Mechanical Assist Devices in Neonates and Infants Angela Lorts,a Farhan Zafar,b Iki Adachi,c and David L.S. Moralesb Clinical advances in the field of mechanical support have led to additional treatment strategies in adult and, subsequently, pediatric heart failure management. The limited number of device options available to the pediatric population has led to a reallocation of resources in order to broaden the pediatric device armamentarium. Although there are very few device options in pediatrics, there are short-term support options that include the RotaFlow and PediMag. The longer-term support option for small children is limited to only the Berlin heart EXCOR device, which had been approved by the FDA since December 2011. There is a dire need for further device options for the pediatric patient and many devices funded by the PumpKIN program are under development to further the care of this population. Semin Thorac Cardiovasc Surg Pediatr Card Surg Ann 17:91-95 C 2014 Elsevier Inc. All rights reserved.

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entricular Assist Devices (VADs) are becoming a routine therapeutic option in the management of adult heart failure. In adult medicine, devices are being used as a bridge to transplantation and as destination therapy to prolong the life of patients with heart failure. This has not been true in pediatrics. During the last decade there was a paucity of device options to support the pediatric circulation, limited mainly to extracorporeal membrane oxygenation (ECMO).1 In the last 5 years there has been a newly kindled interest in mechanical circulatory support for children, leading to the US Food and Drug Administration (FDA) approval of the Berlin heart in December of 2011.2,3 In recognition of the fact that the pediatric field is not prepared to take care of a quickly increasing number of a

Department of Cardiology, The Heart Institute, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH. b Department of Congenital Heart Surgery, The Heart Institute, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH. c Department of Congenital Heart Surgery, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX. Presented at the 92nd Annual Meeting of American Association of Thoracic Surgeon at Postgraduate Congenital Heart Disease Symposium on April 29th 2012 in San Francisco, CA. This article was originally scheduled to appear in the 2013 edition of the Pediatric Cardiac Surgery Annual. The Publisher apologizes for inadvertently excluding this article from the 2013 edition. Therefore, the Authors and Editor have elected to include this article in this 2014 edition. Address correspondence to David L. Morales, MD, Cincinnati Children’s Hospital Medical Center, The University of Cincinnati College of Medicine, 3333 Burnet Ave. – MLC 2004, Cincinnati, OH 45229. E-mail: david. [email protected]

http://dx.doi.org/10.1053/j.pcsu.2014.02.001 1092-9126/& 2014 Elsevier Inc. All rights reserved.

children with heart failure, especially neonates and infants, the National Heart, Lung and Blood Institute (NHLBI) of the National Institute of Health (NIH) issued a request for a proposal for the development of a pediatric VAD. This proposal was the impetus for the Pediatric Circulatory Support Program that was started in 2004 and is led by Dr. Tim Baldwin. Since this time the NHLBI has awarded contracts to five institutions/ companies to develop a VAD to accommodate the smallest patients (Fig. 1). Although some progress was made, none of the devices were close to clinical application at the end of the 5year award contracts. At the end of these contracts, the NIH still did not have their desired product, a pediatric VAD. In October of 2008, another request for a proposal was published; this program was named PumpKIN (Pumps for Kids, Infants and Neonates). This unique program has two parts. The pre-clinical awards are designed to support the most promising concepts and projects and are issued to bring the projects to clinical trial. The second phase will finance a data coordinating center to assist the awardees in writing investigational device exemptions (IDE) applications, and to run the clinical trial. This is a unique amount and type of support for the NIH to award in order to bring a product to clinical use. This program clearly demonstrates the NIH’s desire to efficiently help develop a long-term, reliable VAD for the growing population of small children and infants with heart failure.4

Investigational Devices Funded in the PumpKIN Program These are four investigational devices currently funded in the PumpKIN trial (Fig. 2). Two of which are ECMO systems; the 91

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Figure 1 NHLBI’s PumpKIN program.

pCAS or the Ension. This device has the pump as well as the oxygenator; its console is a touch-screen console and is being developed as a small unit for easy mobility. Second is the PediPL, which is the Levitronix pump with the addition of an oxygenator; portable and small. The two VADs in the program are the PediaFlow (Pittsburgh) program, which is going to be for neonates/infants to 2 years but, unfortunately, has now been ended because of a lack of an industry partner; and the Jarvik Pediatric 2000, which is incredibly small with a priming volume of only 1 cc and sits inside the ventricle wall. The remaining

three devices are being developed and protocols for clinical trials are being devised, but they are still far away from clinical use. Not only does the NIH appreciate the need for pediatric devices, but industry has also expressed their understanding of the newly found market. Until recently, companies viewed pediatric mechanical circulatory support as non-profitable. In 2012, there is not a single VAD-producing company that does not have an active pediatric device initiative (Table 1). This change in strategy and attitude is based on their due diligence and our demonstration of an emerging market. Industry also

