Noncompaction Cardiomyopathy 2

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Third Generation Ventricular Assist Device: Mid-Term
Outcomes of the HeartWare HVAD in Pediatric Patients
*Mustafa Pac, *Sinan Sabit Kocabeyoglu , *Umit Kervan, *Dogan Emre Sert,
†Serhat Koca, †Ibrahim Ece, and †Feyza Aysenur Pac
*Department of Cardiovascular Surgery, Turkey Yuksek Ihtisas Hospital; and †Department of Pediatric Cardiology,
Turkey Yuksek Ihtisas Hospital, Ankara, Turkey
Abstract: The HeartWare HVAD is a small, third genera-
tion continuous flow pump that is intracorporeally placed
for support of a failing ventricle in adult patients. This
device is small in size when compared to other left ventric-
ular assist devices and can therefore be used in smaller
sized pediatric patients. We present our initial experience
using the HVAD as a bridge to heart transplantation in
the pediatric population. We performed a retrospective,
single center, nonrandomized review of 17 pediatric
patients who underwent HVAD implantation between
June 2013 and March 2016. The primary endpoints evalu-
ated in this study were overall survival to heart transplan-
tation, ongoing device support, or death. In this patient
cohort, nine (53%) of 17 patients were male. The median
age of the patients was 13.46 3.8 (range 5–17) years. The
median body surface area was 1.46 0.4(0.7–2) m2. Etiolo-
gies of heart failure requiring HVAD support were dilated
cardiomyopathy (n5 8), myocarditis (n5 5) and noncom-
paction cardiomyopathy (n5 4). The overall mean length
of HVAD support was 2546 298 (range 2–804) days. A
successful outcome (bridge to transplant and ongoing
mechanical support) was achieved in 13 patients (76.5%).
Of the 13 patients, nine (69.2%) were bridged to heart
transplantation and four continue to receive support
(30.7%) and are eligible for transplantation. Post-
transplant survival has been 100%, with a mean follow-up
of 2966 264.5 (range 18–785) days. The most common
complication was pump thrombosis (23.5%) in follow-up.
Four patients (23.5%) experienced no complications. The
HVAD continuous flow ventricular assist device can be
safely used to bridge pediatric patients to cardiac trans-
plantation. Favorable outcomes of this device are compa-
rable to the adult population. This analysis demonstrated
safe and effective implantation of the HVAD System in a
child with a BSA of 0.7 m2. Key Words: Ventricular
Assist devices—Pediatrics—Mechanical circulatory
support.
The incidence of pediatric end-stage heart failure
hospitalizations has been on the rise in recent
years. Although heart transplantation has been
established as definitive therapy for end-stage car-
diac failure in children, there continues to be signif-
icant mortality during the waiting interval between
listing and transplantation (1). In addition, the
number of heart transplants world-wide has
remained stagnant for the last 10 years. Mechanical
circulatory support (MCS) plays an important role
for children with end-stage heart failure who are
still waiting for transplant due to the shortage of
donor hearts, by increasing their survival.
Implantable ventricular assist device (VAD) sys-
tems that are suitable for adult patients make it dif-
ficult for the application in pediatric patients due to
the large size of the device. Extra-corporeal mem-
brane oxygenation (ECMO) and centrifugal pumps
have been successfully used to treat children with
advanced heart failure, due to the suitability for
patients of all sizes, widespread availability, and
ease of implantation. Their usage is however,
largely limited to the short-term support and immo-
bilization of the patient (2,3). Several adult sized
VADs are available and have been shown to
doi: 10.1111/aor.12989
Received February 2017; revised May 2017; accepted June
2017.
Address correspondence and reprint requests to Sinan Sabit
Kocabeyoglu, Department of Cardiovascular Surgery, Turkey
Yuksek Ihtisas Hospital, 06100 Sıhhiye, Ankara, Turkey.
E-mail: s4126k@yahoo.com.tr
Artificial Organs 2017, 00(00):00–00
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Copyright VC 2017 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.
effectively support larger children and adolescents
to transplantation; a process described as bridge to
transplant (4,5).
