The use of a continuous flow device (CFD) is a well-established means of durable mechanical support in adult patients with end-stage heart failure. Compared with pulsatile devices, CFDs are smaller, intracorporeally placed, and are more durable. Importantly, CFD support is predominantly used in adults because of the well-studied survival advantages over pulsatile devices.1 The Sixth Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) report demonstrated adults supported on CFD have a 1 year survival of 81%.2 Furthermore, CFDs in adults have been associated with improved quality of life when compared with pulsatile devices.1,3
The Berlin Heart, Excor (Berlin Heart AG, Berlin, Germany), a paracorporeal pulsatile device, is one of the only two Food and Drug Administration (FDA)-approved ventricular assist devices (VADs) for pediatric use. It has gained wide acceptance and is regularly used to support children of all sizes with medically refractory heart failure. This VAD has been shown to be effective in bridging children to heart transplantation; however, there still remains significant morbidity in the form of bleeding (42–50%), infection (50–63%), and stroke (29%) with this device.4,5 Furthermore, in the United States, there are limitations on quality of life for these patients because they must remain hospitalized until heart transplantation.
Furthermore, the number of patients with heart failure in the pediatric population continues to rise, whereas the donor pool remains constant.6–8 This will inevitably lead to longer wait-times and higher attrition rates. As such, there is a tremendous need for the development of a durable VAD that can be applied to the pediatric population with low morbidity during long waiting periods and does not restrict the child’s quality of life.
Newer third generation CFDs currently only approved for adult use may be applicable for adolescent patients with end-stage heart failure to improve survival to transplantation and decrease morbidity. Data regarding CFD use in children are currently limited to case reports and small series in select patients.9–13
Here in, we report our results from an observational single center study with a CFD to evaluate efficacy as a bridge to heart transplantation in adolescent patients. Furthermore, we compared whether our initial outcomes in this group of adolescents was different to a selected group of adult control subjects who were bridged to transplantation during the same time period.
Institutional review board approval was obtained for the study protocol and implantation of this device. Data were extracted retrospectively from the VAD registries at St Louis Children’s and Barnes-Jewish hospitals. Preimplantation variables, including demographics, primary diagnosis, INTERMACS profile, and laboratory values, along with outcomes and adverse events (AEs), were recorded.
The adolescent cohort included all patients younger than 18 years of age with medically refractory heart failure who were implanted with the HVAD device at St. Louis Children’s Hospital in the Washington University Medical Center from October 2012 to March 2014.
The adult control subjects consisted of patients older than 18 but younger than 40 years of age with nonischemic heart disease on HVAD as bridge to transplantation. They were matched based on diagnosis, body surface area (BSA), and the time period devices were implanted.
The CFD used in this study was the HVAD HeartWare. The concepts and design of this CFD as well as implantation technique for left heart support has previously been described.14 In summary, all patients underwent a median sternotomy and were placed on cardiopulmonary bypass (CPB) via aortic and atrial cannulation. A suitable site for inserting the inflow portion of the device is chosen. This is slightly anterior and to the left of the left ventricular apex (LVA). The sewing ring is then anastomosed to the LVA. Myocardium from within the sewing ring is cored out. The inflow cannula of the HVAD is inserted and secured to the sewing ring. The pump is located within the pericardial space. The ascending aorta is then partially occluded using a side-biting clamp, and the 10 mm hemashield outflow graft is anastomosed to the ascending aorta. The pump is connected to an external controller via a driveline that is tunneled subcutaneously from the pump in the pericardial space to the right upper quadrant.
Postoperative Management and Anticoagulation
After completion of implant, all patients were transitioned from CPB to HVAD support at a pump speed of 2,200 rpm. Hemodynamics were assessed, and HVAD speeds were optimized utilizing intraoperative transesophageal echocardiography (TEE) to ensure midline position of the ventricular septum. Right heart support was also initiated and consisted of low-dose epinephrine, milrinone, and inhaled nitric oxide.
Anitcoagulation followed HeartWare recommendations. Heparin was initiated 24 hours after implantation if there were no bleeding issues. Once adequate gastrointestinal function was evident, all patients were transitioned to oral coumadin with an international normalized ratio (INR) goal of 2–3 and acetylsalicylic acid (ASA) 325 mg daily. After cessation of epinephrine infusion, Milrinone was weaned daily by 0.1 μg/kg/min for 5–7 days. Daily transthoracic echocardiograms were performed during the first postimplant week, and pump speeds were adjusted to maintain midline ventricular septal position and aortic valve closure. If needed, antihypertensive agents including nitroprusside, beta-blockers, and angiotensin converting enzyme inhibitors were used to maintain a mean Doppler blood pressure between 70 and 80 mm Hg.
Outcomes evaluated included overall survival to heart transplantation, days of device support, mortality on device, percent of patients discharged on device, and posttransplant survival. Adverse events were recorded based upon INTERMACS criteria and were reported as an event rate (i.e., number of times the event occurred per total patient days of support). One year survival was compared between the adolescent and adult groups.