Figure 2 Four pediatric-specific devices awarded under the PumpKIN program. (Per communications with John Timothy Baldwin, Project Officer, NHLBI Pediatric Ventricular Devices.)

Mechanical assist devices in neonates and infants Table 1 Pediatric VAD initiatives in United States Pediatric pCAS (Ension, Inc., Pittsburgh, PA) Pediatric pVAD (CardiacAssist, Inc., Pittsburgh, PA) SynCardia TAH 50cc (Syncardia Systems, Inc., Tucson, AZ) PediVAS (Levitronix Technologies LLC, Waltham, MA) Pediatric Impella (ABIOMED, Inc., Danvers, MA) PedM-Pump (MC3, Inc., Ann Arbor, MI) PediPump (Foster-Miller Technologies, Inc., Waltham, MA) Ultramag Pediatric VAS (Levitronix Technologies LLC) PediaFlow Pediatric VAD (World Heart, Inc., Salt Lake City, UT) Penn State Infant and Child-size Pediatric VADs Jarvik Pediatric 2000 (Jarvik Heart, Inc., New York, NY)

recognizes the government’s strong commitment and their desire to fund pediatric initiatives. However, these funds will not only help companys to develop technology for children, but will also further the field of adult mechanical support. A decade ago there was no pediatric VAD initiative supported by industry in the United States (US), now there are at least 10 different pediatric VAD initiatives. There are devices available to mechanically support children, but the options are limited and the pediatric technology is not as advanced as that of adult devices. A majority of pediatric institutions use ECMO as the only mechanical option for children with cardiac failure. The widespread use of ECMO is secondary to provider comfort and the availability of equipment/devices. The major difference between ECMO and a VAD circuit is the addition of an oxygenator or a heat exchanger that provides respiratory function to an ECMO circuit. Therefore, patients supported with ECMO have both cardiac and pulmonary support as opposed to soley cardiac support. In many cases, the patient does not need pulmonary

93 support, leading to an unnecessary increased risk of complication. More importantly, ECMO is significantly limited in providing an effective period of support (usually 10 to 20 days). Whereas the median wait time for infants on a transplant list is approximately 120 days. This has resulted in poor survival to heart transplant for children supported with ECMO.5 Our policy has been to avoid mechanical support complications by preventing the need for ECMO support whenever possible. The overall goal is to institute support prior to respiratory failure. Our experience has been pivotal in the implementation of a policy to define the optimal timing of instituting mechanical support and which device should be used. Figure 3 presents our institutional policy in supporting children of all sizes with either short- or long-term support.

Short-Term VADs Short-term VADs have a simple circuit with no oxygenator, unlike ECMO. They will allow for support for an average of 7 to 14 days. They require low levels of anticoagulation, provide decompression of the supported ventricle, and are far less of a surgical commitment than a long-term VAD. Unfortunately, however, they require central cannulation in small patients and there is little control of temperature.

RotaFlow RotaFlow is a temporary VAD used to support all sized patients, from the neonate to the adult patient. It has a centrifugal pump, 50 mm in diameter, made of polycarbonate material that is extracorporeal, requires 32 ml of priming

Figure 3 Protocol for supporting infants and neonates at our institution.

94 volume, and can provide flow rate from 0 to 10 L/min. The pump runs on an electromagnetic mechanism with the circuit levitated in three magnetic fields with one point bearing, which produces laminar flow immediately. It reduces the mechanical friction and heat production and, thus, damage to blood; overall wear is greatly reduced compared with the older centrifugal pumps. The company also plans to have the RotaAssist Temporary VAD available for clinical use, hopefully in 2013. It is similar in mechanism than the present RotaFLow but will be able to measure inflow and outflow pressures and have in-line technology to measure certain parameters, such as oxygen level.