The use of MCS has undergone considerable evolu-
tion in the pediatric heart failure patient population
over the past two decades. The challenge for the
development and improvement in pediatric VADs
hinge on the need for a smaller sized pump and the
ability to implant in patients with complex anatomy
and physiology. One such device, the HeartWare
HVAD System (HeartWare Inc., Framingham, MA,
USA), is an intracorporal, centrifugal continuous flow
VAD that is implanted directly into the left ventricu-
lar apex, and remains within the pericardial space
(6,7). Due to its smaller size, the lack of the need for a
pump pocket, and the ease of implantation, there has
been expanding use of the HeartWare System in chil-
dren and adolescent patients (8,9). Similar to adult
patients, these children can be discharged home and
resume regular activities of daily living. We hereby
present our initial experience using the HVAD Sys-
tem as a bridge to heart transplantation in the pediat-
ric population in our institution.
MATERIALS AND METHODS
Study population
This is a retrospective, nonrandomized review of
17 consecutive patients under 17 years of age who
underwent implantation of HVAD System between
June 2013 and March 2016 in our center. Nine
(53%) patients were male, eight (47%) were
female. The median age was 13.46 3.8 years (range
5–17 years) with a median patient weight of 49.46
22.3 kg (17–91 kg). The median body surface area
of the patients was 1.46 0.4(0.7–2) m2. All patients
had severe systemic ventricular dysfunction, with a
mean ejection fraction of 21% (range 15–25%).
The study was approved by the Medical Advisory
Board. All medical records were reviewed and data
were summarized and expressed as a mean or
median value. Preimplantation variables, primary
diagnosis, Interagency Registry for Mechanically
Assisted Circulatory Support (INTERMACS) pro-
files, along with outcomes and adverse events, are
summarized in Table 1.
Etiologies of HF requiring left VAD (LVAD)
support were dilated cardiomyopathy (n5 8), myo-
carditis (n5 5), and noncompaction cardiomyopa-
thy (n5 4). All patients were optimally managed
on their heart failure medications. The study
patients were followed up until heart transplant,
death, or ongoing mechanical support.
Operative technique
Cardiopulmonary bypass was established under
normothermic conditions. A median sternotomy
approach was used in 16 of the 17 patients; a mini
thoracotomy with hemi sternotomy was used in one
patient. All procedures were performed on a beat-
ing heart.
TABLE 1. Patients characteristics
Age
Weight
(kg) BSA Implant date Diagnosis
Implant
duration
(days) Complications
Pump
changes Outcomes INTERMACS
17 55 1.55 September 16, 2015 Noncompaction 14 RVF, medical 0 Tx 3
13 40 1.26 January 20, 2014 Noncompaction 300 Sepsis after discharge 0 Died 2
16 91 2.05 July 31, 2014 dcmp 15 MOF 0 Died 1
17 64 1.76 May 25, 2013 dcmp 57 MOF 0 Died 1
15 74 1.96 March 26, 2014 dcmp 330 – 0 Tx 3
9 27 0.95 March 05, 2014 Noncompaction 95 RVAD thrombosis
LVAD thrombosis
0 Tx 1
17 62 1.66 September 18, 2014 dcmp 530 Driveline infection 0 On support 2
14 52 1.54 July 09, 2015 Myocarditis 240 – 0 On support 2
17 60 1.66 March 02, 2012 dcmp 790 – 0 Tx 3
12 32 1.34 June 10, 2013 dcmp 786 Thrombosis, t-PA 0 Tx 3
16 77 1.94 March 22, 2013 dcmp 804 Thrombosis, t-PA 0 Tx 3
10 32 1.12 January 07, 2015 Noncompaction 286 Thrombosis, t-PA 0 Tx 2
16 75 1.91 December 15, 2015 dcmp 2 RVF, ECMO 0 Died 1
6 17 0.72 January 16, 2016 Myocarditis 19 BIVAD 0 Tx 1
5 20 0.77 February 10, 2016 Myocarditis 28 – 0 On support 1
16 35 1.25 February13, 2016 Myocarditis 25 RVF, ECMO 0 On support 1
12 30 1.04 February 15, 2016 Myocarditis 2 BIVAD 0 Tx 1
Preimplantation variables, primary diagnosis, INTERMACS profiles, along with outcomes and adverse events, are summarized in
Table 1.
