CO2 removal within the budget and capability of more ICUs.

Extracorporeal gas exchange requires the passage of oxygen and carbon dioxide (CO2) across an artificial membrane. Current European Union regulations do not require the transfer to be assessed in models using clinically relevant haemoglobin, making it difficult for clinicians to understand the CO2 clearance of a membrane, and how it changes in relation to sweep gas flow through the membrane. The characteristics of membrane CO2 clearance are described using a single membrane at different sweep gas flows in an in vitro model with clinically relevant haemoglobin concentrations using three separate methods of calculating CO2 clearance. To define the CO2 removal characteristics of the extra-corporeal CO2 removal (ECCO2R) device, we devised an in-vitro gas exchange circuit formed by a dedicated ECCO2R circuit (ALung, Pittsburgh, USA) in series with two membrane oxygenators. The system was primed with donated expired human red cells provided by the local blood bank. The experimental set-up allowed constant CO2 input (via one membrane oxygenator) with variable removal from a portion of the blood in a manner which was analogous to that seen in vivo. Blood gases were measured from different ports in the circuit in order to measure the experimental membrane CO2 clearance (VCO2). Results demonstrate that the relationship between VCO2 and gas flow at a constant blood flow of 0.4 L/minute with a haemoglobin of 7 g/dL increases sharply from a gas flow of 0 to 2 L/min but plateaus at gas flows >4 L/minute. VCO2, calculated using three different methods, showed a strong linear correlation with minimal bias. The CO2 clearance of the membrane used in this bench test is non-linear. This has implications for clinical practice, especially during the weaning phase of the device.

Background: Protective ventilation (PV) with low tidal volumes is recommended in acute respiratory distress syndrome (ARDS). However, hypercapnic acidosis resulting from PV enhances pulmonary hypertension. Aim: We investigated if extracorporeal veno-venous CO 2 removal therapy could have beneficial effects on pulmonary circulation. Methods: This study was performed on an experimental model of ARDS obtained in 8 anaesthetized pigs connected to a volume-cycled ventilator. A micromanometer-tipped catheter was inserted into the main pulmonary artery and an admittance micromanometer-tipped catheter was inserted into the right ventricle. ARDS was obtained by repeated bronchoalveolar lavage. PV was then achieved and the pigs were connected to a pump-driven extracorporeal membrane oxygenator (PALP, Maquet, Germany) in order to achieve CO 2 removal. Results: ARDS induced severe hypercapnic acidosis. Systolic pulmonary artery pressure significantly increased from 29.6±1.8 to 43.9±2.0 mm Hg (p<0.001). After the PALP was started, acidosis was corrected and normocarbia was maintained despite protective ventilation. Pulmonary artery pressure significantly decreased to 31.6±3.2 mm Hg (p<0.001). Conclusions: Veno-venous CO 2 removal therapy enabled PV while maintaining normocarbia during ARDS. CO 2 removal therapy decreased pulmonary hypertension and may be an effective lung- and RV- protective adjunct to mechanical ventilation.

This study was performed to examine the role of transglutaminase 2 (TG2) in ventilator-induced lung injury (VILI). C57BL/6 mice were divided into six experimental groups: 1) control group; 2) lipopolysaccharide (LPS) group; 3) lung protective ventilation (LPV) group; 4) VILI group; 5) VILI with cystamine, a TG2 inhibitor, pretreatment (Cyst+VILI) group; and 6) LPV with cystamine pretreatment (Cyst+LPV) group. Acute lung injury (ALI) score, TG2 activity and gene expression, inflammatory cytokines, and nuclear factor-κB (NF-κB) activity were measured. TG2 activity and gene expression were significantly increased in the VILI group (P < 0.05). Cystamine pretreatment significantly decreased TG2 activity and gene expression in the Cyst+VILI group (P < 0.05). Inflammatory cytokines were higher in the VILI group than in the LPS and LPV groups (P < 0.05), and significantly lower in the Cyst+VILI group than the VILI group (P < 0.05). NF-κB activity was increased in the VILI group compared with the LPS and LPV groups (P < 0.05), and significantly decreased in the Cyst+VILI group compared to the VILI group (P = 0.029). The ALI score of the Cyst+VILI group was lower than the VILI group, but the difference was not statistically significant (P = 0.105). These results suggest potential roles of TG2 in the pathogenesis of VILI.

