Extracorporeal life support is used to support patients of all ages with refractory cardiac and/or respiratory failure. Extracorporeal membrane oxygenation (ECMO) has been used to rescue patients whose predicted mortality would have otherwise been high. It is associated with acute central nervous system (CNS) complications and with long- term neurologic morbidity. Many patients treated with ECMO have acute neurologic complications, including seizures, hemorrhage, infarction, and brain death. Various pre-ECMO and ECMO factors have been found to be associated with neurologic injury, including acidosis, renal failure, cardiopulmonary resuscitation, and modality of ECMO used. The risk of neurologic complication appears to vary by age of the patient, with neonates appearing to have the highest risk of acute central nervous system complications. Acute CNS injuries are associated with increased risk of death in a patient who has received ECMO support. ECMO is increasingly used during cardiopulmonary resuscitation when return of spontaneous circulation is not achieved rapidly and outcomes may be good in select populations. Economic analyses have shown that neonatal and adult respiratory ECMO are cost effective. There have been several intriguing reports of active physical rehabilitation of patients during ECMO support that is well tolerated and may improve recovery. Although there is evidence that some patients supported with ECMO appear to have very good outcomes, there is limited understanding of the long-term impact of ECMO on quality of life and long-term cognitive and physical functioning for many groups, especially the cardiac and pediatric populations. This deserves further study.

Extracorporeal life support (ECLS) is used to provide pulmonary, cardiac, or cardiopulmonary support in neonate, pediatric, and adult patients refractory to conventional management. Deployment of ELCS may be planned, urgent/emergent, or associated with cardiopulmonary resuscitation (ECPR). Various cannulation strategies exist with the dominant differentiating factor being veno-venous (VV) vs veno-arterial (VA) circuits. Survival has improved since extracorporeal membrane oxygenation (ECMO) was first utilized in the 1970s and indications and populations supported have expanded as techniques and strategies of deployment have evolved.

Patients supported by ECLS are at risk of neurologic injury from pre-ECLS factors including hypoxia, acidosis, hypotension and low cardiac output, infection, and organ failure, and from ECLS factors including hemorrhage, infarction, seizures, disrupted cerebral circulation, and development of new organ failure. Functional outcome after critical care, including ECLS support, is difficult to assess on a systematic basis, as follow up studies are limited and not standardized. Although children and adults are treated with ECMO, nearly 50% of treated patients are neonates[1] and assessing their long-term outcomes requires both time and an appropriate comparison population to account for severity of illness and social factors[2,3]. Neurodevelopmental and longitudinal outcomes after ECLS are most important to assess but are largely limited to neonatal and limited adult studies. More information is available on the incidence and risk factors for acute neurologic complications associated with ECLS.

The Extracorporeal Life Support Organization (ELSO) collects utilization, mortality, and complication data from 200 centers internationally on all technologies used to support cardiopulmonary function. Acute neurologic complications (seizures, infarction, hemorrhage, and brain death) are reported but functional outcome or disability is not. Administrative databases such as the Pediatric Health Information System or the Kids Inpatient Database also collect complication diagnoses but do not collect functional outcome specifically. Most reports of functional outcome after ECMO support are from single centers or multiple centers over a small time period[4-9].

Neurologic injury associated with ECLS ranges from subtle neurocognitive defects to devastating intracranial hemorrhage to brain death. Injury may be sustained prior to ECLS support, during ECLS support, or after ECLS support has been discontinued. Neurologic complications reported to ELSO include hemorrhage and infarction documented by ultrasound and or computed tomography, clinical seizures, EEG documented seizures, and brain death (Table 1). The incidence of complications may be underreported due to the difficulty of obtaining reliable imaging in critically ill patients during extracorporeal support, and many patients who sustain neurologic injury likely have increased risk of death and may die without imaging[10-12].

Hemorrhage is generally poorly tolerated due to the anti-coagulation that is needed during ECLS support. Most common hemorrhagic injuries include intraventricular, intracerebral, and subdural hemorrhages. Risk factors for intraventricular hemorrhage have been most clearly demonstrated in neonatal patients[13]. Intra-cerebral hemorrhages are thought to be at significant risk of extension due to anti-coagulation but there is little published information on the natural history of intracranial pathology during ECMO[14].

Infarctions may be small and related to micro emboli of clot or air, or may be large and related to large embolic clots. The incidence of image documented infarction is roughly similar to that of hemorrhage. Clinical seizures occur in 5%-10% of neonatal and pediatric patients, and 1%-2% of adult patients[1]. The difference between the adult and pediatric incidence of seizures may be related to trends in VV versus VA cannulation techniques[12] or may be due to relative sparing of cerebral vessels given that adults are more likely to be cannulated through femoral vessels or may be due to increase likelihood of infants to seizures due to developmental vulnerability[15].