Abbreviations: BIVAD, biventricular assist device; BSA, body surface area; ECMO, extracorporeal membrane oxygenator; LVAD,
left ventricular assist device; MOF, multiorgan failure; RVF, right ventricular failure; t-PA, tissue plasminogen activator; Tx, transplant.
M. PAC ET AL.2
Artif Organs, Vol. 00, No. 00, 2017
Transesophageal echocardiography was per-
formed in all patients to exclude the presence of
patent foramen ovale and to confirm ideal place-
ment and orientation of the inflow cannula. The
sewing ring was placed at the left ventricular apex,
and the ventricle was cored with the HVAD coring
tool. The HVAD pump was seated into the sewing
ring, followed by anastomosis of the outflow graft
to the ascending aorta with partial clamping. Trans-
esophageal echocardiography confirmed satisfac-
tory de-airing. A tunneling device was used to
tunnel the driveline under the abdominal fascia.
The device was then started at 1800 rpm, and speed
adjustments were made in increments based on
echocardiographic evaluation of the location of the
ventricular septum and appearance of both ven-
tricles, confirming adequate ventricular unloading
and intermittent aortic valve opening. Ongoing
hemodynamic assessment was performed to main-
tain a physiologic blood pressure and central
venous pressure. At the end of the procedure, hep-
arin was fully neutralized with the administration
of protamine. Once the patient was stabilized, they
were accepted to the intensive care unit for ongoing
management.
Postoperative anticoagulation management
The chronic anticoagulation regimen was initiated
on the first postoperative day, once the patient was
able to tolerate medications by mouth, with oral war-
farin to keep the international normalized ratio
(INR) between 3 and 3.5. Aspirin (5 mg/kg/day) was
added to the anticoagulation therapy. Intravenous
(I.V.) heparin infusion was initiated on the first post-
operative day, continued unless patients could be
extubated or targeted INR could be achieved.
RESULTS
Preimplant characteristics
The preimplantation demographic characteristics
of patients are listed in Table 1. No patient had
signs of severe renal dysfunction before surgical
procedure or required dialysis. All patients were
receiving diuretics preoperatively to maintain an
adequate fluid balance. The median pre-VAD pul-
monary vascular resistance was 2.49 Woods units.
Early complications
Of the 17 patients, two required mediastinal re-
exploration in the early postoperative period
related to bleeding, and two patients required post-
operative dialysis. There were no acute neurologi-
cal events, no pump exchanges, and no observed
hemolysis. In three patients, biventricular VAD
(BIVAD) (in two patients right VAD (RVAD)
with ECMO, in one patient RVAD with Centri-
MAG (Thoratec, Pleasanton, CA, USA) implanta-
tion was performed. In one of the BIVAD patients,
the temporary RVAD (CentriMAG) was throm-
bosed on postoperative day 11. This patient was
successfully weaned from the thrombosed RVAD
and her postoperative follow-up was uneventful.
Unfortunately, her HVAD thrombosed during the
first postoperative year necessitating heart trans-
plant, which was ultimately successful. Both of the
other two BIVAD patients were successfully trans-
planted in the early postoperative period. One
another patient died due to RV failure on postop-
erative day two after temporary RVAD implanta-
tion with ECMO.
There were three (18.7%) deaths in the first 30
days postoperatively. One patient died due to septi-
cemia after pneumonia 300 days’ post LVAD
implantation while waiting on the transplant list,
and two patients succumbed to death after multi-
system organ failure. Adverse events during
HVAD support are summarized in Table 2.
