The population of children with advanced heart failure is growing. Because of improvements in both congenital heart surgery and perioperative care, complex congenital heart disease patients are surviving longer but frequently develop late heart failure requiring advanced therapies [1,2]. In addition, children with cardiomyopathies are receiving more aggressive medical management and surviving the initial phase of their illness. This leads to the need for more advanced care later in the course. These advanced heart failure patients may progress to symptomatic heart failure requiring cardiac transplantation. In some cases, heart failure progresses and acute mechanical support is required to bridge to transplant. The diverse nature of pediatric advanced heart disease makes the approach to pediatric mechanical circulatory support differ dramatically from adult care. In adult medicine, ventricular assist devices (VAD) are routinely used to support end-organ function and to improve quality of life while waiting for transplant or for destination therapy. In pediatrics, this approach is often desired but becomes much more difficult because of limited experience and the small number of devices suitable for children, both for short- and long-term support. Although more challenging to support, in the current era 15–20% of children awaiting organ availability receive a VAD as a bridge to transplant [3▪▪]. With small patient volume at each center, pediatric leaders have recognized the importance to develop an aggregate of experiences to deliver the ‘best care’ and improve the outcomes.
PEDIATRIC VAD REGISTRY-PediMACS (PEDIATRIC MECHANICALLY ASSISTED CIRCULATORY SUPPORT)
In 2012, NHLBI joined the academic community and the FDA to support the need for a pediatric-specific VAD database. Working in parallel with the adult VAD database, Interagency Registry for Mechanically Assisted Circulatory Support (InterMACS), Pediatric Mechanically Assisted Circulatory Support (PediMACS) was developed to serve as a comprehensive registry with global participation and pediatric-specific inclusion criteria, data elements and adverse event definitions. The goals of this registry are to delineate the best support strategies for unique populations, refine patient selection for VAD therapies, develop ‘best practices’ by analyzing outcomes and facilitate and guide the development and clinical evaluation of pediatric devices. The most recent quarterly report from PediMACS shows 251 devices from 216 unique patients, from 36 centers . The experience from the current era (2012–2014) reports that 85% of the VADS placed are being used as a bridge to transplant. Rarely, do children receive a VAD as rescue (2.5%) or destination therapy (7%). Results for the continuous flow devices revealed a 97% favorable outcome (57% transplanted and 40% alive on device) at 6-months postimplant although numbers are still small (n = 72) when compared with the adult experience . The adverse event rate remains high with the most common being bleeding, infection, neurological dysfunction and rehospitalization. These data have incited the development of many hypothesis-driven studies to define the at-risk population, as well as quality improvement initiatives to decrease the rates of adverse events.
The most critical, yet most difficult, decisions to be made by a pediatric transplant team are as follows: first, should a child undergo a surgical procedure to implant a VAD and second, when is the ‘right’ time to commit to a VAD. Among adults with homogenous diagnoses and similar body size, the improvement in clinical outcomes using continuous flow VADs has prompted earlier device placement . Although there has been a trend toward earlier use in children, the debate about when to initiate VAD support continues. There is significant practice variation within the field, and the timing of when to place a child on support remains as much an art as a science with much of the ‘optimal timing’ extrapolated from adult data [7,8].
In general, the use of mechanical support is indicated when medical therapy has failed. In adults, patients who are INTERMACS stages I and 2 have been shown to have worse outcomes post-VAD placement [4,7]. In pediatrics, similar results were shown in the Berlin Heart EXCOR trial, as patients with preimplant renal dysfunction or increased bilirubin had significantly worse outcomes  when compared with those who did not. Despite the data supporting earlier implantation, implantation in cases of cardiogenic shock remains common, if not the rule, in pediatrics. Data from EXCOR trial database showed 44% of patients were INTERMACS profile 1  and a slightly higher percentage (57%) in the compassionate use cohort . Furthermore, 27% of the patients from the EXCOR investigational device exemption study cohort  and 48% of the compassionate use cohort had undergone preimplant extracorporeal membrane oxygenation (ECMO) . In addition to the Berlin data, the PediMacs experience revealed that 84% of pediatric patients were INTERMACS profile 1 or 2 at the time of implantation. Increasing center experience may fundamentally alter the clinical choices and outcomes as a mechanical support team matures . Currently, most institutions with VAD availability begin evaluating transplant-eligible patients who are inotrope dependent and have evidence of end-organ dysfunction.
