**3. Anticoagulation**

One of the biggest challenges in children and MCS is achieving the ideal balance between bleeding and anticoagulation to prevent thrombosis. This balance is particularly difficult to achieve in pediatric patients due to alterations in hemostasis during development, pro-inflammatory states, or various genetic syndromes [9]. Pharmocologic regimens and combinations differ with a variety of options including the usage of a heparin infusion, low-molecular-weight-heparin, anti-platelet therapy, direct thrombin inhibitors, or warfarin. In addition to differences in pharmacology, target goals and measurements for monitoring are also variable. In the Berlin EXCOR study evaluating pump size [10], this institution describes measuring anti-Xa levels, international normalized ratio, as well as obtaining thromboelastography and platelet aggregation tests for patients also being treated with acetylsalicyclic acid and dipyridamole (or clopidogrel) to ensure therapeutic effect. Reported thrombosis rates for the Berlin Heart are 20–29%. It is hypothesized that larger pump size, due to limitations of appropriate device size for patient body, may be a risk for thromboembolic events [10]. There is variability in whether studies find that <10 kg body weight is a risk factor for thrombosis. Optimal protocols and regimes have been studied to decrease the risk of thromboembolic events while also keeping rates of bleeding low, especially around the perioperative period.

### **4. Clinical pathways after device implantation**

There are several clinical outcomes for children after VAD implantation. It seems that there are increased hospitalizations for decompensated heart failure and more utilization of VADs. Mechanical circulatory device clinical pathways can include bridge-to-transplant, bridge-to-recovery, or currently alive [6]. If it is unknown whether the patient will be suitable for transplant, bridge-to-decision is also an option, but less likely for a durable device in the era of other temporary MCS options. A subset of patients may also require biventricular assist device placement in both the right and left ventricle. Given the growing number of device implantation in children, it is imperative that we continue to review early and late outcomes, as well as measure the impact of quality of life (QOL) in these complex patients.

#### **4.1 Bridge-to-transplant**

Some CHD patients may fail surgical repair or multi-stage surgical palliation and require bridging support prior to heart transplantation. One of the benefits of implanting durable VADs in children awaiting transplant is the improved posttransplant survival and decreased waitlist times compared to using temporary mechanical circulatory support such as ECMO. This includes improved nutrition, function of other organs, and rehab prior to transplant – with reports of increased VAD utilization in this pediatric population. Unfortunately, the number of pediatric heart transplantation donors continues to be static within North America [5].

In the most recent era, reference [14] studied the pediatric VAD implantation across two eras (1999 to 2004 or 2005 to 2012). There have been more pediatric patients listed Status 1A – indicating the highest critical need. However, despite this increase, there has been a significant decrease from 2005 to 2012 of 50% in transplant waitlist mortality compared to the previous era. Risk factors for waitlist mortality included weight < 10 kg, CHD, ECMO, mechanical ventilation, or renal dysfunction. VAD was protective and improved waitlist survival [14].

When analyzing whether racial disparities exist in post-transplant survival after VAD implantation, reference [15] elucidates that disparities still exist. Studies have shown that racial minorities experience inferior outcomes after heart transplant. Black children were most ill with a greater proportion Status 1A. Outcomes at 1-year post-transplant were equivalent, but long-term survival was worse for non-whites. On multivariable analysis, black race independently predicted mortality. This study showed that even though the most ill patients receive VADs, with similar pretransplant and early transplant outcomes, black and Hispanic pediatric patients experienced inferior post-transplant survival after VAD as a bridge-to-transplant.