Outcomes
The primary end-points of this study were overall
survival to heart transplant, ongoing device sup-
port, or death. Adverse events and hospital length
of stay were also evaluated. The overall mean
length of HVAD support was 2546 298 (range 2–
804) days. Of the 17 patients, nine (53%) patients
were bridged to heart transplantation, and four
(23.5%) continue to receive ongoing HVAD sup-
port while awaiting a transplant. A successful out-
come (bridge to transplant and on mechanical
support) was achieved in 13 (76.5%) patients. A
mean VAD support duration 3476 254 (range 2–
804) days was achieved. Post-transplant survival has
been 100%, with a mean follow-up of 2966 264.5
(range 18–785) days. Eight of 17 patients were
identified as INTERMACS profile 1; we had found
high mortality rate (37.5%) in these patients (three
of these eight patients died early postoperative
period).
TABLE 2. Adverse events during VAD support
Adverse event Number of patients
Pump change 0/17 (0%)
Infection 2/17 (11.7%)
Right ventricular failure 6/17 (35.2%)
Neurological complication 0/17 (0%)
Bleeding requiring re-exploration 2/17 (11.7%)
Death 4/17 (23.5%)
MID-TERM OUTCOMES OF HVAD IN PEDIATRIC PATIENTS 3
Artif Organs, Vol. 00, No. 00, 2017
The mean mechanical ventilatory support dura-
tion after VAD insertion was 26 3.3 days (range 1–
57 days). The mean length of stay in the intensive
care unit was 13.56 15.71 days. After surgical pro-
cedure, all patients were started on inhaled nitric
oxide at 20 ppm and milrinone, norepinephrine and
dobutamine infusions. All patients received sildena-
fil after extubation. One patient developed early
right ventricular (RV) failure and was successfully
managed with medical therapy, while two patients
developed right heart failure necessitating ECMO
support.
Patient discharge
Of the 14 patients who were survived in early
postoperative period, 12 patients could be dis-
charged home and two were in still hospital, on
support and waiting for transplant. All patients
were discharged on warfarin and aspirin. Ongoing
INR monitoring was performed at a minimum of
weekly. Patients were examined for follow-up on a
weekly basis initially, and then monthly thereafter.
Readmissions and outpatient complications
The most frequent reason for readmission was
pump thrombosis (4/14, 28.5%), followed by drive-
line infection (2/14, 14.2%). Of the four patients
who developed pump thrombosis, three responded
positively to medical therapy with tissue plasmino-
gen activator (t-PA) and one required cardiac
transplantation due to nonresponsiveness to t-PA.
INR levels were found to be above 2.5 in all
patients. No neurologic complications, neither
thrombotic nor hemorrhagic, were observed.
DISCUSSION
Considering current shortage of donor organs,
and the increased number of children awaiting a
transplant, bridge to transplant or comparatively
rarely, bridge to myocardial recovery, is an attrac-
tive alternative. Mechanical support as a bridge to
heart transplant improves survival in children with
end-stage heart failure (10,11). Options for
mechanical circulatory support in pediatric patients
include intra-aortic balloon pumps, ECMO, pulsa-
tile VAD devices and, more recently, centrifugal
pumps (2,11,12). ECMO has been the mainstay for
circulatory support in pediatric patients (13,14).
ECMO assures total cardiopulmonary support and
allows a flexible choice between peripheral and
central cannulation. However, ECMO and short-
term centrifugal pumps are largely limited to lack
of mobility, the need for continuous intensive care,
and the unsuitability for prolonged mechanical
support (15). Pediatric VAD therapy has multiple
advantages when compared with ECMO including
decreased risk of infection and inflammatory
response (16,17). Supporting a patient with a VAD
allows forearly extubation, early mobilization, and
improvement in nutritional status given that the
child can be fed orally. These factors contribute to
the overall optimization of the patient’s condition
during the VAD support period. VADs directly
decompress the left ventricle and provide enough
blood flow, which could restore end-organ function
(18,19).
The most important current issue in pediatric
VAD practice is the lack of an approved device
with an acceptably low-risk profile and the versatil-
ity to provide durable support for the entire range
of size and anatomic complexity. The vast majority
of pediatric VAD implants have been adult devices,
but none of the devices are approved for use in
patients with a body surface area (BSA) of less
than 1.3 m2. Miniaturization of devices such that
they will be suitable for children is a continuing
area of emphasis.
