1. ISSN: 1524-4539
Copyright © 2006 American Heart Association. All rights reserved. Print ISSN: 0009-7322. Online
72514
Circulation is published by the American Heart Association. 7272 Greenville Avenue, Dallas, TX
DOI: 10.1161/CIRCULATIONAHA.106.623488
2006;113;2266-2268Circulation
David Rosenthal and Daniel Bernstein
Pediatric Mechanical Circulatory Support: Challenges and Opportunities
http://circ.ahajournals.org/cgi/content/full/113/19/2266
located on the World Wide Web at:
The online version of this article, along with updated information and services, is
http://www.lww.com/reprints
Reprints: Information about reprints can be found online at
journalpermissions@lww.com
410-528-8550. E-mail:
Fax:Kluwer Health, 351 West Camden Street, Baltimore, MD 21202-2436. Phone: 410-528-4050.
Permissions: Permissions & Rights Desk, Lippincott Williams & Wilkins, a division of Wolters
http://circ.ahajournals.org/subscriptions/
Subscriptions: Information about subscribing to Circulation is online at
by on July 14, 2008circ.ahajournals.orgDownloaded from

2. Pediatric Mechanical Circulatory Support
Challenges and Opportunities
David Rosenthal, MD; Daniel Bernstein, MD
C
ardiomyopathy is rare in the pediatric age group, with
an annual incidence of only 6 to 12 cases per million
children.1–3 In addition to the genetic and acquired
cardiomyopathies, heart failure in children also occurs as a
complication of congenital cardiac anomalies, ranging from
hypoplastic left heart syndrome to tetralogy of Fallot. In the
registry of the International Society of Heart and Lung
Transplantation (ISHLT), approximately 65% of heart trans-
plantations in infants were performed as the result of congen-
ital cardiac anomalies, whereas in older children that percent-
age decreases to 24%.4,5
Article p 2313
In early stages, heart failure in children is treated pharma-
cologically, as in adults, although there are comparatively
few clinical trial data specific to children.6–8 As the disease
severity increases, definitive therapy of heart failure in
children consists of heart transplantation. Approximately 350
pediatric heart transplantations are performed in the United
States annually, and, because of a robust national database,
outcomes after transplantation are well characterized.4 Less is
known about outcomes in pediatric patients awaiting heart
transplantation. For children, mortality rates of 7% at 30 days
have been reported, whereas mortality rate for infants—a
uniquely challenging group in terms of donor availability—
ranges from 25% to 31% at 6 months in multi-institutional
studies.9–11 Some centers report improved pretransplantation
survival in more recent eras as the result of improved medical
therapy, innovative strategies to improve the efficiency of
donor allocation (eg, ABO incompatible transplantation in
infants), and increased use of mechanical support devices in
children.12–15 Because sudden death in children awaiting heart
transplantation is rare, the majority of deaths in this popula-
tion are due to progressive heart and multi-organ failure and
are therefore, at least in theory, amenable to salvage therapy
with mechanical circulatory support (MCS).10
The experience with adults supported long-term by MCS is
sobering, with a 66% mortality rate at 1 year.16 Shorter
courses of support are more promising, with a survival rate of
83% at 1 month.16 In adults, risk factors for death are
reasonably well understood and include older age as well as
the need for biventricular support. An important difference
between the use of MCS in adults and children is the
suitability of the devices. For adults, there are many choices
of devices designed specifically for these patients, whereas
for children, the choices have included only extracorporeal
membrane oxygenation (ECMO; a technique best reserved
for short-term support), the Thoratec (Pleasonton, Calif)
ventricular assist device (VAD; a device designed for adults,
but which can be placed in larger children and adolescents),
the EXCOR Berlin Heart (Berlin Heart AG; Berlin, Ger-
many), and the MEDOS VAD (MEDOS Medizintechnik AG;
Stolberg, Germany). The latter 2 devices are the only devices
designed specifically for children and have until recently
been available in Europe and Canada but not the United
States.
In comparison to adults, experience with MCS in children
is quite limited. The current indications for MCS use in
children are bridge to transplantation, and, occasionally,
bridge to recovery. There are several single-center reports of
MCS use in children, and 1 larger series of Thoratec use in
older children.17–21 Reports from Hetzer, Stiller, et al22–24 at
the Berlin Heart Institute describe results in 45 pediatric
patients, using one of the few available devices designed
specifically for children, with excellent results.
