Good morning. First I would like to thank the SCCM and SPENIC for giving me the opportunity to talk about ECMO. Candidacy in patients with liver disease is stretching too far. I have no disclosure or any conflicts of interest except the fact that I think that transplant medicine is extremely fascinating. At the end of my talk, I hope that you will have a better understanding on which patients with liver disease are candidates for ECMO and how this can be done safely. We'll start with a little bit of mythology. After Prometheus gave fire to humans, Zeus bonded him to a rock where an eagle would come every day and eat a piece of his liver. However, that liver will regenerate overnight, causing the eternal torment. While the liver can regenerate and advances in science allowed for temporary support for different organs such as dialysis for kidneys or ECMO for cardiovascular and pulmonary function, currently there is no system or substitute for the immune metabolic and sustaining function of the liver other than transplantation. We care about patients with end-stage liver disease because only in the United States, each year 600 children are added to the waiting list for liver transplantations. More than half would wait for an offer for more than one year, with 1 in 20 children dying while waiting for an organ. They are critical year requiring a recurrent admission to the intensive care units while receiving life-saving treatments and therapies such as mechanical ventilation, blood pressure monitoring, and medications plus dialysis. We all have taken care of those patients, and we know that they are in multi-organ failure. And to me, it's very relevant that we have those kids with big bellies that look like a peach, but they are a ticking bomb, as we can call. Pre-transplant, there is profound vasodilatation that leads to high cardiac output as well as distributive shock physiology. Hypoxia and fluid load will cause respiratory failure. During transplant, patient will experience massive fluid shifts and bleeding. There is increased risk for air emboli during dissection while patients are at high risk for cardiac arrest and reperfusion. Most operatively, we must focus on making sure that hemodynamics and oxygenation are appropriate to assure great function of the graft. If those complications are caused by reversible causes, all are potential ECMO indication per ELSO guideline. The question is who is an ECMO candidate when, according to the same guidelines, acute liver failure along with trauma and immune disorders, diseases are relative contraindication for ECMO. I mentioned in trauma and immune disorders, I both put the patient at risk for bleeding and sepsis, similar with patients receiving liver transplantation. Over the years, with improvement in technology and patient care, we were able to achieve similar outcomes for this patient population as we achieve for pediatric ECMO. A little bit of history, I think it's worth mentioning as well because it's relevant to the topic. In green, I have ECMO history and brown, it's transplantation. In 1950, the first heart-lung machine and membrane oxygenator were developed, followed by first successful ECMO in a neonate with respiratory failure in 1972. The first human liver transplantation was performed in 1967 by Stasel, the father of liver transplantation. Unfortunately, that baby died secondary to major bleeding during surgery. Major achievements in transplantation occurred in 1976 when cyclosporine was developed and we were able to prevent ejection. In 84, Dr. Stasel performed the first liver transplantation when ECMO was used successfully to save the patient. Since, more ECMO and liver transplantation were performed with improved outcomes. In the United States, 600 patients received liver transplantation in 2021, according with the transplant registry. We have about 10 to 15% of those have liver failure. Unfortunately, there is still 2.4 patients dying on the waiting list are too sick to be transplanted. According with literature, the survival rate for children receiving liver transplantation needing ECMO support is between 56 and 68%. But also live dashboard, each year, 3,000 to 4,000 cardiac ECMO cases are performed with a 55 survival rate. It is not a surprise that there is limited scientific evidence for use of ECMO in liver transplantation. PubMed search gives approximately 50 manuscripts on ECMO for liver transplantation with majority being case reports, case series, and systematic reviews. There are some papers that I thought are most relevant to our talk here. In summary, the number of patients per study vary with up to 34 patients for the larger study. As expected, VBA ECMO was used for hepatopulmonary syndrome and RDS, while VA ECMO was used for cardiac indications. Early ECMO initiation led to better outcomes with a survival to discharge rate approximately of 60%. Each day between liver transplantation and ECMO initiation, there were 3.5 days added to the ECMO run. Sepsis, multi-organ failure, as well as bleeding were major cause for death in this patient population. Most patients experienced at least one complication during ECMO run, and it is common to have more than two complications per run. Bleeding is the most common, while anticoagulation practice varied from no anticoagulation to full anticoagulation. In addition to bleeding, related to anticoagulation, patients are at risk for ischemic stroke and hypoxia. Channel replacement is very important, especially in VBA ECMO, when it can migrate and can cause hepatic infraction. As patients are on immunosuppression, there is increased risk for infection in sepsis. Now let's compare if complications for liver transplantation and ECMO are different from complications on ECMO or CAMRS. First, we are going to look at coagulopathy. Again, brown refers to liver transplantation, green to ECMO. In the pre-transplant phase, a balanced coagulopathy helps preventing spontaneous bleeding, as both clotting and fibrinolysis factors are impaired equally. Immediately post-transplantation, all coagulation and fibrinolysis factors are deficient. And thrombosis is more likely related to surgical variants or techniques, anastomosis-size presence of graft for the vasculature. Both post-surgical