The use of VADs and choice of VAD configura-
tion in children with acutely decompensating heart
failure is controversial. Selection criteria for device
use in infants and children are evolving. Berlin
Heart VAD or EXCOR is a paracorporeal pneu-
matically driven pulsatile-flow VAD. It is only
device suitable for all pediatric patients, including
neonates, and is capable of providing biventricular
VAD support. Serious adverse events, including
infection (46%), major bleeding (44%), respiratory
failure (29%) were recorded in previous series with
EXCOR, and neurological dysfunction (mostly
from thromboembolic events) occurred in %29 and
was the leading cause of death (20). The success
rate (transplantation or successful weaning) with
EXCOR ranges between 69 and 75% (20,21). The
duration of support with EXCOR may extend up
to 400 days (20,21). According to these literature
information, our success rate was comparable with
lower serious adverse events rate and better dura-
tion of support time up to 800 days. To date, the
pediatric experience with continuous flow (CF)
devices is very limited due to small patient size.
Several adult designed VADs have been adopted
for the use in children like the Heartmate II used
in teenagers between 12 and 13 years (22). The
HVAD has been implanted successfully in children
as young as 6 years of age (8). Single-center experi-
ence with follow-up data and outcomes of the third
generation (HVAD) implanted in pediatric patients
remains very limited. This study reports the
M. PAC ET AL.4
Artif Organs, Vol. 00, No. 00, 2017
outcomes of 17 pediatric patients exclusively sup-
ported by the HeartWare with a 76,5% survival,
53% bridged to transplantation, 23.5% on support.
However, our pump thrombosis events were 23.5%.
Timing of device implantation and patient selec-
tion are two important aspects for improving out-
comes in VAD recipients (23). Implantation before
deterioration of organ function yielded significantly
better outcomes. The goal is to avoid premature
exposure to mechanical support and device-related
morbidities, but at the same time, to prevent the
onset of any end-organ dysfunction.
One of the most important issues in the follow-
up of the pediatric patient is anticoagulation man-
agement. The anticoagulation management remains
the biggest challenge in the treatment of patients
on mechanical circulatory support (24). It has been
reported that children and adolescents on support
are suffering from a higher rate of thrombo-
embolic and hemorrhagic complications than the
adults (25). The anticoagulant and antiplatelet
effects in small infants and young children might be
different from older adolescents and adults. There
is still much to be learned about contemporary
devices, anticoagulation protocols, and thromboem-
bolism in children. No standard anticoagulation
protocol has been developed specifically for this
cohort, and the fact that VAD speeds are many
times run at a lower rpm than adults, raises the
question whether this creates a higher rate of
thrombosis. This hypothesis warrants further inves-
tigation. Our anticoagulation regimen includes oral
warfarin to keep the INR between 3 and 3.5, as
well as aspirin, at a dose of 3 mg/kg/day. Our pump
thrombosis rate was found 23.5%, it was relatively
high when compared to other series with CF VAD
(26,27). The criteria for VAD thrombosis were
determined as follows: (i) presence of hemolysis
without another etiologic cause, (ii) increased
pump power parameters and impaired flow param-
eters, (iii) isolated LDH> three times normal
upper limit value. The protocol that we apply to
our patients with pump thrombosis is: Initiation of
infusion of unfractionated heparin even if INR val-
ues in therapeutic range, followed by a 10-min infu-
sion of 0.1 mg/kg tissue plasminogen activator (t-
PA) followed by 0.1 mg/kg/h t-PA 6 h infusion, 2 h
after t-PA infusion, intravenously heparin infusion
is restarted. If LDH values do not fall below 50%
within 24 h or the power parameters are still high,
a second dose of t-PA is given in the same way
without 10 min of bolus and heparin infusion is
continued for at least 48 h.
Considering that we had experienced four pump
thrombosis events with INR in therapeutic range, it
begs the question as to whether there was a direct
correlation between lower pump speeds and throm-
bosis in this pediatric population.
