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Pediatric Mechanical Circulatory Support

Mechanical circulatory support (MCS) in the pediatric heart failure population has a limited history especially for infants, and neonates. It has been increasingly recognized that there is a rapidly expanding population of children diagnosed and living with heart failure. This expanding population has resulted in increasing numbers of children with medically resistant end-stage heart failure. The traditional therapy for these children has been heart transplantation. However, children with heart failure unlike adults do not have symptoms until they present with end-stage heart failure and therefore, cannot safely wait for transplantation. Many of these children were bridged to heart transplantation utilizing extracorporeal membranous oxygenation as a bridge to transplant which has yielded poor results. As such, industry, clinicians, and the government have refocused interest in developing increasing numbers of MCS options for children living with heart failure as a bridge to transplantation and as a chronic therapy. In this review, we discuss MCS options for short and long-term support that are currently available for infants and children with end-stage heart failure.


INTRODUCTION
Additionally, there has been a reported increase of greater than 30% in pediatric hospitalizations for heart failure over a 3 year period [1]. Improved recognition of children living with cardiomyopathy, and improved surgical outcomes for children with congenital heart disease (CHD) is credited as contributors. The traditional therapy for children with end stage heart failure has been heart transplantation. Heart transplantation is a significantly limited resource given the limited donor population, and is also associated with potential morbidity. The outcomes utilizing extracorporeal membranous oxygenation (ECMO) as a BTT with prolonged wait times have yielded poor results [2]. As such, industry and science  Aorto-pulmonary shunts, both surgically created (i.e., Blalock Taussig shunt) and pathological (i.e., aorto-pulmonary collateral arteries) can be challenging as one must supply greater than normal cardiac output. It is with these complexities in mind that MCS results in children with CHD must be interpreted. In children with single ventricles VAD support has been more successful at the Glenn stage than any other of the two stages. A trial of adequacy of the Glenn shunt for oxygenation can be attempted with placement of a systemic VAD (SVAD) using a temporary centrifugal pump (common atrium and aortic cannulation). If the patient is well supported in this fashion then one can return to place a more long-term device (i.e., Berlin Heart EXCOR). The failing Fontan patients are a sub-group of the single ventricle patients who often present for MCS. Past results of VAD support in the failing Fontan population have been inconsistent.
It is only in those who show features of isolated systemic ventricular failure (i.e., high end diastolic pressures ＞15 mmHg) in which SVAD therapy is effective [3]. Should Fontan failure be due to other hemodynamic complications, the patient is not a candidate for Fontan conversion and the patient has a body surface area (BSA) of ＞1.7 m 2 , then total artificial heart (TAH) is an option. TAH has also been used in complex CHD patients and may represent a preferable option in settings where there is poly-valvular disease and or multiple residual abnormalities. Technical considerations due to anatomical constraints should be considered  in the placement of TAH in patients with complex anatomy (i.e., CCTGA and Fontan variations) [4]. Devices may be categorized into their expected length of support as short-term or long-term MCS. Fig. 1 illustrates the device selection protocol in authors' current practice. Table 1 describes commonly used VADs for children in North America. There are several additional devices that are currently in development as part of a multi-institutional NHLBI funded trial, the PumpKIN trial, which are not yet available for clinical use.

CONTRAINDICATIONS TO MCS
There are currently three investigational devices funded by the PumpKIN trial. Two of which are ECMO systems. The first is the pCAS or Ension, a pump and oxygenator controlled by a touch screen console being developed as a small  ECMO is only considered if the patient needs cardiac and pulmonary support. It is well documented that prolonged ECMO support is fraught with significant morbidity and mortality. As such, ECMO support is a bridge to other forms of MCS upon recovery of pulmonary function or weaned off in the setting of cardiopulmonary recovery. Should pulmonary function remain intact, then VAD therapy is preferred and is determined based on anticipated length of support. This can be in the form of short-term VAD (＜2 weeks) or long-term VAD (＞2 weeks). Should anticipated 'recovery' be longer than 2 weeks then transition from short-term to long-term VAD is recommended.
DT is the term used to describe long-term support of patients who are deemed not to be candidates for heart transplantation and whose cardiac function is also not felt to be amenable to recovery. DT has been successful in pediatric in-  with ECMO showed a higher mortality than those who had VAD support irrespective of diagnosis [7]. Additional studies utilizing a national database where ECMO was used even after being transitioned to a VAD was associated with a significantly worse survival (40%) compared to the use of VAD only (84%) [8]. Similar results are seen in a study of MCS in children with myocarditis [9]. Also, the use of ECMO as a bridge to 'salvage VAD,' a VAD after a failed congenital palliation, has consistently been shown to yield very disappointing survival results of approximately 27% [8]. Thus ECMO use in patients with isolated heart failure should be avoided.    The Berlin Heart EXCOR is powered by a pneumatic IKUS driver unit currently. However, the new EXCOR Active driver unit, which is currently being tested, will allow for discharge of patients to home (Fig. 3A).
Although it has been widely used in Europe for decades, it has only been consistently used by major centers since 2004 and now its use has spread to even more centers after its ap-     [11,12] (Fig. 3D).