In this context, the report by Blume et al25 in this issue of
Circulation provides important insight into the field of
pediatric MCS in North America. This study used the
Pediatric Heart Transplant Study (PHTS) database to trigger
secondary data collection, and thus represents a comprehen-
sive overview of MCS use in children. Within this database of
more than 2000 pediatric patients listed for heart transplan-
tation between 1993 and 2003, there were 99 patients with
pediatric MCS that were identified and for whom data were
collected. The overall survival to transplantation rate was
86%, which is similar to that in adults on MCS and signifi-
cantly better than earlier reports in children.16,19 Once trans-
planted, survival of patients with MCS was identical at 1 and
5 years after transplantation to those without MCS, indicating
that these patients do not represent a higher risk group for
posttransplantation death. However, the incidence of compli-
cations during pediatric MCS is greater than that in adults.
The incidence of stroke was 19%, and this was often a fatal
event (11 of 19 cases). This is higher than in adults but similar
to other small pediatric series.16,21 The incidence of reopera-
tion for bleeding was very high, at 35%, which may reflect
the technical challenges of device placement in patients with
congenital heart disease or in small patients, particularly as
the only true pediatric chronic devices (EXCOR and Medos)
were scarcely represented in this series. Only the incidence of
infection (35%) was similar to that in adults. Median waiting
The opinions expressed in this article are not necessarily those of the
editors or of the American Heart Association.
From Packard Children’s Hospital and Department of Pediatrics,
Stanford University, Stanford, Calif.
Correspondence to Daniel Bernstein, MD, Stanford University, 750
Welch Rd, Suite #305, Stanford, CA 94304. E-mail danb@stanford.edu
(Circulation. 2006;113:2266-2268.)
© 2006 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
DOI: 10.1161/CIRCULATIONAHA.106.623488
2266
Editorial
by on July 14, 2008circ.ahajournals.orgDownloaded from

3. time until transplantation was 25 days. However, there was
enormous variability in waiting times, with a range of 1 to
465 days. Risk factors for poorer outcome include a diagnosis
of congenital heart disease and earlier era of implantation,
whereas the use of biventricular support did not confer
additional risk, which differs from the findings in adults.
However, the small number of patients on bilateral ventricu-
lar assist device support limits the ability to make these
comparisons. Whether pediatric patients on bilateral ventric-
ular assist device support are more likely than adults to
remodel their pulmonary vascular beds after left ventricular
unloading remains to be determined.
One of the most striking aspects of the report by Blume et
al25 is the fact that there were only 99 cases over 10 years in
23 major pediatric transplant centers. This contrasts with the
655 adults enrolled in the Mechanical Circulatory Support
Database over a 3-year period.16 Nearly half of the centers in
the pediatric report implanted only 1 or 2 VADs during the
10-year study period, and only 2 centers had as many as 10
implantations. This is clearly a challenging environment in
which to provide MCS, and it is remarkable in this context
that the results in this series were as good as they were. The
data in the report by Blume et al25 also suggest a rather low
utilization rate of MCS in the pediatric population, with MCS
used in only 4% of the transplanted patients (99 of 2375
patients). This is much lower than the rate of 27% of MCS
use in adult transplantation candidates.26 The barriers to MCS
use in children include lack of appropriate equipment and
limited expertise, factors that certainly contribute to the low
MCS use rates. Whether patient-specific differences, such as
the presence of complex congenital heart disease, also con-
tribute to the differential utilization of MCS in children
versus adults remains unknown.
