Life after extracorporeal membrane oxygenation : long-term survival and quality of life

Background: The use of Extracorporeal membrane oxygenation (ECMO) has steadily increased in the last decades and has evolved in several ways. From originally being a means to support the neonatal patient with respiratory or circulatory failure for days to weeks, ECMO is now mainly used in paediatric and adult patients. Survival after ECMO varies depending on the underlying condition, and survival to discharge and 6-12 months has been readily reported in the literature. Likewise, quality-of-life and health status are well-investigated in the 3-24-month period after discharge. However, there is a paucity of data concerning long-term outcomes several years after ECMO treatment. Aim: To identify long-term survival and causes of death in ECMO treated patients (study I and II), and to investigate the long-term health and mental status after treatment, including cognitive functions and brain radiographic findings (study III), pulmonary function, pulmonary morphology, mood disorders and quality of life (study IV). Overview of methods: Using the Swedish national causes of death registry, study I and II attained survival status and causes of death in all commonly treated patient groups at the ECMO Centre of the Karolinska University Hospital. Survival was depicted using the Kaplan-Meier technique. For study III and IV, a retrospective cohort was created by contacting consecutive long-term adult survivors, starting with the first adult survivor treated at the centre. Thirty-eight patients treated with ECMO for respiratory failure were investigated. This included magnetic resonance imaging of the brain and extensive neurocognitive tests (study III), followed by computed tomography of the lungs, spirometry, a six-minute walk test and self-reported forms of quality of life and mood symptoms (study IV, including Short form 36, St George’s respiratory questionnaire, Hospital anxiety and depression scale and Trauma screening questionnaire). Summary of research results: Survival status in 255 adults was investigated in median 4.4 years after treatment (study I). The mortality was high in the first three months after treatment (17% of the ECMO survivors died in the first 90 days). This time point served as a cut-off to define late survival. In patients who were alive at 90 days, 87% were alive five years later. Long-term survival differed between groups and was highest in patients treated for a known or suspected infectious disease. In study II, 400 children were investigated in median 7.2 years after treatment. Similar to the results in adults, there was high 90-day mortality, and 93% of neonates and 89% of paediatric patients were alive 10 years later in the group who survived to this time point. Patients who died generally had severe comorbidities or an underlying disease which caused deterioration later in life. Brain lesions were seen in 37% of the long-term survivors (14/38, study III). In the group treated with venoarterial ECMO, 64% had signs of brain lesions. General intelligence depicted as the full-scale intelligence quotient (normal mean 100, SD 15) was 97 in median (IQR 86-104). In patients with brain lesions, the median full-scale intelligence quotient was 88, compared to 102 in patients with normal brain imaging (p=0.28). Memory functions and executive functions, also reported as indices with a normal mean of 100 and a SD of 15, were significantly reduced in patients with brain lesions (p=0.03 and 0.02, respectively). Patients with hypoxaemia during ECMO treatment, defined as <93% pulse oximetry haemoglobin saturation in median during ECMO treatment (or the first 10 days if treated for a long time) had similar intelligence as patients with normoxaemia. Quality of life was reduced in the present cohort, but the results were similar to previously published data on patients with acute respiratory distress syndrome not treated with ECMO. A reduction in diffusion capacity was seen in 47% of the patients, and lung function varied greatly between patients. Lung parenchymal damage was common, in mean 7% of the parenchyma was damaged (range 0-44%). In 50% of the patients, this damage was predominantly localised anteriorly, possibly indicating ventilator-induced lung injury. Parenchymal damage correlated with time on ECMO and time with mechanical ventilation, and with reductions in quality of life and diffusion capacity

Administration of mesenchymal stem cells during ECMO results in a rapid decline in oxygenator performance