Devices available as bridge to transplant are divided into short-term and long-term support options (Table 1). Short-term devices are defined as those that will be used for approximately 2 weeks and usually are not a bridge-to-transplant but are used as bridge to the next step. The long-term VADs are more durable and designed to support patients as a bridge-to-transplant. Although the Berlin EXCOR (Berlin, Germany) is considered a long-term, durable device, it is not yet feasible for outpatient use.
Patients may present with cardiogenic shock needing rapid deployment of mechanical support. In pediatrics, acute myocardial infarction is an uncommon etiology but diagnoses including myocarditis, dilated cardiomyopathy and postcardiotomy dysfunction are seen more frequently. Historically, ECMO was used to support these patients . Although the use of cardiac ECMO has increased since the mid-1990s, the development of short-term continuous flow, temporary VADs has provided an alternate method to support patients with acute decompensated heart failure [12▪,13▪,14]. It should be noted that the potential beneficial effects of the new temporary VADs are theoretical and an improvement in clinical outcomes has not yet been demonstrated. The brand of temporary continuous flow device favored is variable among institutions, most commonly the Rotaflow (Maquet) or PediMag/CentriMag (Thoratec) are used. In addition, pediatric centers are using percutaneous placed, axial flow devices, such as the Impella (Abiomed) in adolescents, but the size requirements of these devices have limited their use in children to date 
Short-term continuous flow VADs may be used to provide temporary support in the setting of potentially reversible cardiac dysfunction (i.e., myocarditis) or to allow time to assess end-organ function or potentially reverse acute end-organ dysfunction prior to placement of long-term support. On occasion, a short-term support strategy is sufficient to withstand the time needed to wait for an adequate organ.
Although recent years have seen a significant increase in the implantation of durable VADs in children, patient size continues to be an important factor in choosing a long-term device. The device options are fairly standard at the upper (second or third-generation continuous flow device) and lower ends (Berlin EXCOR) of the size spectrum, whereas school-age children are perhaps the greatest conundrum.
For infants and small children, the sole device option is the first generation, pulsatile Berlin EXCOR VAD (Berlin Heart). Results from the EXCOR investigational device exemption study form the basis of the largest pediatric VAD experience to date . These studies have identified risk factors for adverse outcomes while on the device (patient size <5 kg, end-organ dysfunction and biventricular support) [10,16,17▪] and following transplant . Although congenital heart disease was not a predictor of adverse outcome on multivariate analysis, patients with single-ventricle circulation remain a challenge [19▪]. Outcomes following the support of first-stage palliation (Norwood) remain particularly poor with nearly 100% mortality [19▪].
Continuous-flow devices have become the dominant VAD technology in adults . It is also true that continuous-flow devices make up the vast majority of devices used in adolescents, as early evidence suggests the outcomes in adolescents implanted with the HeartMate II (Thoratec) are equivalent to those of adults [21,22]. In addition, the initial data from the PediMACS registry [23▪] reveal favorable results in 97% (70 of 72 patients were alive or transplanted at 6 months) of patients at 1-year postimplant of a continuous-flow device . In 2012, the third-generation HVAD (HeartWare) was approved for adults greater than 1.5 m2 as a bridge-to-transplant. It is clear from the literature that multiple groups are utilizing these devices, off label, in smaller and smaller children [23▪,24,25]. It remains to be seen if pump to patient size mismatch alters the risk–benefit profile of these devices in small children.