Pediatric heart failure is commonly associated
with biventricular failure and elevated pulmonary
vascular resistance, both of which may limit left
ventricular diastolic filling. Biventricular VAD
(BIVAD) support is more common in pediatric
patients. However, this has been associated with
increased mortality in both adults and children.
Our strategy is to first implant a LVAD and intrao-
peratively manage pulmonary vascular resistance
by inhaled nitric oxide and pharmacologic agents.
In our experience, we found six patients that devel-
oped signs of RV failure based on transesophageal
echocardiographic findings. One patient responded
to medical therapy, however, the other four
patients required temporary RVAD support with
ECMO and one with CentriMAG.
In the pediatric population, selected patients may
benefit from a mini thoracotomy1mini-J hemi
sternotomy approach as opposed to conventional
median sternotomy. We think less right ventricular
failure can be seen in the early postoperative
period with the use of the thoracotomy approach
due to intact pericardium integrity. Accordingly, we
believe that it would be advantageous to consider
this approach in pediatric patients with limited right
ventricular function. In this patient population, we
preferred this approach in only one patient, there-
fore, further investigations are needed to introduce
this approach is favorable or not.
One of the significant advantages of the third
generation, smaller, CF VADs is that the majority
of patients implanted can be discharged home and
resume regular activities. This has significant impli-
cations for the psychosocial well-being of pediatric
patients and their families. An ideal discharge pro-
tocol concerning training and education should
include: training of the patient and family members,
as well as education of school staff and classmates.
Children discharged with a VAD should have
emergency reference cards at hand with contact
information for their VAD care center. In our
study, two patients were successfully transplanted
before discharge, two remained on support in hos-
pital, and ten patients were discharged successfully.
Those that were discharged to home were able to
return back to their daily life.
Heart transplantation limits long-term survival
and quality of life in young children. Infection,
rejection, graft failure, coronary vasculopathy, and
MID-TERM OUTCOMES OF HVAD IN PEDIATRIC PATIENTS 5
Artif Organs, Vol. 00, No. 00, 2017
complications from immunosuppressive therapy
including renal failure, post-transplant lymphoproli-
ferative disease,diabetes mellitus, and hypertension
are common. The advantage of VAD therapy
allows for the possibility of extended support of the
pediatric patient, thus avoiding potential transplant
associated complications, and could be used as des-
tination therapy in this population.
There continues to be a need for mechanical sup-
port for children suffering from end-stage heart
failure, as the number of patients needing cardiac
transplantation is on the rise. Although there has
been growing use of second and third generation
VADs in this pediatric population, there is an obvi-
ous need for smaller, more miniaturized pumps to
support smaller sized children and those with com-
plex cardiac anatomy and physiology. In children,
up to 0,7 m2 body surface area, the Berlin Heart
EXCOR remains the only VAD for long-term sup-
port, even in neonates EXCOR achieved a survival
of 70% (28). In this study, our analysis revealed
that implantation of the HVAD might be safe and
effective in children with a BSA of 0.7 m2.
LIMITATIONS
This was a single center, retrospective study, and
therefore was subject to its inherent and confound-
ing bias. Due to limited use of MCS for pediatric
patients, our number of pediatric HVAD recipients
remain small. Furthermore, given the small number
of patients evaluated in this study, more vigilant
interpretation of data is essential to provide a
robust set of data. Follow-up was limited and there-
fore prevented adequate assessment and confirma-
tion of patient outcomes.
CONCLUSION
With the increasing use of CF devices in pediat-
ric patients with end-stage heart failure, the experi-
ence will improve. At the time of our initial
experience, HVAD provided efficient and reliable
mechanical support in children with favorable out-
comes compared to adult VAD patients. As tech-
nologic innovations progress, miniaturized
implantable devices which are suitable for all sizes
of children will be possible. This will allow many
more children to benefit from mechanical support,
with the hope of minimizing transplant wait list
time mortality. With the evolution of the field of
pediatric MCS, more effort is now being directed
toward early decision making, appropriate patient
identification, and device selection strategies.
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