3) Implantable devices
Median sternotomy incision is used to gain exposure for almost all the devices except in the rare occasion when a temporary device is required in a patient where mediastinal access is to be avoided as in these rare patients an LVAD can be placed via a thoracotomy. It is important to choose your aortic cannulation site prior to CPB so one can appreciate the right shoulder of the heart when it is full, this is especially true of the EXCOR whose cannula is non-compliant.
Once this has been chosen, cannulation of the aorta should be determined keeping in mind with the smaller children one always has the option of sewing a graft into the innominate artery at time of implant or heart transplantation. We do not arrest the heart but to close a patent foramen of ovale and even then will restart it as quickly as possible to avoid arrest time which can have deleterious effects on the RV. One should re-member that CPB is usually a time when these children are experiencing the best cardiac output they have seen in months to years and one should also take advantage to do aggressive ultrafiltration while on CPB. The latter has clearly been shown to improve right heart function. Also, the left heart in children is almost always full even when on CPB with the right side completely emptied so we also place a left heart vent via the left atrial appendage which also allows you to control level of blood when you have opened the left ventricular. We will not describe the implantation techniques of each device we use but in general we do an apical cannulation except for temporary VADs and use 12 plegetted sutures and Tisseel once tied down. The aortic cannula if a graft is placed in standard fashion and for the EXCOR cannula we use purse strings and an inkwell technique.

Regardless of technique one must avoid bleeding and with
proper timing and meticulous technique post-operative bleeding and transfusion can be avoided. We do the majority of our VADs with no use of post-operative blood products. We wean all patients off CPB on iNO, epinephrine, and milrinone. It is important as you wean off CPB that you do not allow the right ventricle to descend so I rapidly increase LVAD support as I come off CPB.

4) POSTOPERATIVE CARE
Successful post-operative care relies on a multi-disciplinary approach with other subspecialties (i.e., hematology, infectious disease, nephrology, psychiatry, family support).

OUTCOMES
Little is known with regards to the long-term outcomes of pediatric MCS patients. In the first multi-institutional prospective trial of a pediatric VAD (Berlin Heart EXCOR) reported by Fraser et al. [13]., 92% had a favorable outcome (transplant, recovery or alive on device) at around 6 months for both cohorts (＜0.7 m 2 and 0.7 to 1.5 m 2 ). This was sig-nificantly better than matched ECMO groups. In this study, side effects including bleeding, infection, and stroke remained concerns. In these cohorts bleeding was noted in 42% and 50%, infection in 63% and 50%, and stroke in 29% and 29%. This was not dissimilar to other reported studies in which adolescent children were managed on adult MCS devices [14,15]. In several reported adult studies these complications although less frequent, remain significant concerns [16,17]. It must be noted that the study reported by Fraser  age ＜1 year, weight ＜5 kg, severe renal dysfunction and higher bilirubin levels [18].
Pediatric MCS use, development, and experience is growing rapidly. Only a single device is currently FDA approved for infants, and young children but several devices are approved for adolescents and young adults. In adult studies, continuous-flow LVAD support (e.g., HeartMate II LVAD) has been associated with improvements in quality of life, functional capacity, and survival [19]. In pediatrics these devices may provide similar benefits, and also provide both temporary support for those with acute reversible myocardial injury and the potential for chronic support for those with continued irreversible myocardial insults. MCS use in acute fulminant myocarditis has been shown to provide acute hemodynamic support while allowing for myocardial inflammation to subside with promising results [9,20,21].
Similarly MCS has been used in pediatric heart transplant patients with acute graft rejection to allow for hemodynamic support while immunosuppressant modifications take effect,

Ivan Wilmot, et al
− 400 − and also as a bridge to retransplant [22]. Additionally, novel use of MCS in patients with chronic myocardial insults such as seen in Duchene Muscular Dystrophy have been reported.
Recent reports measuring quality of life (QOL) in this population, may allow for future quantitative improvement in their QOL through the use of MCS therapy [23]. MCS has been used successfully in both acute myocardial injury such as myocarditis, and also in chronic injury with reverse remodeling [24][25][26]. Our current protocol for device selection ( Fig. 1) relies on early identification of patients with medically refractory heart failure, short-term support for those felt to have an acute reversible injury with the transition to long-term support beyond 2 weeks, and initial long-term support for those with a chronic myocardial injury allowing for both BTT and DT. Early identification of medically refractory heart failure and initiation of MCS improves survival [27].
Early recognition and initiation of MCS should limit the need for BiVAD support, which has been associated with increased morbidity and mortality in children [28]. For the smallest of children, namely infants and neonates, MCS options remain limited. The PumpKIN trial is anticipated to add to this repertoire.

CONCLUSION
Although limited experience exists with regards to long-term outcomes of pediatric MCS, current outcomes are promising. Despite positive outcomes several significant side effects remain including bleeding, infection, and stroke.
Patient selection, timing of support, device selection and perioperative care remain critical components in a successful outcome for these patients.