Extracorporeal Lung Research Articles

Extracorporeal Membrane Oxygenation and Lung Transplantation: Initial Experience at a Single Brazilian Center

OBJECTIVE:To report initial experience from the use of extracorporeal membrane oxygenation (ECMO) in patients who received lung transplantation.METHODS:Retrospective study of a single tertiary center in the Brazilian state of São Paulo, a national reference in lung transplantation, based on the prospective collection of data from electronic medical records. The period analyzed extended from January 2009 (beginning of the program) until December 2018.RESULTS:A total of 75 lung transplants were performed, with ECMO used in 8 (10.7%) cases. Of the patients, 4 (50%) were female. The mean age was 46.4±14.3 years. The causes of the end-stage lung disease that led to transplantation were pulmonary arterial hypertension in 3 (37.5%) patients, bronchiectasis in 2 (25%) patients, pulmonary fibrosis in 2 (25%) patients, and pulmonary emphysema in 1 (12.5%) patient. In our series, 7 (87.5%) cases were sequential bilateral transplantations. Prioritization was necessary in 4 (50%) patients, and in 1 patient, ECMO was used as a bridge to transplantation. The ECMO route was central in 4 (50%), peripheral venovenous in 2 (25%) and peripheral venoarterial in 2 (25%) patients. The mean length of the intensive care unit (ICU) stay was 14±7.5 days and of the hospital stay was 34.1±34.2 days. The mean ECMO duration was 9.3±6.6 days with a 50% decannulation rate. Three patients were discharged (37.5%).CONCLUSION:Lung transplantation requires complex treatment, and ECMO has allowed extending the indications for transplantation and provided adjuvant support in the clinical management of these patients.

Multiday maintenance of extracorporeal lungs using cross-circulation with conscious swine

ObjectivesLung remains the least-utilized solid organ for transplantation. Efforts to recover donor lungs with reversible injuries using ex vivo perfusion systems are limited to <24 hours of support. Here, we demonstrate the feasibility of extending normothermic extracorporeal lung support to 4 days using cross-circulation with conscious swine. MethodsA swine behavioral training program and custom enclosure were developed to enable multiday cross-circulation between extracorporeal lungs and recipient swine. Lungs were ventilated and perfused in a normothermic chamber for 4 days. Longitudinal analyses of extracorporeal lungs (ie, functional assessments, multiscale imaging, cytokine quantification, and cellular assays) and recipient swine (eg, vital signs and blood and tissue analyses) were performed. ResultsThroughout 4 days of normothermic support, extracorporeal lung function was maintained (arterial oxygen tension/inspired oxygen fraction >400 mm Hg; compliance >20 mL/cm H2O), and recipient swine were hemodynamically stable (lactate <3 mmol/L; pH, 7.42 ± 0.05). Radiography revealed well-aerated lower lobes and consolidation in upper lobes of extracorporeal lungs, and bronchoscopy showed healthy airways without edema or secretions. In bronchoalveolar lavage fluid, granulocyte-macrophage colony-stimulating factor, interleukin (IL) 4, IL-6, and IL-10 levels increased less than 6-fold, whereas interferon gamma, IL-1α, IL-1β, IL-1ra, IL-2, IL-8, IL-12, IL-18, and tumor necrosis factor alpha levels decreased from baseline to day 4. Histologic evaluations confirmed an intact blood–gas barrier and outstanding preservation of airway and alveolar architecture. Cellular viability and metabolism in extracorporeal lungs were confirmed after 4 days. ConclusionsWe demonstrate feasibility of normothermic maintenance of extracorporeal lungs for 4 days by cross-circulation with conscious swine. Cross-circulation approaches could support the recovery of damaged lungs and enable organ bioengineering to improve transplant outcomes.

A CO2 removal system using extracorporeal lung and renal assist device with an acid and alkaline infusion.

The patients with respiratory failure need high tidal volume by mechanical ventilation, which lead to the ventilator-induced lung injury. We developed an extracorporeal lung and renal assist device (ELRAD), comprising acid infusion, membrane lung, continuous hemodiafiltration and alkaline infusion. To evaluate this system, we conducted in vivo studies using experimental swine which were connected to the new system. In vivo experiments consist of four protocols; baseline = hemodiafiltration only (no O2 gas flow to membrane lung); membrane lung = "Baseline" plus O2 gas flow to membrane lung; "Acid infusion" = "Membrane lung" plus continuous acid infusion; ELRAD = "Acid infusion" plus continuous alkaline infusion. We changed the ventilatory rate of the mechanical ventilation to maintain PCO2 at 50-55mmHg during the four protocols. The results showed that there was statistically no significant difference in the levels of pH, HCO3-, and base excess when each study protocol was initiated. The amount of CO2 eliminated by the membrane lung significantly increased by 1.6 times in the acid infusion protocol and the ELRAD protocol compared to the conventional membrane lung protocol. Minute ventilation in the ELRAD protocol significantly decreased by 0.5 times compared with the hemodiafiltration only protocol (P < 0.0001), the membrane lung (P = 0.0006) and acid infusion protocol (P = 0.0017), respectively. In conclusion, a developed CO2 removal system efficiently removed CO2 at low blood flow and reduced minute ventilation, while maintaining acid-base balance within the normal range.