Hypoxic ischemic damage due to poor cardiac output or acidosis prior to, during, or after mechanical support is difficult to quantify and makes outcome studies difficult to interpret in the absence of appropriate control groups.

ECMO was developed in the 1970’s and although the first reported case was an adult, the first series of neonates[16,17] reported success whereas the first series of adults reported dismal survival (9%)[18]. It became clear that ECMO was efficacious for patients with reversible disease and that prematurity or other risk factors for bleeding posed a significant risk. The importance of early recognition of intraventricular hemorrhage in neonates became evident. It appears that after the first week of life premature infants have reduced risk of intracranial hemorrhage[19].

Neonatal respiratory ECMO volume peaked in the early 1990s and has remained relatively stable since the early 2000’s. Overall survival has diminished likely reflecting advances in standard therapies and application of ECMO to more diverse and ill patients. Neonates with congenital diaphragmatic hernia continue to be a high-risk group with high mortality among respiratory patients. The majority of neonatal respiratory ECMO support is VA. Pediatric respiratory ECMO has increased substantially in the past 3 decades with a peak in 2009 coincident with the H1N1 influenza pandemic. About half of pediatric respiratory ECMO support is VA but there is increasing utilization of VV support modes. Adult ECMO was rarely performed until late in the 2000s and has also increased substantially in 2009, with further increases since. The significant majority of adult ECMO support is VV.

ECMO support for cardiac indications in all age groups has increased steadily since the early 1990s[1]. ECPR was first described in 1992[20] and its application has expanded substantially in the past several years though indications remain controversial.

Increasingly quality of life and functional and school related outcomes are appreciated as important indicators of the efficacy of critical care. Several reports have described relatively subtle cognitive, physical, and school related problems in survivors of pediatric critical care. A recent report showed that pediatric survivors or critical illness had verbal, spatial, and memory problems, attention and problem solving difficulty, and school performance following paediatric intensive care unit (PICU) admission[54]. A different study evaluated health care related quality of life and adaptive behavior functioning and found it to be significantly reduced in survivors of urgent PICU admission[55]. In this study prolonged ECMO support was one factor associated with reduced quality of life.

Looking at the issue of quality of life differently, a study that looked at patients with prolonged ICU stays (> 28 d) found that the majority of children (57%) had a normal quality of life, with 22.9% having impaired quality of life and 20% having poor quality of life[56]. In a single institution cohort of cardiac ECMO survivors physical health related quality of life was lower than that of the general population but similar to those with complex congenital heart disease. Psychosocial quality of life as reported by parents and by older surviving patients was similar to that of the general population[8].

There have been relatively few analyses of the cost-effectiveness of ECMO but there have been some positive reports. The United Kingdom Collaborative ECMO Trial was a randomized, controlled trial of neonatal respiratory ECMO. Over 7-year follow-up of enrolled subjects they found an incremental cost per disability-free life year gained to be below the nationally acceptable threshold[24]. Similarly the CESAR trial found referral to an ECMO center to be cost effective when evaluated in terms of quality of life year expense[36]. In a single institution evaluation of ECPR for patients with congenital heart disease, ECMO was found to be within acceptable cost efficacy[57].

Along with evolving indications for ECMO, the support and monitoring technology has changed dramatically over the past 30 years. Most recently newer dual lumen VV cannulas for respiratory support have been introduced and centrifugal pumps are increasingly being used to support pediatric patients. There have been advances in anticoagulation strategies as well as the development of more biocompatible circuits and oxygenators. Near infrared spectroscopy monitoring is increasingly being used during ECMO support. With the exception of a VV cannulation strategy none of these technologies has yet been shown to improve neurologic outcome[34].

An intriguing development in the care of the ECMO patient is the concept of active rehabilitation during ECMO support. Critical illness of any sort leads to deconditioning due to immobility and this is especially problematic with highly invasive support technologies. If patients can be exercised and kept mobile during mechanical support they may be more able to progress quickly once liberated from invasive support. There have been several small series of patients who received active physical or occupational therapy, advancing to ambulation, while undergoing ECMO support[58-60]. Thus far this strategy has been limited to older patients supported for respiratory indications, almost exclusively with single dual lumen catheters.

Neurologic outcomes after ECMO support vary by patient age, type of support, indications for support, and underlying diagnosis. There are not widely accepted standards for initiation of ECMO outside of the neonatal respiratory population so severity of illness and underlying conditions among patients supported by ECMO may vary widely between institutions. Acute severe neurologic complications are more prevalent in neonates and children than adults. The long-term impact of ECMO support on development, school performance, and quality of life is poorly defined and needs further study. Where it has been evaluated, ECMO appears to be cost effective.