Mesenchymal stem cells (MSCs) have attracted attention as a potential therapy for Acute Respiratory Distress Syndrome (ARDS). At the same time, the use of extracorporeal membrane oxygenation (ECMO) has increased among patients with severe ARDS. To date, early clinical trials of MSCs in ARDS have excluded patients supported by ECMO. Here we provide evidence from an ex-vivo model of ECMO to suggest that the intravascular administration of MSCs during ECMO may adversely impact the function of a membrane oxygenator. The addition of clinical grade MSCs resulted in a reduction of flow through the circuit in comparison to controls (0.6 ±0.35 L min -1 vs 4.12 ± 0.03 L min -1 , at 240 minutes) and an increase in the transoygenator pressure gradient (101±9 mmHg vs 21±4 mmHg, at 240 minutes). Subsequent immunohistochemistry analysis demonstrated quantities of MSCs highly adherent to membrane oxygenator fibres. This study highlights the potential harm associated with MSC therapy during ECMO and suggests further areas of research required to advance the translation of cell therapy in this population. </p

Combined Mesenchymal Stromal Cell Therapy and ECMO in ARDS:A Controlled Experimental Study in Sheep

Rationale: Mesenchymal stromal cell (MSC) therapy is a promising intervention for acute respiratory distress syndrome (ARDS), although trials to date have not investigated its use alongside extracorporeal membrane oxygenation (ECMO). Recent preclinical studies have suggested that combining these interventions may attenuate the efficacy of ECMO. Objectives: To determine the safety and efficacy of MSC therapy in a model of ARDS and ECMO. Methods: ARDS was induced in 14 sheep, after which they were established on venovenous ECMO. Subsequently, they received either endobronchial induced pluripotent stem cell-derived human MSCs (hMSCs) (n = 7) or cell-free carrier vehicle (vehicle control; n = 7). During ECMO, a low VT ventilation strategy was employed in addition to protocolized hemodynamic support. Animals were monitored and supported for 24 hours. Lung tissue, bronchoalveolar fluid, and plasma were analyzed, in addition to continuous respiratory and hemodynamic monitoring. Measurements and Main Results: The administration of hMSCs did not improve oxygenation (PaO2/FIO2 mean difference =2146mmHg; P= 0.076) or pulmonary function.However, histological evidence of lung injury(lung injuryscoremeandifference=20.07;P=0.04) and BALIL-8 were reduced. In addition, hMSC-treated animals had a significantly lower cumulative requirement for vasopressor. Despite endobronchial administration, animals treated with hMSCs had a significant elevation in transmembrane oxygenator pressure gradients. Thiswas accompanied by more pulmonary artery thromboses and adherent hMSCs found on explanted oxygenator fibers. Conclusions: Endobronchial hMSC therapy in an ovine model of ARDS and ECMO can impair membrane oxygenator function and does not improve oxygenation. These data do not recommend the safe use of hMSCs during venovenous ECMO. </p

The effects of nitric oxide on coagulation and inflammation in ex vivo models of extracorporeal membrane oxygenation and cardiopulmonary bypass

Background Extracorporeal life support (ECLS) has extensive applications in managing patients with acute cardiac and pulmonary failure. Two primary modalities of ECLS, cardiopulmonary bypass (CPB) and extracorporeal membrane oxygenation (ECMO), include several similarities in their composition, complications, and patient outcomes. Both CPB and ECMO pose a high risk of thrombus formation and platelet activation due to the large surface area of the devices and bleeding due to system anticoagulation. Therefore, novel methods of anticoagulation are needed to reduce the morbidity and mortality associated with extracorporeal support. Nitric oxide (NO) has potent antiplatelet properties and presents a promising alternative or addition to anticoagulation with heparin during extracorporeal support. Methods We developed two ex vivo models of CPB and ECMO to investigate NO effects on anticoagulation and inflammation in these systems. Results Sole addition of NO as an anticoagulant was not successful in preventing thrombus formation in the ex vivo setups, therefore a combination of low-level heparin with NO was used. Antiplatelet effects were observed in the ex vivo ECMO model when NO was delivered at 80 ppm. Platelet count was preserved after 480 min when NO was delivered at 30 ppm. Conclusion Combined delivery of NO and heparin did not improve haemocompatibility in either ex vivo model of CPB and ECMO. Anti-inflammatory effects of NO in ECMO systems have to be evaluated further