Haematocrit heterogeneity in blood flows past microfluidic models of oxygenating fibre bundles

Blood oxygenators act as an extracorporeal artificial lung during certain types of cardiac surgery and intensive care therapies. Inside these devices, blood is forced to flow across an oxygenating bundle, encountering interstitial gaps comparable to those typical of the microvasculature. Despite the well-known effects of such length scales on haemorheology and red blood cell (RBC) behavior, these are generally overlooked in oxygenator modeling and design; it is persistently assumed that RBCs are homogeneously distributed throughout the oxygenating bundle, independently of their microstructure arrangement or main flow directions.The goal of this study is to provide preliminary experimental evidence of heterogeneous RBC distributions inside oxygenating fibre bundles. To this end, a number of microchannels were manufactured inspired by actual oxygenating devices, considering simplified versions of their microstructure. These comprise staggered arrays of micro pillars, which were perfused with RBC suspensions, with feed haematocrit (Ht) and velocities relevant for clinical use. The microchannels were imaged using a microscope and high-speed camera to accurately capture cell distribution.The imaged blood flows revealed the non-uniform nature of RBC distributions in the arrays, characterized by local Ht gradients particularly around the O2 sources inside the bundle. These heterogeneous distributions should be accounted for during oxygenator design, as RBC concentration plays a key role in O2 transport and, ultimately, overall device performance.

Current techniques for extracorporeal decarboxylation

The widespread use of extracorporeal lung assist (ECLA) in recent years has led to the introduction of different decarboxylation systems into clinical practice. Due to the large CO2 transport capacity of the blood such systems require considerably lower extracorporeal blood flows and therefore allow for effective decarboxylation with reduced invasiveness and complexity. While systems derived from classical lung assist are mainly used to control severe acute hypercapnic respiratory failure, recently agrowing number of therapies based on renal replacement platforms have become available ("respiratory dialysis"). Such low-flow systems still allow for effective partial CO2 elimination and can control respiratory acidosis as well as facilitate or even enable protective and ultraprotective ventilation strategies in acute lung failure (ARDS). While the use of extracorporeal CO2 elimination (ECCO2R) has been shown to decrease ventilator-induced lung injury (VILI), positive effects on hard clinical endpoints such as mortality or duration of mechanical ventilation are still unproven. In light of limited evidence, ECCO2R must be regarded as an experimental procedure. Its use should therefore at present be restricted to centers with appropriate experience.

Indications and limitations of ECMO therapy : Considerations on evidence, treatment decisions and ethical challenges

The present work sheds light on the possibilities and limitations of modern extracorporeal membrane oxygenation (ECMO) therapy in the case of heart or lung failure. Since the number of applications of extracorporeal lung and heart/lung replacement procedures has increased dramatically in the last few years in severely ill patients, decision-making for ameaningful indication and in the course of apossible therapy target change has become particularly difficult, especially with regard to the complex situation in organ transplantation in Germany. An attempt is made to elucidate the dilemma between data from large controlled trials and epidemiological studies and the patients' individuality.

Outcome after extracorporeal membrane oxygenation-bridged lung retransplants: a single-centre experience.

A lung retransplant has been shown to be a valid option in selected patients with chronic lung allograft dysfunction (CLAD). However, a subgroup of patients may require, in addition to invasive mechanical ventilation, extracorporeal membrane oxygenation (ECMO) as a bridge to a retransplant. Overall and CLAD-free survival after ECMO-bridged retransplants are compared to first transplants with and without bridging ECMO and to retransplants without bridging ECMO. We reported a retrospective, single-institution experience based on a prospective data set of all patients undergoing lung transplants between January 2004 and December 2016 with a mean follow-up of 51 ± 41 months. A total of 230 patients (96 men, 134 women, mean age 47.3 years) had lung transplants: 200 had first transplants without bridging ECMO; 13 had first transplants with bridging ECMO; 11 had retransplants without bridging ECMO; and 6 had retransplants with bridging ECMO. The 3- and 5-year survival rates were 81%/76%, 68%/68%, 69%/46% and 50%/25%, respectively. There was no significant difference in overall survival between those who had first transplants with and without bridging ECMO or retransplants without bridging ECMO. In contrast, patients undergoing ECMO-bridged retransplants had a significantly lower overall survival rate than those with a first transplant without bridging ECMO (P = 0.007). In addition, the post-transplant CLAD-free survival curves varied significantly among the 4 treatment groups (P = 0.041), paralleling overall survival. Patients requiring ECMO as a bridge to a retransplant had lower overall and CLAD-free survival rates compared to those who had a first transplant with and without bridging ECMO and a retransplant without bridging ECMO.