Subsequent to the close of data collection in the report by
Blume et al,25 use of the Berlin Heart EXCOR dramatically
increased in the United States. Although this device is not
approved by the Food and Drug Administration (FDA) for
routine use in children, it has been possible to have the
EXCOR approved on the basis of compassionate use on a
case-by-case basis. Despite the necessity to petition the FDA
for approval in each case, the EXCOR has been implanted in
approximately 40 young children over the past 18 months
(Berlin Heart AG, written communication, 2006). This con-
firms the notion that there is a significant unmet need for
pediatric MCS, particularly in younger children, who are not
well served by the Thoratec VAD and who are notably absent
from the series presented by Blume et al, which ended data
collection in 2003. With the availability of the EXCOR, the
volume of pediatric cases can be expected to continue to
grow, although it will not likely exceed 100 cases per year,
based on the number of pediatric heart transplantations
performed annually and extrapolating from current utilization
rates in adult patients.26
Thus, MCS in children will remain uncommon. It will be
difficult for centers to acquire significant expertise in the
field. Similarly, it will be unprofitable for companies who
might wish to bring a pediatric device to market. Develop-
ment costs are no less for pediatric devices than for those
suited for adults, but the potential market is much more
limited. In recognition of this problem, the National Institutes
of Health (NIH) recently initiated a development program in
pediatric MCS, funding a number of sites in the United States
to perform device development work.27 It is hoped that this
effort will result in one or more devices being available for
clinical trials by 2009. This is a welcome and critical first step
toward improving the quality and availability of MCS devices
for children. However, device development is only the first
obstacle to be overcome. Conducting a suitable clinical trial
to obtain regulatory approval for a pediatric MCS device will
be daunting and expensive under current regulatory stan-
dards. Such a trial would require participation from the vast
majority of sites performing pediatric heart transplantation in
the United States and would necessarily extend over several
years to accrue sufficient patients. These are considerable
practical problems. Given the limited size of the market for
these devices, it is unclear whether market forces would be
sufficient to generate funding for such trials or whether the
NIH might again find it necessary to step forward to provide
funding, so that this field might continue to advance.
Under existing guidelines, MCS devices must be approved
either though the PMA (pre-marketing approval) pathway, or
through the HDE (Humanitarian Device Exemption) path-
way. The first of these is the more rigorous and is the pathway
by which current adult devices such as the Novacor and
Thoratec have been approved for use in the United States.
The HDE pathway is available only for conditions that occur
in less than 4000 patients per year and does not require
demonstration of “effectiveness,” which is a key component
of the PMA. Thus, the HDE approval is in some aspects more
accessible than the PMA, and it certainly appears consistent
with the epidemiology of pediatric heart failure. However, it
is still necessary to show that the device does not pose a
significant or unreasonable risk of injury, and that the
probable benefit outweighs the risks of its use.28 Importantly,
although manufacturers can recover direct costs associated
with a device approved by the HDE pathway, there is no
opportunity to generate profit from such devices. This provi-
sion may well prove fatal to the HDE pathway for pediatric
MCS devices. A careful examination of the HDE regulation
and its applicability to pediatric MCS devices is warranted.
What should be the agenda for the next decade in the field
of pediatric MCS? First, we need improved, pediatric-specific
devices to emerge from the current development pathways.
Second, we need to develop better treatment protocols for
anticoagulation management, given the higher risks of both
bleeding and stroke in the pediatric age group. Third, inves-
tigators across the United States will need to work coopera-
tively on a very limited number of devices and protocols.
Fragmentation of effort will render the conduct of any
meaningful trial impossible. Cooperation is also a necessity if
investigators are to develop sufficient expertise to use exist-
ing and future devices effectively. Fourth, Congress and the
FDA will need to reevaluate the regulatory environment to be
certain that it provides a proper balance of safety and
opportunity. Without this scrutiny, the chances of bringing a
device to market appear slim. The NIH will likely find it
necessary to provide funding for clinical trials in areas
traditionally funded by industry. Finally, we will need to
Rosenthal and Bernstein Pediatric Mechanical Circulatory Support 2267
by on July 14, 2008circ.ahajournals.orgDownloaded from

4. continue to evolve the criteria for making the switch from
pharmacological support to MCS, especially as pediatric-
specific devices become more readily available. The trend in
the study by Blume et al25 toward higher mortality rates for
patients on mechanical ventilatory support at the time of
initiation of MCS suggests that earlier switch to MCS is
beneficial, but when is it too early?
The payoff for this effort will be, in the short term, the
ability to save the lives of those children with advanced heart
failure who now die waiting for a suitable donor. In the long
term, the possibilities are even more exciting, as improved
technology offers the hope of long-term cardiac support for
children with more indolent forms of heart failure such as the
palliated univentricular heart.
Disclosures
None.
References
1. Lipshultz SE, Sleeper LA, Towbin JA, Lowe AM, Orav EJ, Cox GF,
Lurie PR, McCoy KL, McDonald MA, Messere JE, Colan SD. The
incidence of pediatric cardiomyopathy in two regions of the United
States. N Engl J Med. 2003;348:1647–1655.