bleeding and thrombosis incidence are under 10%. How do I go back? Acute liver failure and ECMO coagulopathy are similar in the fact that both have impairment in clotting, as well as fibrinolysis, but the mechanism is different, leading to more bleeding and thrombosis on ECMO. According with VAT and all, bleeding occurs in 70% of ECMO cases, while thrombosis is up to 37.5% in that patient population. Neurodevelopment and liver failure in transplant area are of interest, as well as both patient population are at risk for developing cognitive motor and language impairments, according with multiple studies. Same for ECMO development, the patient develops an array of neurologic complications, up to 34% having acute neurologic impairment or discharge that improves over time. Lastly, in terms of immunosuppression, over time, we were able to achieve similar survive in patients with lung transplantation, heart transplantation, as well as immune-mediated disorder-resilient ECMO. Also it's worth mentioning that tycholimus pharmacokinetics parameters are not altered, but ECMO, which is really important as rejection is very scary and we do not want that to happen. There are three ways to deploy ECMO in liver transplantation. We can do elective ECMO, ECMO as bridge for transplantation, as well as emergent ECMO for acute organ failure. Now I would like to take a few minutes to present some data from Stanford and how we use ECMO in this patient population. First case, we use ECMO as a preventative measure in a six-month-old baby with biliary atresia, FECASI, with severe pulmonary, hepatopulmonary syndrome. She was calibrated for VBA ECMO during induction as she developed severe hypoxia. Prior to all liver transplantation, we have a multidisciplinary huddle to discuss the case, and for this patient, it was decided to preventively initiate ECMO if hypoxia occurs. She was maintained on ECMO for four days, extubated shortly after, and she is alive, having some global development delay, especially fine motor that is improving. We use VA ECMO as bridge for transplantation in a four-month-old with unknown acute liver failure that developed grafnum function after his transplant. He was transplanted with a split liver 33 hours after ECMO convalescent and 60 hours after his first transplant. His ECMO run during transplantation was relatively smooth and required only a circuit change, giving his massive blood transfusion. He received approximately three times his blood volume. This was possible as all the details and scenarios were discussed during the preoperative huddle. He is alive, having great function, and only mild receptive language disorder. We had three patients for which we used emergent ECMO for acute organ failure with mixed results. First patient was convalescent for hypoxic cardiac arrest. His run was 25 days, and it was the longest for us. And he had major complications that require daily procedure at the bedside, including portal vein thrombectomy, bilateral thoracotomies, wound changes, bronchoscopy. He also was discharged home three months after his transplant with intact neurologic exam, and he has normal graft function six years out. Second patient was transplanted with a very critical state, secondary to severe sepsis, and continued to be very unstable after his surgery. He was on EVA ECMO for 20 days, and unfortunately, during his ECMO run, he had an air emergency that led to hypoxia and progressive severe neurologic injury. He is alive and had normal graft function eight years after his transplant. The last patient was placed on ECMO for multi-organ failure, secondary to acute pancreatitis and sepsis that developed after his second transplant. Unfortunately, he did not survive, and care was withdrawn by family. In addition, we had three ECMO runs for cardiac indication for combined liver, heart-liver transplants. The survival rate for Stanford for isolated liver transplant is about 70%, and early and anticipated ECMO was the way to go and led to shorter runs and less complications. So for the last part of the talk, I will focus on how can we improve outcomes for ECMO used for pediatric patients with end-stage liver disease. Both from experience and available literature, I believe that anticipation is the most important factor. Adequate case selection and preparation for ECMO initiation is the first step in promoting good outcomes. We need clear standards for initiation and management. To do so, we need to have deep understanding of ECMO and transplant physiology. While on ECMO, appropriate neurologic monitoring and bleeding assessments are extremely important, those are major complications. One should consider no anticoagulation if there is risk for bleeding. An important aspect of PQ is to assure rehabilitation with PT or T, initiate early and perform daily, having counseling, nutrition, and, of course, PQ up for all those patients. QI work is part of both transplant and ECMO programs and are required for accreditation. Each program should have well-designed and implemented projects that will focus on preoperative care of the liver transplant patients. Development of transplant ICU will create an environment that will promote advancing the care of this fragile patient population by developing more protocols, promoting education, and specialized pediatric nursing care with streamlined patient care. I cannot stress enough how important open and direct communication with all services is here. In conclusion, ECMO can save lives, and it can be done safely. It should be done case by case and initiated for reversible causes of hypoxia and cardiac failure. Early ECMO, preventive ECMO to achieve better outcomes is desired, and each program should have standard protocols for initiation and management that will focus on preventing complication. Hospitals must have all systems and structure to support ECMO deployment in difficult cases. We need to share our knowledge, and we should not forgive that the fact that we can do it, but unnecessary mandatory should not do it. And I would like to thank and also acknowledge all my teams that I couldn't do the work without. Thank you.

ECMO

liver transplant

pediatric patients

multidisciplinary communication

neurodevelopmental impacts