Extrakorporale Membranoxygenierung in der Thoraxchirurgie: Etablierung funktioneller und technischer Operabilität

Functional and technical operability has to be evaluated and defined prior to thoracic surgical procedures. Sometimes patients assigned to thoracic surgery procedures have to be declared inoperable due to functional und technical limitations. Extracorporeal lung support is an important tool to establish functional and technical operability in patients undergoing thoracic surgical procedures. This ensures perioperative safety and minimises the risk during extended lung resection.

ECMO in der Thoraxchirurgie: Grundlagen und Pathophysiologie

Extracorporeal lung support (ECLS) is of increasing importance in general thoracic surgery. Different modes of ECLS may be applied in several situations throughout the perioperative phase and are adapted to the individual patient's needs and the planned surgical procedures. ECLS is not a static procedure and should be always evaluated according to the present condition of the patient. Therefore, it is essential to understand the pathophysiology of the disease and the different ECLS modes, as well as the different cannulation options, in order to be able to use the different escalation and de-escalation techniques in accordance with the clinical situation.

Extracorporeal Lung Support for Hypercapnic Ventilatory Failure.

Extracorporeal lung support can be achieved using extracorporeal membrane oxygenation (ECMO) and extracorporeal CO2 removal. The ECMO systems allow a total lung support, providing both blood oxygenation and CO2 removal. Unlike ECMO, extracorporeal CO2 removal refers to an extracorporeal circuit that provides a partial lung support and selectively extracts CO2 from blood. The concept of partial extracorporeal lung support by removing only CO2 without effect on oxygenation was first proposed in 1977 by Kolobow and Gattinoni, with the aim to reduce breathing frequency, ventilator tidal volumes, and inspiratory pressures, facilitating lung-protective ventilation. Patients with end-stage chronic lung disease can survive, while waiting for lung transplantation, only if treated with mechanical ventilation or extracorporeal lung support. ECMO has been considered a suitable approach as a bridge to lung transplantation for patients with advanced respiratory failure waiting for lung transplantation. Extracorporeal CO2 removal has been proposed for the treatment of COPD patients suffering from exacerbation to avoid invasive mechanical ventilation. The rationale is to combine the improvement of alveolar ventilation by using noninvasive ventilation with muscle unload provided by removing CO2 directly from the blood, using an extracorporeal device. Increasing attention has been given to the possibility of patients performing a variety of physical activities while receiving extracorporeal lung support. This is possible thanks to the continuous development of technology together with the customization of sedative protocols. Awake extracorporeal support is a specific approach in which the patient is awake and potentially cooperative while receiving ECMO. The present analysis aims to synthesize the main results obtained by using extracorporeal circuits in patients with respiratory failure, particularly in those patients with hypercapnia.

Obesity-related respiratory failure: a new area for extracorporeal lung support?

In the ICU, the main challenges with obese patients are to take into account the pulmonary pathophysiological characteristics when choosing the best management options.

Efficient CO2 removal using extracorporeal lung and renal assist device.

We developed a novel system comprising acid infusion, membrane lung, and a continuous renal replacement therapy console for efficient CO2 removal at a low blood flow. To evaluate the new system, we used an ex vivo experimental model using swine blood. A liter of aliquoted blood adjusted to pH 7.25 and pCO2 65mm Hg was mixed with acid (0, 10, or 20mL of lactic or hydrochloric acid [1mol/L]) and was immediately delivered to the system in a single pass. We collected blood samples at each point of the circuit and calculated the amount of CO2 eliminated by the membrane lung. The new system removed 13.2 ± 0.8, 32.0 ± 2.1, and 51.6 ± 3.7mL/min of CO2 (with 0, 10, and 20mEq/L of lactic acid) and 21.2 ± 1.2, 27.3 ± 0.3, and 42.0 ± 1.3mL/min (with 0, 10, and 20mEq/L of hydrochloric acid), respectively. The levels of lactate and Cl- ions for acid-base equilibrium were restored after continuous hemodiafiltration. Thus, the amount of CO2 eliminated by the membrane lung was 3.9 times higher with lactic acid and 2.0 times higher with hydrochloric acid compared with non-acid controls. In conclusion, this easy-to-setup CO2 removal system was safe, effective, and removed CO2 at a low blood flow.