Continuous variables are reported as median with interquartile range (IQR) and comparison performed using Mann–Whitney t-test for nonparametric data. Categorical variables were analyzed using Fisher’s exact testing. Survival analysis performed using Kaplan–Meier testing with logrank Mantel–Cox comparison.
Cohort Characteristics and Postoperative Course
During the study period, six adolescent patients underwent implantation of HVAD device. Table 1 demonstrates the individual patient characteristics. The median age was 13.4 (IQR, 11.35–14.4) years with a median weight and BSA of 48.2 (IQR, 37.6–59.1) kg and 1.45 (IQR, 1.23–1.58) m2, respectively. Fifty percent were female, and all carried the diagnosis of dilated cardiomyopathy (idiopathic, n = 4; anthracycline-related, n = 1; autoimmune myocarditis, n = 1).
At implantation, all patients were on at least two inotropes. There were three patients in INTERMACS profile-1 with two initially supported on an Impella (Abiomed, Danvers, MA) before HVAD implantation because of acute decompensation and shock at presentation. Biomarkers of renal (blood urea nitrogen [BUN] and creatinine) and liver function (serum bilirubin) were normal in all adolescents before implant.
Postimplant outcomes for adolescent patients are listed in Table 2. After implantation, the median initial pump speed was 2,450 (IQR, 2,235–2,575) rpm. At 7 days after implantation, it was 2,470 (IQR, 2,250–2,555) rpm. There was variability in pump speed within individual patients during a 1 week period postimplantation with differences ranging from 500 rpm faster to 360 rpm slower at 1 week when compared with the initial settings. The median initial device flow reading was 3.7 (IQR, 3.1–4.5) L/min and increased to 4.3 (IQR, 4.1–4.6) L/min. Intrapatient variation in flow was noted from a drop of 0.1 L/min to an increase of 1.3 L/min at 7 days in comparison with the initial device flow rate.
The median days of mechanical ventilation and inotropic support were 2.5 (IQR, 1.3–3.0) days and 11 (IQR, 7.5–13) days, respectively. The median days in the intensive care unit (ICU) after implant were 12.5 (7.5–18) days, whereas hospital stay was 17 (IQR, 9.75–25) days for the four adolescents who were discharged home. Adolescents discharged were in New York Heart Association (NYHA) I, were able to attend school, and participate in non-contact sporting activities. There were two adolescents who remained hospitalized until transplantation. Both were in NYHA II. One remained hospitalized because the patient was our index case using this device, whereas the second patient required right VAD support with a paracorporeal CFD device.
Adolescents were supported for median 107.5 (IQR, 61.3–195) days with total patient-days of support of 1,017 days. Time to listing for heart transplantation occurred at a median of 75 (IQR, 27–104) days postimplant. One patient with treated osteosarcoma remains on device currently awaiting 2 years of remission before listing. At 1 year postimplant, the remaining adolescents listed while on device underwent successful heart transplantation with a median wait list time of 12 (IQR, 10–26) days. There was no posttransplant mortality. Median follow-up time for the adolescent cohort was 247 (185–545) days.
Adults were followed up for a similar period of 294 (199–979) days. Table 3 illustrates comparison of adolescents with the five matched adults. There was no difference with respect to weight, BSA, gender, INTERMACS profile-1, and preoperative bilirubin. The adolescent group was younger (13.4 [10.9–14.8] vs. 33 [22–46] years, p = 0.004) with lower preimplantation creatinine (0.7 [0.6–0.85] vs. 1.49 [1.07–1.74], p = 0.015). The median ICU stay was longer in the adolescent patients (12.5 [7.5–18.3] vs. 4 [5.1–8.6], p = 0.046); however, as shown in Figure 1, the 1 year survival was not statistically different between the two groups (100% vs. 80%, p = 0.317).
Table 4 illustrates AEs for adolescent patients. There were a total of 18 AEs in the adolescent group with 1 AE occurring every 170 days on device. Major bleeding, stroke, and infectious complications were low. One adolescent required Centrimag (Thoratec Corporation, Pleasanton, CA) device support for severe right ventricular dysfunction post-HVAD implant. Of the four adolescent patients discharged after device implant, there were a total of six readmissions: pump thrombosis (n = 1), driveline disruption (n = 1), sepsis (n = 2), epistaxis (n = 1), and subtherapeutic anticoagulation (n = 1). Of those readmitted, one patient who presented with sepsis remained hospitalized until transplantation.
To our knowledge, with a total time of support of 1,017 days, this is the largest patient days-on-device experience reported to date using the HVAD in a pediatric population. We showed that, in adolescents with dilated cardiomyopathy, this CFD provides excellent support and is highly successful as a bridge to transplantation. Similarly, Hetzer et al. published their first experience with seven adolescents supported on HVAD for a total of 588 patient-days of support with six of seven successfully bridged to transplant and one continuing on device.9 Unique to our study is that we showed comparable survival between adolescents and matched adults supported with the HVAD during the same time period. The only difference between the two groups was that the ICU stay was longer in the adolescent group. This may have reflected caution to keep adolescents in the ICU during our initial experience.