In the majority of pediatric cases, VADs are implanted as a bridge to transplantation. As VADs have become more common in pediatrics there has been a 50% decrease in waitlist mortality despite an increase in waitlist time in the current era [3▪▪]. Not only has waitlist mortality decreased but in many cases the VAD patient is stabilized and rehabilitated, making the posttransplant period easier. Unfortunately, device support in pediatrics is associated with a high adverse event rate including a 29% risk of stroke while being supported [16,26▪]. In addition, VAD use is associated with an increased risk of sensitization in both children and adults supported with VADs. Adult sensitization rates of patients supported with a VAD have been reported to be as high as 60% on modern devices . Pediatric patients supported on a pulsatile device, the Berlin EXCOR, also were highly sensitized with 69% developing HLA antibodies after VAD placement . In some situations, the sensitization profile associated with VADs has resulted in a more cautious approach to implantation as increased panel reactive antibody has been demonstrated to be an important risk factor for both waitlist and posttransplant mortality . Currently, there are conflicting data regarding the influence of VAD-associated antibody production and posttransplant outcomes in children. Knowledge of the impact of VAD associated sensitization is important because avoidance of antigens diminishes the potential donor pool and may lead to higher risk of morbidity and mortality while waiting.
POSTTRANSPLANT OUTCOMES OF CHILDREN SUPPORTED WITH VENTRICULAR ASSIST DEVICE
The first multi-institutional study to evaluate outcomes of VAD support in pediatric patients revealed that 77% of children bridged to transplant survived . The risk factors for mortality in the VAD cohort in this study included earlier era and congenital heart disease. This study also revealed that there was no difference in 5-year survival after transplantation for patients on VAD at the time of transplant as compared with those not requiring VAD . In addition, Davie et al. evaluated posttransplant outcomes after VAD support in children using the UNOS database. Of the patients supported with an EXCOR, 11.3% died in the first year posttransplant period, not significantly different than the survival at 1-year posttransplant in the overall UNOS cohort . Interestingly, survival posttransplant was much improved in VAD patients when compared with patients supported on ECMO. The mortality of the ECMO cohort after transplant was 39.7% within 1 year. In addition, these data did detect a late decrement in survival among VAD patients approximately 5 years after transplantation . At this time, the factors contributing to this late decrement are undefined and may be multifactorial and will need to be evaluated with further prospective studies.
MECHANICAL SUPPORT IN CONGENITAL HEART DISEASE
Although most pediatric cardiac patients have congenital heart disease, only 20% all children undergoing VAD implantation have structural disease . Children with congenital heart disease who require VAD support are much more difficult to support and have a higher rate of mortality when compared with children with cardiomyopathy . In multiple studies, congenital heart disease appears to be a risk factor, with single-ventricle population at greatest risk [19▪]. An ideal support strategy has not yet been defined for the single-ventricle population; however, substantial effort has been made to establish a multiinstitutional data set to improve the outcomes of failing single ventricles . Mechanical support has been reported after all stages of single-ventricle palliation (systemic to pulmonary shunt, superior cavopulmonary anastomosis or Fontan completion). Mortality was very high (42%) among functional single ventricles in the EXCOR trial, although the risk was not uniform across all stages of palliation [19▪]. One of the nine patients who received an implant following their stage I palliation survived, whereas 58–60% of patients supported following stage II or III palliation survived. In circumstances in which a patient has significant diastolic dysfunction or residual structural lesions a SynCardia total artificial heart (SynCardia) may be the most viable option for support  and has been successful in the case of a teenage failing the Fontan procedure .
Unlike adult medicine, the number of children supported with a VAD is small, and children are almost exclusively supported as a bridge to transplant. Our current pediatric literature has shown a decrease in waitlist mortality, a favorable posttransplant outcome and a high number of VAD-associated adverse events. These results will continue to drive the pediatric VAD field to share experiences to define ‘best practices’ and determine innovative support strategies for children with complex congenital heart disease. Although there may be an increase in the number of children supported, the diversity of sizes and diagnoses, as well as the small number of patients, will continue to hinder randomized controlled trials from being performed. Therefore, in addition to pediatric efforts, we will continue to develop new study designs, analyze postmarket approval study data and look to the adult experience as we move forward.
Financial support and sponsorship
This work was supported by The Heart Institute at Cincinnati Children's Hospital and The Heart Center at Boston Children's Hospital.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
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