A clinically relevant sheep model of orthotopic heart transplantation 24 h after donor brainstem death

BACKGROUND: Heart transplantation (HTx) from brainstem dead (BSD) donors is the gold-standard therapy for severe/end-stage cardiac disease, but is limited by a global donor heart shortage. Consequently, innovative solutions to increase donor heart availability and utilisation are rapidly expanding. Clinically relevant preclinical models are essential for evaluating interventions for human translation, yet few exist that accurately mimic all key HTx components, incorporating injuries beginning in the donor, through to the recipient. To enable future assessment of novel perfusion technologies in our research program, we thus aimed to develop a clinically relevant sheep model of HTx following 24 h of donor BSD. METHODS: BSD donors (vs. sham neurological injury, 4/group) were hemodynamically supported and monitored for 24 h, followed by heart preservation with cold static storage. Bicaval orthotopic HTx was performed in matched recipients, who were weaned from cardiopulmonary bypass (CPB), and monitored for 6 h. Donor and recipient blood were assayed for inflammatory and cardiac injury markers, and cardiac function was assessed using echocardiography. Repeated measurements between the two different groups during the study observation period were assessed by mixed ANOVA for repeated measures. RESULTS: Brainstem death caused an immediate catecholaminergic hemodynamic response (mean arterial pressure, p = 0.09), systemic inflammation (IL-6 - p = 0.025, IL-8 - p = 0.002) and cardiac injury (cardiac troponin I, p = 0.048), requiring vasopressor support (vasopressor dependency index, VDI, p = 0.023), with normalisation of biomarkers and physiology over 24 h. All hearts were weaned from CPB and monitored for 6 h post-HTx, except one (sham) recipient that died 2 h post-HTx. Hemodynamic (VDI - p = 0.592, heart rate - p = 0.747) and metabolic (blood lactate, p = 0.546) parameters post-HTx were comparable between groups, despite the observed physiological perturbations that occurred during donor BSD. All p values denote interaction among groups and time in the ANOVA for repeated measures. CONCLUSIONS: We have successfully developed an ovine HTx model following 24 h of donor BSD. After 6 h of critical care management post-HTx, there were no differences between groups, despite evident hemodynamic perturbations, systemic inflammation, and cardiac injury observed during donor BSD. This preclinical model provides a platform for critical assessment of injury development pre- and post-HTx, and novel therapeutic evaluation. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40635-021-00425-4

Extracorporeal membrane oxygenation (ECMO) and the acute respiratory distress syndrome (ARDS): a systematic review of pre-clinical models

Extracorporeal membrane oxygenation (ECMO) is an increasingly accepted means of supporting those with severe acute respiratory distress syndrome (ARDS). Given the high mortality associated with ARDS, numerous animal models have been developed to support translational research. Where ARDS is combined with ECMO, models are less well characterized. Therefore, we conducted a systematic literature review of animal models combining features of experimental ARDS with ECMO to better understand this situation.MEDLINE and Embase were searched between January 1996 and December 2018.Inclusion criteria: animal models combining features of experimental ARDS with ECMO.clinical studies, abstracts, studies in which the model of ARDS and ECMO has been reported previously, and studies not employing veno-venous, veno-arterial, or central ECMO.Data were extracted to fully characterize models. Variables related to four key features: (1) study design, (2) animals and their peri-experimental care, (3) models of ARDS and mechanical ventilation, and (4) ECMO and its intra-experimental management.Seventeen models of ARDS and ECMO were identified. Twelve were published after 2009. All were performed in large animals, the majority (n = 10) in pigs. The median number of animals included in each study was 17 (12-24), with a median study duration of 8 h (5-24). Oleic acid infusion was the commonest means of inducing ARDS. Most models employed peripheral veno-venous ECMO (n = 12). The reporting of supportive measures and the practice of mechanical ventilation were highly variable. Descriptions of ECMO equipment and its management were more complete.A limited number of models combine the features of experimental ARDS with ECMO. Among those that do, there is significant heterogeneity in both design and reporting. There is a need to standardize the reporting of pre-clinical studies in this area and to develop best practice in their design