BackgroundVeno-venous extracorporeal CO2 removal (vv-ECCO2R) and non-invasive neurally adjusted ventilator assist (NIV-NAVA) are two promising techniques which may prevent complications related to prolonged invasive mechanical ventilation in patients with acute exacerbation of COPD.MethodsA physiological study of the electrical activity of the diaphragm (Edi) response was conducted with varying degrees of extracorporeal CO2 removal to control the respiratory drive in patients with severe acute exacerbation of COPD breathing on NIV-NAVA.ResultsTwenty COPD patients (SAPS II 37 ± 5.6, age 57 ± 9 years) treated with vv-ECCO2R and supported by NIV-NAVA were studied during stepwise weaning of vv-ECCO2R. Based on dyspnea, tolerance, and blood gases, weaning from vv-ECCO2R was successful in 12 and failed in eight patients. Respiratory drive (measured via the Edi) increased to 19 ± 10 μV vs. 56 ± 20 μV in the successful and unsuccessful weaning groups, respectively, resulting in all patients keeping their CO2 and pH values stable. Edi was the best predictor for vv-ECCO2R weaning failure (ROC analysis AUC 0.95), whereas respiratory rate, rapid shallow breathing index, and tidal volume had lower predictive values. Eventually, 19 patients were discharged home, while one patient died. Mortality at 90 days and 180 days was 15 and 25%, respectively.ConclusionsThis study demonstrates for the first time the usefulness of the Edi signal to monitor and guide patients with severe acute exacerbation of COPD on vv-ECCO2R and NIV-NAVA. The Edi during vv-ECCO2R weaning was found to be the best predictor of tolerance to removing vv-ECCO2R.

Introduction. Extracorporeal membrane oxygenation (ECMO) support for severe acute respiratory distress syndrome (ARDS) is nowadays widely used with notable results on the overall survival as reported in the ELSO registry near to 55% at 90 days. This is the reason why ECMO teams force the use of this extreme technique to several populations, even though there is still a lack of data about its use on hematological patients. Case Report. A 39-year-old woman without a history of previous diseases, but a new diagnosis of acute myeloblastic leukemia (AML) was admitted to intensive care unit (ICU) for worsening hypoxia and respiratory acidosis, presenting an ARDS with PaO2/FiO2 < 100 in spontaneous breathing treated with noninvasive ventilation via full-face mask. Meanwhile, chemotherapy was started leading to a severe bone marrow aplasia that was managed with multiple blood and platelet transfusions. These conditions did not allow physicians to start any invasive approaches. After 14 days, ARDS worsened whereas bone marrow recovered, making possible the beginning of an invasive mechanical ventilation, with low positive end-expiratory pressure and a low tidal volume. Moreover, an immediate extracorporeal CO2 removal (ECCO2R) therapy was added. Despite these efforts, no improvement was achieved, and that is why venovenous ECMO throughout femoral-jugular cannulation was applied. A full protective lung ventilation by ultralow tidal volumes was guaranteed. After 2 weeks of ECMO, a gradual weaning from ECMO support was started and completed after two days. No ECMO-related complications were registered. In the end, the patient started her weaning from the mechanical ventilation and reached 12 hours of spontaneous ventilation in oxygen therapy. Discussion. ECMO is used as a rescue therapy in patients affected by severe respiratory failure with life-threatening hypoxia and respiratory acidosis nonresponsive to other maneuvers. However, immunosuppression and coagulopathies of hematological malignancies are considered relative contraindications for ECMO, while long-lasting respiratory failure represents another relative contraindication to extracorporeal support. ECMO could be a valid option to improve the survival of hematological patients with severe ARDS and thrombocytopenia, and management could change case by case, even if high incidence of recurrency.

The lung-protective mechanical ventilation strategy has been standard practice for management of acute respiratory distress syndrome (ARDS) for more than a decade. Observational data, small randomized studies and two recent systematic reviews suggest that lung protective ventilation is both safe and potentially beneficial in patients who do not have ARDS at the onset of mechanical ventilation. Principles of lung-protective ventilation include: a) prevention of volutrauma (tidal volume 4 to 8 ml/kg predicted body weight with plateau pressure <30 cmH2O); b) prevention of atelectasis (positive end-expiratory pressure ≥5 cmH2O, as needed recruitment maneuvers); c) adequate ventilation (respiratory rate 20 to 35 breaths per minute); and d) prevention of hyperoxia (titrate inspired oxygen concentration to peripheral oxygen saturation (SpO2) levels of 88 to 95%). Most patients tolerate lung protective mechanical ventilation well without the need for excessive sedation. Patients with a stiff chest wall may tolerate higher plateau pressure targets (approximately 35 cmH2O) while those with severe ARDS and ventilator asynchrony may require a short-term neuromuscular blockade. Given the difficulty in timely identification of patients with or at risk of ARDS and both the safety and potential benefit in patients without ARDS, lung-protective mechanical ventilation is recommended as an initial approach to mechanical ventilation in both perioperative and critical care settings.