Levitronix PediMag The Levitronix PediMag is a pediatric-specific pump. The pump is magnetically levitated and there are no wearing parts. There is no point source of friction; therefore, there is even less heat and blood damage than other centrifugal pumps. This device is capable of delivering up to 1.5 L/min flow and is portable, facilitating patient transfer in emergency situations. It has been implanted in more than 650 pediatric patients worldwide, including patients in 10 centers across the US, and this number continues to grow. In most cases, it has been paired with an oxygenator to provide ECMO (95% of patients; and in only 5% of cases was it used solely as a VAD). Texas Children’s Hospital (TCH) experience with shortterm VADs A total of 35 children at a median age of 5 years (range, 2 days to 20 years) with a median weight of 19 kgs (range, 2 kg to 93 kg) were supported with short-term VADs. Median time on the device was 6 days (range, 3 to 19 days). Survival for patients with an acute etiology was 95% (19/20), whereas for patients with chronic cardiac disease with an acute decompensation, survival was only 87% (13/15). All patient who died on device were under 3 kg. Survival to hospital discharge was 77% (27/35). Acute etiologies included myocarditis, acute graft rejection, and post-cardiotomy low cardiac output syndrome, whereas in chronic heart failure the etiologies included cardiomyopathy and congenital heart disease. Recovery was noted in 85% (17/20) of the patients with an acute etiology; however, the majority of chronic heart failure patients (80%: 12/15) required bridge to long-term VAD or transplant.

Long-Term VADs Berlin Heart EXCOR is the only long-term VAD available (FDA approved in December 2011) for neonates and infants in the US and is the most commonly used pediatric VAD throughout the world. It has been implanted in more than 325 pediatric patients in the US and more than 1,000 pediatric patients worldwide. The Berlin Heart is a paracorporeal VAD with pulsatile flow and is used soley as a bridge to transplant. It works with a mobile driving unit. Before Berlin Heart, there was no pediatric long-term VAD in the US. Pediatric mechanical support consisted of ECMO

A. Lorts et al. and adult VADs being placed in larger adolescents. The EXCOR is the first true pediatric VAD to gain widespread use across the US and has been used both as an LVAD and BiVAD. Pump sizes vary from 10 ml to 60 ml (10, 25, 30, 50, 60 mls) and it is capable of supporting children of every age and size. It is currently powered by a bedside driver unit, but an EXCOR Active driver is being tested and will allow discharge of patients to home. It is expected to have Conformité Européenne (CE) approval in 2012 and plans for Humanitarian Device Exemption (HDE) in the third or fourth quarter of 2013. As is known to most of the pediatric cardiology community, the Circulatory System Devices Advisory Panel of the FDA approved the Berlin Heart in December of 2011 for use in children, but it is important to read the approval letter, which states that any pediatric patient with uni- or bi-ventricular heart failure who is a candidate for heart transplant can receive the EXCOR. This means that there is no age, weight, or diagnosis restriction. It has given clinicians the ability to make the decision of when to use the VAD in pediatrics. There is a postmarket study being designed to continually evaluate the use in the first 40 patients. It should be noted that it is still an HDE device, allowing the placement of up to 4,000 devices, and will still need IRB approval. Almond et al6 summarized the results of all patients undergoing EXCOR over the IDE study period, including patients not at the IDE sites. Two hundred four patients at all 42 sites (15 IDE and 27 non-IDE sites) were analyzed, a non-selective consecutive patient cohort. A total of 101 infants underwent EXCOR during the study period; median age was 129 days (range, 7 to 360 days). There were only 18 (18%) neonates. Median weight was 5.6 kg (range, 2.8 to 14.7 kg) and median support time was 26 days (range, 0 to 232 days). Primary diagnosis included 44% dilated cardiomyopathy, 35% congenital heart disease, 19% myocarditis, and only 3% hypertrophic cardiomyopathy. Device type was LVAD for two thirds of the cases and BiVAD for one third. The most common device size used was the 10-cc pump, which was expected for this cohort. Fifty percent of the cohort was successfully bridged to transplant, 12% were weaned, and 39% died on the support. Competing outcomes analysis demonstrated that at 6 months, 47% were transplanted, 11% weaned, 4% were still on device, and 39% died; therefore, overall positive outcome was 61% in infants. This was different than the overall cohort, which had a positive outcome of 75%.6 Analysis of the overall cohort showed lower weight (infants) as a risk factor for mortality. Also important to note is that BiVAD support was a significant independent risk factor of mortality. A BiVAD was used in one third of the infants in the cohort. The authors state that BiVAD support is rarely needed, at least in children, except for some selected etiologies such as severe cardiac graft rejection and patients with arrhythmias as the predominant cause of heart failure. It is suggested that if you decide to support early, avoid arresting the heart to place the VAD and perform continuous ultrafiltration on bypass, a BiVAD can potentially be avoided. There are certain technical aspects of putting in the EXCOR. The aortic cannula is stiff and there is a tendency to place it too