2. Arola A, Jokinen E, Ruuskanen O, Saraste M, Pesonen E, Kuusela AL,
Tikanoja T, Paavilainen T, Simell O. Epidemiology of idiopathic cardio-
myopathies in children and adolescents: a nationwide study in Finland.
Am J Epidemiol. 1997;146:385–393.
3. Nugent AW, Daubeney PE, Chondros P, Carlin JB, Cheung M, Wilkinson
LC, Davis AM, Kahler SG, Chow CW, Wilkinson JL, Weintraub RG.
The epidemiology of childhood cardiomyopathy in Australia. N Engl
J Med. 2003;348:1639–1646.
4. Boucek MM, Edwards LB, Keck BM, Trulock EP, Taylor DO, Hertz MI.
Registry of the International Society for Heart and Lung Transplantation:
eighth official pediatric report–2005. J Heart Lung Transplant. 2005;24:
968–982.
5. Boucek MM, Edwards LB, Keck BM, Trulock EP, Taylor DO, Mohacsi
PJ, Hertz MI. The Registry of the International Society for Heart and
Lung Transplantation: Sixth Official Pediatric Report–2003. J Heart
Lung Transplant. 2003;22:636–652.
6. Rosenthal D, Chrisant MR, Edens E, Mahony L, Canter C, Colan S,
Dubin A, Lamour J, Ross R, Shaddy R, Addonizio L, Beerman L, Berger
S, Bernstein D, Blume E, Boucek M, Checchia P, Dipchand A,
Drummond-Webb J, Fricker J, Friedman R, Hallowell S, Jaquiss R, Mital
S, Pahl E, Pearce B, Rhodes L, Rotondo K, Rusconi P, Scheel J, Pal Singh
T, Towbin J. International Society for Heart and Lung Transplantation:
Practice guidelines for management of heart failure in children. J Heart
Lung Transplant. 2004;23:1313–1333.
7. Kouatli AA, Garcia JA, Zellers TM, Weinstein EM, Mahony L. Enalapril
does not enhance exercise capacity in patients after Fontan procedure.
Circulation. 1997;96:1507–1512.
8. Hoffman TM, Wernovsky G, Atz AM, Kulik TJ, Nelson DP, Chang AC,
Bailey JM, Akbary A, Kocsis JF, Kaczmarek R, Spray TL, Wessel DL.
Efficacy and safety of milrinone in preventing low cardiac output
syndrome in infants and children after corrective surgery for congenital
heart disease. Circulation. 2003;107:996–1002.
9. Morrow WR, Naftel D, Chinnock R, Canter C, Boucek M, Zales V,
McGiffin DC, Kirklin JK. Outcome of listing for heart transplantation in
infants younger than six months: predictors of death and interval to
transplantation: The Pediatric Heart Transplantation Study Group.
J Heart Lung Transplant. 1997;16:1255–1266.
10. Rosenthal DN, Dubin AM, Chin C, Falco D, Gamberg P, Bernstein D.
Outcome while awaiting heart transplantation in children: a comparison
of congenital heart disease and cardiomyopathy. J Heart Lung
Transplant. 2000;19:751–755.
11. Chrisant MR, Naftel DC, Drummond-Webb J, Chinnock R, Canter CE,
Boucek MM, Boucek RJ, Hallowell SC, Kirklin JK, Morrow WR. Fate of
infants with hypoplastic left heart syndrome listed for cardiac transplan-
tation: a multicenter study. J Heart Lung Transplant. 2005;24:576–582.
12. McMahon AM, van Doorn C, Burch M, Whitmore P, Neligan S, Rees P,
Radley-Smith R, Goldman A, Brown K, Cohen G, Tsang V, Elliott M, de
Leval MR. Improved early outcome for end-stage dilated cardiomyopathy
in children. J Thorac Cardiovasc Surg. 2003;126:1781–1787.
13. Tsirka AE, Trinkaus K, Chen SC, Lipshultz SE, Towbin JA, Colan SD,
Exil V, Strauss AW, Canter CE. Improved outcomes of pediatric dilated
cardiomyopathy with utilization of heart transplantation. J Am Coll
Cardiol. 2004;44:391–397.