Microfluidic cell sorting: Towards improved biocompatibility of extracorporeal lung assist devices

Extracorporeal lung assist technology is one of the last options in critical care medicine to treat patients suffering from severe oxygenation and decarboxylation disorders. Platelet activation along with the consequent thrombus formation is a potentially life-threatening complication of this technique. To avoid platelet-dependent clot formation, this study aims at developing a microfluidic cell sorting chip that can bypass platelets prior to the membrane oxygenator of the extracorporeal lung assist device. The cell sorting chips were produced by maskless dip-in laser lithography, followed by soft lithography replication using PDMS. Citrated porcine whole blood with a clinically relevant haematocrit of 17% was used for the cell sorting experiments involving three different blood flow rates. The joint effects of flow focusing and hydrodynamic lifting forces within the cell sorting chip resulted in a reduction of up to 57% of the baseline platelet count. This cell sorting strategy is suitable for the continuous and label-free separation of red blood cells and platelets and is potentially applicable for increasing the biocompatibility and lifetime of current extracorporeal lung assist devices.

Logistic regression analysis of risk factors for primary graft dysfunction after lung transplantation

Objective: To explore the risk factors of primary graft dysfunction (PGD) after lung transplantation and provide a new therapeutic strategy for PGD. Methods: A retrospective analysis of lung transplant patients from January 2014 to July 2017 in Henan Provincial People's Hospital.According to the PGD classification standard established by the International Society for Heart and Lung Transplantation, the association of potential risk factors with PGD was analyzed by using multivariable Logistic regression. Results: Fourteen of 30 patients (46.7%) developed grade 3 PGD.There was no significantly statistical difference in gender, etiology, duration of anesthesia, amount of blood transfusion, amount of blood transfusion and donor gender(all P>0.05). Body mass index (BMI), donor pulmonary cold ischemia time, duration of operation, extracorporeal membrane lung oxygenator (ECMO), systolic pulmonary arterial pressure and donor smoking history were all higher than those of non-PGD patients (all P<0.05). Independent risk factors for PGD were donor pulmonary cold ischemia time (OR 1.032, 95%CI 1.000-1.065, P=0.048); systolic pulmonary arterial pressure (OR 1.258, 95%CI 0.969-1.632, P=0.007); donor smoking (OR 8.879, 95%CI 1.096-71.913, P=0.041). Conclusion: Donor pulmonary ischemic time, systolic pulmonary arterial pressure and donor smoking history are PGD risk factors, which provide new ideas for PGD treatment.

The Development of Extracorporeal Membrane Oxygenation

Evolving from the development of heart-lung machines for open-heart surgery, extracorporeal membrane oxygenation has reemerged as a rescue modality for patients with acute respiratory failure that cannot be supported by conventional modes of ventilation. The history of extracorporeal membrane oxygenation begins with the discovery of heparin, fundamental to the success of extracorporeal circulation and membrane lungs. Engineers and scientists created suitable artificial membranes that allowed gas exchange while keeping gas and blood phases separate. Special pumps circulated blood through the devices and into patients without damage to delicate red cells and denaturing plasma. Initial attempts in adults ended in failure, but Robert Bartlett, first at Loma Linda, CA, then at Ann Arbor, MI, succeeded in applying the technology in newborn infants with persistent pulmonary hypertension. Preserved in the critical care of infants, the technology in time could be reapplied in the life support of older children and adults.

When the momentum has gone: what will be the role of extracorporeal lung support in the future?

There has been expanding interest in and use of extracorporeal support in respiratory failure concurrent with technological advances and predominantly observational data demonstrating improved outcomes. However, until there is more available data from rigorous, high-quality randomized studies, the future of extracorporeal support remains uncertain. Outcomes for patients supported with extracorporeal devices continue to show favorable trends. There are several large randomized controlled trials that are in various stages of planning or completion for extracorporeal membrane oxygenation (ECMO) and extracorporeal carbon dioxide removal (ECCO2R) in the acute respiratory distress syndrome (ARDS) and chronic obstructive pulmonary disease (COPD), which may help clarify the role of this technology for these disease processes, and which stand to have a significant impact on a large proportion of patients with acute respiratory failure. Novel applications of extracorporeal lung support include optimization of donor organ quality through ex-vivo perfusion and extracorporeal cross-circulation, allowing for multimodal therapeutic interventions. Despite the ongoing rise in ECMO use for acute respiratory failure, its true value will not be known until more information is gleaned from prospective randomized controlled trials. Additionally, there are modalities beyond the current considerations for extracorporeal support that have the potential to revolutionize respiratory failure, particularly in the realm of chronic lung disease and lung transplantation.