Mechanical assist devices in neonates and infants low, which can cause the right heart to be impinged or for the heal of the anastomosis to be stressed, which can lead to bleeding at the heal, which is very difficult to control. The avoidance of bleeding is extremely important because infusion of blood products will increase the risk of right heart failure. In the authors’ experience with the Berlin Heart EXCOR the sternum was closed in all of the infants and none required reexploration for bleeding. Right heart support with inotropes, specifically Milrinone and epinephrine, should be continued until the patient is extubated. Inhaled nitric oxide is also used to off-load the right heart and can be used through extubation and may be delivered via nasal cannula. If the decision to support is made early enough and the right ventricular insult is minimized, theoretically LVAD implantation should only improve right heart function. We have not used CVP, echocardiogram, or any other criteria for deciding whether to use a BiVAD and, in our experience, the use of a BiVAD is mostly based on the diagnosis. Overall less than 8% of all mechanical circulatory support was in the form of a BiVAD, three were temporary BiVADs; two after cardiac arrest and one after severe primary graft rejection. There was one Thoratec Peripheral BiVAD placed for unremitting antibody mediated rejection in a transplant patient.

TCH experience with EXCOR in infants A total of 11 infants were supported with the EXCOR. Median age was 165 days (range, 69 to 315 days), median weight was 6.7 kg (range, 3.3 to 7.8 kg). Most of the infants had dilated cardiomyopathy (9; 82%) and only two (18%) had congenital heart disease as a cause of heart failure. Two of these infants had suffered from cardiac arrest and went on to temporary devices; one was on ECMO before EXCOR implant. No BiVADs were used. Median duration of support was 59 days (range, 2 to 144 days). All 11 infants (100%) were transplanted with 100% hospital survival.

Conclusion In summary, the number of children with cardiac failure is growing; therefore, industry and government have begun

95 to support the development of technology to help support neonates/ infants and young children. The use of ECMO should become limited to only cases of severe cardiorespiratory failure where oxygenation is an issue. All cases of isolated cardiac failure should be able to be supported with a temporary or long-term VAD, if device placement is early enough in the process. Early decision-making and right heart support with careful surgical technique should prevent the need for BiVAD support. Berlin Heart, especially for the very small children, will probably be the main device to be implanted for the next 5 years, but we as a pediatric community should continue to take advantage of the ongoing adult VAD technological advancements that result in smaller and more reliable devices by placing these intracorporeal second- and thirdgeneration devices is children. Clearly, there are currently enough devices available to have an independent, robust, pediatric VAD program to support children of all sizes, including neonates and infants.

References 1. Kirk R, Dipchand AT, Edwards LB, et al: The Registry of the International Society for Heart and Lung Transplantation: Fifteenth Pediatric Heart Transplantation Report - 2012. J Heart Lung Transplant 2012;31: 1065-1072 2. Fraser CD Jr , Jaquiss RD, Rosenthal DN, et al: Prospective trial of a pediatric ventricular assist device. N Engl J Med 2012;367:532-541 3. US Food and Drug Administration. 2011 Device approvals. Available at: http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/ DeviceApprovalsandClearances/Recently-ApprovedDevices/ucm241 143.htm. 4. National Heart, Lund, and Blood Institute. NHLBI funds preclinical tests on devised for infants and children with congenital heart defects. Available at: http://www.nhlbi.nih.gov/news/press-releases/2010/nhlbifunds-preclinical-tests-on-devices-for-infants-and-children-with-conge nital-heart-defects.html 5. Jeewa A, Manlhiot C, McCrindle BW, et al: Outcomes with ventricular assist device versus extracorporeal membrane oxygenation as a bridge to pediatric heart transplantation. Artif Organs 2010;34:1087-1091 6. Almond C, Morales D, Buchholz H, et al: outcomes of children supported with the Berlin heart EXCOR Pediatric VAD: Impact of patient characteristics at implant on mortality. Circulation 2011;124: A11366