### **4.2 Biventricular assist device support**

Another portion of CHD patients after placement of left VAD may experience severe right ventricular dysfunction, necessitating a right VAD: biventricular assist device (BiVAD) support. In adults, attempts have been made to identify risk factors and subsequent risk scoring to try and predict which patients may need both ventricles supported [16, 17]. Physiologically, LVAD support may augment worsening RVAD failure through many factors, but predicting the level to which a second device placement is warranted is difficult [18]. In Ref. [18], authors reviewed long-term VAD implantation to try and identify risk factors. Unfortunately, patients requiring temporary right VAD support or BiVAD support were at increased risk of mortality [12, 18]. Also, emergent RVAD implantation was associated with worse outcomes. After multivariate logistic regression indicated that decreased milrinone application was a preoperative risk factor associated with requiring BiVAD instead of sole left VAD support. But, in other terms, patients who received preoperative milrinone had decreased odds of developing right heart dysfunction, which was statistically significant [18]. This paralleled some findings in adults as well [17]. However, none of the many other variables evaluated were correlated with predisposing to BiVAD support. It was also observed that the frequency of BiVAD placement in pediatric patients has been decreasing, possibly from improved implantation techniques [18].

### **4.3 Outcomes and quality of life**

In the past few decades, outcomes for pediatric VAD implantation continue to improve. Patients can be successfully bridged to transplant in over 20% of patients [19]. Unfortunately, some of the outcomes data are currently outdated due to use in previous studies of devices that are no longer available [9, 12]. In the early experience of HeartMate 3, short-term follow-up of 35 patients demonstrated an early survival of 97%, with only one mortality [11]. Almost 60% were able to achieve transplantation. Early results were encouraging with no stroke or pump thrombosis after an average of 3-months of follow-up. Not evaluating just by device type, the larger registry among the 471 patients enrolled in the Pediatric Interagency Registry for Mechanical Circulatory Support from 2012 until 2017, groups were divided looking at outcomes for biventricular versus single ventricle patients, specifically with CHD, compared with non-CHD pediatric patients [8]. At 6 months, CHD patients had a higher mortality (36.4%) compared to non-CHD VAD patients (12.1%) and almost half transplantation rate of 29% versus 60%. However, this study also included patients with paracorporeal devices as well as implantable continuous devices. Despite looking at multiple variables, CHD seemed to be the highest association of mortality with VAD placement. As experience with implantation and increased number of children receiving these devices, more data from large registries will be able to help predict which patients will achieve the best outcomes from VAD implantation [9].

One of the earliest studies to compare outcomes of Berlin Heart to ECMO for bridge to transplant demonstrated that longer duration of support without significant risk of stroke and suggested improved survival on Berlin versus ECMO: 86% versus 56%. An updated study looking at more children in 47 centers identified about 200 children requiring support between 2007 and 2010, with median duration of support 40 days. The authors concluded that with the dramatic rise in usage, about 75% of patients survived to transplant or recovery. Risk factors associated with mortality included smaller patients, renal/hepatic dysfunction, and use of biventricular support [20].

Another large, single-center summarized the morbidity for patients requiring MCS associated with mortality from 1998 to 2007. In [21], some major complications the authors noted included infection, respiratory failure, major bleeding, hepatic/ renal failure, right heart failure, and neurologic injury. They cited major neurologic injury occurring in almost half of the 25 patients. Although survival to transplant was still three-quarters, consistent with other reports, the monitoring of neuro status changes continues to be challenging requiring aggressive evaluation for potential injury with patient sympatoms.

In a prospective study from 2014, VAD questionnaires were administered to parents to assess children's Pediatric Quality of Life Inventory pre- and post- VAD placement [19]. These scores were compared to healthy children, outpatients with heart failure, and children after heart transplant. Out of 13 patients, 11 were able to receive a heart transplant and one was still alive on VAD support. Patients reported lower physical QOL scores and lower psychosocial scores. In Ref. [22], 82 children from the Pediatric Interagency Registry for Mechanical Circulatory Support completed a selfreport quality of life assessment from pre- and post- VAD implantation. QOL scores were lower than normal for physical and psychosocial scores in both groups pre-VAD. However, it appeared that psychosocial scores improved in children post-VAD at 3 and 6 months post-op. Patients seemed to be mostly concerned physically with being unable to resume usual play activities compared to other children. However, this survey suggests that VAD placement may improve children's psychosocial health after implantation.