Combined Application of Percutaneous Extracorporeal Lung Assistance System Together with Catheter-Directed Therapy for the Rescue of Massive Pulmonary Embolism after Failed Systemic Thrombolysis

A 56 year-old, formerly healthy man, who had undergone surgery of the shoulder joint earlier that same day,

Extracorporeal lung support for advanced lung failure: a new era in thoracic surgery and translational science.

For the patients with progressively decompensating acute or acute-on-chronic respiratory failure, the first-choice treatment remains as mechanical ventilation. Despite the consistent value of mechanical ventilation, the majority of lung specialists are aware of its limitations, in particular for the patients with advanced lung failure, and inherent drawbacks that augment disease progression. More recently, the concept of allowing the lungs to 'rest and recover' has been supported by quite a few clinical studies. The pressure and volume of gas delivered to the lungs are reduced compared with mechanical ventilation. Based on recent remarkable evidence and experiences using extracorporeal lung support (ECLS) before, during and after lung transplant, there is growing interest in and expectations for the use of ECLS beyond lung transplant to encompass the entire field of pulmonary medicine. The purpose of this review article is to provide an update on evolving ECLS technologies and their effectiveness and discuss the future of ECLS for advanced lung failure as a new subspecialty in cardiothoracic surgery.

Effects of pumpless extracorporeal lung assist on hemodynamics, gas exchange and inflammatory cascade response during experimental lung injury.

Pumpless extracorporeal lung assist (pECLA) has been reported to efficiently remove the systemic CO2 production and provide mild to moderate oxygenation, thereby allowing for ventilator settings and modes prioritizing oxygenation and lung protection. However, an adequate bypass flow, the capacity to provide respiratory support and the effect on the inflammatory cascade response and tissue perfusion require further study to be determined. After induction of acute lung injury (ALI) by oleic acid injection, pECLA was implemented in 12 anaesthetized and mechanically ventilated dogs for 48 h. Improved oxygenation [partial oxygen pressure (PaO2) and oxygen saturation (SaO2) was measured by arterial blood gas analysis, and increased by 29 and 18%, respectively] and CO2 elimination (partial CO2 pressure decreased by 43.35%) were obtained after pECLA implementation. A maximum arterio-venous shunt flow of up to 25% of the foundational CO resulted in stable hemodynamics. The pECLA procedure did not elicit any further increase in the concentration of tumor necrosis factor-α, interleukin (IL)-6, IL-8 and endothelin-1 compared with that in the group subjected to oleic acid injection only. In addition, the pECLA procedure had no effect on lactate levels and urine production. In conclusion, pECLA is an efficient and promising strategy for providing a mild to moderate oxygenation and adequate decarboxylation, while avoiding excessive inflammatory cascade response and tissue hypoperfusion in an experimental ALI model.

Is Extracorporeal CO2 Removal Really "Safe" and "Less" Invasive? Observation of Blood Injury and Coagulation Impairment during ECCO2R.

Extracorporeal CO2 removal (ECCO2R) is promoted with attributes like "safe" and "less invasive" compared with (high-flow) venovenous extracorporeal membrane oxygenation (ECMO) systems. With our experience in coagulation disorders during ECMO therapy with this observational study, we for the first time prospectively evaluate hemolysis and coagulation disorders during ECCO2R. Eight consecutive patients with predominant hypercapnic respiratory failure were treated with the Hemolung respiratory assist system (Alung-Technologies, Pittsburg, PA). Bleeding as well as changes of coagulation parameters was prospectively assessed. Overall therapy was observed in seven patients with 52 treatment days. In four of seven patients (57%), relevant clinical bleeding symptoms occurred. Thrombocytopenia, hemolysis, factor XIII deficiency and acquired von Willebrand syndrome (loss of high-molecular-weight von Willebrand factor multimers) were typical findings, and the patients spontaneously recovered after discontinuation of the extracorporeal system. In one patient, extracorporeal system stopped because of thrombotic occlusion. Six of seven patients required transfusion of red blood cells. Our observation shows that even low-flow extracorporeal lung support is associated with relevant clinical bleeding symptoms, blood cell injury, development of acquired von Willebrand syndrome and need for transfusion. In our opinion, it therefore is too early to quote ECCO2R "safe" and "less invasive."