14. West LJ, Karamlou T, Dipchand AI, Pollock-BarZiv SM, Coles JG,
McCrindle BW. Impact on outcomes after listing and transplantation, of
a strategy to accept ABO blood group-incompatible donor hearts for
neonates and infants. J Thorac Cardiovasc Surg. 2006;131:455–461.
15. West LJ, Pollock-Barziv SM, Dipchand AI, Lee KJ, Cardella CJ, Benson
LN, Rebeyka IM, Coles JG. ABO-incompatible heart transplantation in
infants. N Engl J Med. 2001;344:793–800.
16. Deng MC, Edwards LB, Hertz MI, Rowe AW, Keck BM, Kormos R,
Naftel DC, Kirklin JK, Taylor DO. Mechanical circulatory support device
database of the International Society for Heart and Lung Transplantation:
third annual report–2005. J Heart Lung Transplant. 2005;24:1182–1187.
17. Reinhartz O, Stiller B, Eilers R, Farrar DJ. Current clinical status of
pulsatile pediatric circulatory support. ASAIO J. 2002;48:455–459.
18. Reinhartz O, Hill JD, Al-Khaldi A, Pelletier MP, Robbins RC, Farrar
DJ. Thoratec ventricular assist devices in pediatric patients: update on
clinical results. ASAIO J. 2005;51:501–503.
19. Reinhartz O, Keith FM, El-Banayosy A, McBride LR, Robbins RC,
Copeland JG, Farrar DJ. Multicenter experience with the Thoratec ven-
tricular assist device in children and adolescents. J Heart Lung
Transplant. 2001;20:439–448.
20. Kaczmarek I, Sachweh J, Groetzner J, Gulbins H, Mair H, Rainer KF,
Zysk S, Reichart B, Daebritz S. Mechanical circulatory support in
pediatric patients with the MEDOS assist device. ASAIO J. 2005;51:
498–500.
21. Arabia FA, Tsau PH, Smith RG, Nolan PE, Paramesh V, Bose RK,
Woolley DS, Sethi GK, Rhenman BE, Copeland JG. Pediatric bridge to
heart transplantation: application of the Berlin Heart, Medos and Thoratec
ventricular assist devices. J Heart Lung Transplant. 2006;25:16–21.
22. Hetzer R, Loebe M, Potapov EV, Weng Y, Stiller B, Hennig E, Alexi-
Meskishvili V, Lange PE. Circulatory support with pneumatic paracor-
poreal ventricular assist device in infants and children. Ann Thorac Surg.
1998;66:1498–1506.
23. Merkle F, Boettcher W, Stiller B, Hetzer R. Pulsatile mechanical cardiac
assistance in pediatric patients with the Berlin heart ventricular assist
device. J Extra Corpor Technol. 2003;35:115–120.
24. Stiller B, Weng Y, Hubler M, Lemmer J, Nagdyman N, Redlin M, Lange
PE, Hetzer R. Pneumatic pulsatile ventricular assist devices in children
under 1 year of age. Eur J Cardiothorac Surg. 2005;28:234–239.
25. Blume ED, Naftel DC, Bastardi HJ, Duncan BW, Kirklin JK, Webber SA;
the Pediatric Heart Transplant Study Investigators. Outcomes of children
bridged to heart transplantation with ventricular assist devices: a multi-
institutional study. Circulation. 2006;113:2313–2319.
26. Taylor DO, Edwards LB, Boucek MM, Trulock EP, Deng MC, Keck BM,
Hertz MI. Registry of the International Society for Heart and Lung
Transplantation: twenty-second official adult heart transplant
report–2005. J Heart Lung Transplant. 2005;24:945–955.
27. Baldwin JT, Borovetz HS, Duncan BW, Gartner MJ, Jarvik RK, Weiss
WJ, Hoke TR. The National Heart, Lung, and Blood Institute Pediatric
Circulatory Support Program. Circulation. 2006;113:147–155.
28. Food and Drug Administration. Available at: http://www.fda.gov.
Accessed April 24, 2006.
KEY WORDS: Editorials Ⅲ cardiomyopathy Ⅲ heart-assist device Ⅲ
pediatrics
2268 Circulation May 16, 2006
by on July 14, 2008circ.ahajournals.orgDownloaded from