Mesenchymal stem cells may ameliorate inflammation in an ex vivo model of extracorporeal membrane oxygenation

Mesenchymal stem cells exhibit immunomodulatory properties which are currently being investigated as a novel treatment option for Acute Respiratory Distress Syndrome. However, the feasibility and efficacy of mesenchymal stem cell therapy in the setting of extracorporeal membrane oxygenation is poorly understood. This study aimed to characterise markers of innate immune activation in response to mesenchymal stem cells during an ex vivo simulation of extracorporeal membrane oxygenation.Ex vivo extracorporeal membrane oxygenation simulations (n = 10) were conducted using a commercial extracorporeal circuit with a CO-enhanced fresh gas supply and donor human whole blood. Heparinised circuits (n = 4) were injected with 40 × 10-induced pluripotent stem cell-derived human mesenchymal stem cells, while the remainder (n = 6) acted as controls. Simulations were maintained, under physiological conditions, for 240 minutes. Circuits were sampled at 15, 30, 60, 120 and 240 minutes and assessed for levels of interleukin-1β, interleukin-6, interleukin-8, interleukin-10, tumour necrosis factor-α, transforming growth factor-β1, myeloperoxidase and α-Defensin-1. In addition, haemoglobin, platelet and leukocyte counts were performed.There was a trend towards reduced levels of pro-inflammatory cytokines in mesenchymal stem cell-treated circuits and a significant increase in transforming growth factor-β1. Blood cells and markers of neutrophil activation were reduced in mesenchymal stem cell circuits during the length of the simulation. As previously reported, the addition of mesenchymal stem cells resulted in a reduction of flow and increased trans-oxygenator pressures in comparison to controls.The addition of mesenchymal stem cells during extracorporeal membrane oxygenation may cause an increase in transforming growth factor-β1. This is despite their ability to adhere to the membrane oxygenator. Further studies are required to confirm these findings

Extracorporeal membrane oxygenation (ECMO) and the acute respiratory distress syndrome (ARDS): a systematic review of pre-clinical models

Abstract Objectives Extracorporeal membrane oxygenation (ECMO) is an increasingly accepted means of supporting those with severe acute respiratory distress syndrome (ARDS). Given the high mortality associated with ARDS, numerous animal models have been developed to support translational research. Where ARDS is combined with ECMO, models are less well characterized. Therefore, we conducted a systematic literature review of animal models combining features of experimental ARDS with ECMO to better understand this situation. Data sources MEDLINE and Embase were searched between January 1996 and December 2018. Study selection Inclusion criteria: animal models combining features of experimental ARDS with ECMO. Exclusion criteria: clinical studies, abstracts, studies in which the model of ARDS and ECMO has been reported previously, and studies not employing veno-venous, veno-arterial, or central ECMO. Data extraction Data were extracted to fully characterize models. Variables related to four key features: (1) study design, (2) animals and their peri-experimental care, (3) models of ARDS and mechanical ventilation, and (4) ECMO and its intra-experimental management. Data synthesis Seventeen models of ARDS and ECMO were identified. Twelve were published after 2009. All were performed in large animals, the majority (n = 10) in pigs. The median number of animals included in each study was 17 (12–24), with a median study duration of 8 h (5–24). Oleic acid infusion was the commonest means of inducing ARDS. Most models employed peripheral veno-venous ECMO (n = 12). The reporting of supportive measures and the practice of mechanical ventilation were highly variable. Descriptions of ECMO equipment and its management were more complete. Conclusion A limited number of models combine the features of experimental ARDS with ECMO. Among those that do, there is significant heterogeneity in both design and reporting. There is a need to standardize the reporting of pre-clinical studies in this area and to develop best practice in their design