Similarly, Cabrera et al.10 published a registry-based study comparing outcomes between adolescents and adults supported with the HeartMate II (Thoratec Corporation), another type of CFD that is FDA approved for adults. This study also showed comparable outcomes between the two groups. At 6 months follow-up, composite of survival to transplantation, continued support on device, or recovery was 96% in both groups.10
We were able to show that after CFD implant, all adolescents were well supported and had short ventilatory times enabling early rehabilitation. This allowed for discharge by 2.5 weeks. This was the first time in our heart failure program that we were able to discharge a pediatric patient on a VAD. A number of patients were managed in their local towns, which were at least 300 miles away. To this end, we accomplished the development of an outpatient VAD clinic to evaluate these patients periodically. Although we did not directly assess quality of life measures, this strategy of outpatient rehabilitation subjectively appeared to improve the quality of life of these patients. The four adolescents discharged home were in NHYA 1. All were able to attend school and engage in non-contact sporting activities. This is consistent with adult studies that have shown significant improvement in quality of life measures in patients supported on a CFD.3,15,16
Importantly, because of the highly effective support of the device, a flexible strategy on when to list a patient for heart transplantation can be developed. As previously mentioned, our median time to listing was 75 days. This delay in listing reflects our strategy to optimize transplantation outcomes by allowing an individualized period of time for adequate recovery that primarily focused on outpatient rehabilitation. Furthermore, anticipated short waiting times for adolescent patients (12 days for our cohort) reduces the urgency to list these patients early. This approach may have impacted our 100% success-rate for those who underwent heart transplantation. Furthermore, as evident in two of our patients, one with osteosarcoma and another with autoimmune myocarditis, this device provided excellent support during which treatment of these conditions could occur. This demonstrates the potential of this device for use as a bridge to decision in select patients.
Adverse events are not uncommon with CFD use in adult populations with a reported 1 year freedom from AEs of only 30%.17 Importantly, we were able to quantify AE in this small group of adolescents supported with a CFD. In this cohort, the most common AE was bleeding followed by infection. We followed the HeartWare anticoagulation guidelines as outlined in “Methods” section. However, with major bleeding events (e.g., mediastinal, perirenal), we stopped all anticoagulation and antiplatelet therapy for 3 days. An arbitrary period was based on a large VAD experience. This was followed by reinitiation of coumadin then ASA. Using this management strategy, there was no pump thrombosis evident. For minor bleeding events, such as epistaxis, we reduced the level of ASA from 325 to 81 mg only, which resolved the issue. Especially, pertinent to the field of pediatric mechanical support, there was only one neurological event documented during more than 1,000 days of support.
Children may pose unique challenges, which may lead to differences in the type of AE and AE rates seen in adults. Adolescents treated for a number of medical conditions are known to have difficulties with medical adherence and risk-taking behavior. This may impact issues of pump thrombosis and test the robustness of drivelines and controller/battery packs. It is worth noting, that of our six patients, two had device related complications and two with significant driveline infections.
Implanting these devices required institutional planning and coordination. At our center, we have a long-standing and successful pediatric inpatient VAD program. Further development of the program was needed for utilization of the HeartWare HVAD device. First, a collaborative effort between the adult and pediatric VAD teams was established. The first patient underwent implantation at the adult hospital with both adult and pediatric teams present. This patient was then transitioned back to the children’s hospital 3 days after implantation to the pediatric cardiac ICU for further management. The remaining devices were all implanted at our institution with tapering support from the adult program as we established our learning curve. Patients were eventually transitioned to the ward for discharge planning. Second, we established our outpatient VAD program developing a communication network between patients, VAD coordinators, and cardiologists. Heart failure cardiologists and VAD coordinators primarily staffed our VAD clinics, but it was not infrequent that our surgical colleagues were asked to evaluate drivelines and wounds.
Limitations of this study are that it is retrospective and is a small single center experience. It is insufficiently powered to draw definitive conclusions. The recently established PEDIMACS registry and the PumpKIN trial may serve as a platform to study the North American experience with CFD and allow for the synthesis of management strategies for these critically ill patients. Furthermore, this study evaluated only adolescents with dilated cardiomyopathy, and as a result, lessons imparted are not applicable to adolescents with congenital heart disease. This is an increasing population with a significant number presenting in end-stage heart failure. There are limited studies evaluating support with a CFD in patients with congenital heart disease.18,19
In conclusion, the HeartWare HVAD provides excellent cardiac support in older children as a bridge to transplantation, early rehabilitation, and the potential to improve quality of life. Morbidity is not negligible but appears comparable with that seen in adults. Broader application of CFD in pediatric patients requires further study.
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Keywords:Copyright © 2015 by the American Society for Artificial Internal Organs
continuous flow device; adolescents; bride-to-transplantation; HeartWare; durable mechanical support