Pediatric Bridge to Heart Transplantation: Application of the Berlin Heart, Medos and Thoratec Ventricular Assist Devices

Pediatric Bridge to Heart Transplantation: Application of the Berlin Heart, Medos and Thoratec Ventricular Assist Devices Francisco A. Arabía, MD,a Pei H. Tsau, MD,a Richard G. Smith, CCE,b Paul E. Nolan, PharmD,c Venki Paramesh, MD,a Raj K. Bose, MD,a Daniel S. Woolley, MD,a Gulshan K. Sethi, MD,a Birger E. Rhenman, MD,a and Jack G. Copeland, MDa Background: Bridge to transplantation (BTT) is an accepted option when a donor heart is not available. Extensive clinical study has been done with BTT in the adult population, but comparatively fewer data are available in the pediatric population with regard to pulsatile devices. Methods: Ten pediatric patients are presented, all of whom underwent BTT or recovery with pneumatic paracorporeal systems. The Berlin Heart bi-ventricular assist device (BVAD) was utilized in 1 patient, the Medos VAD in 4 patients (1 left ventricular assist device [LVAD], 3 BVADs) and the Thoratec VAD in 5 patients (3 BVADs, 2 LVADs). The pediatric population consisted of 3 females and 7 males. Mean age of the population was 7.4 years, weight 25 kg and body surface area (BSA) 0.88 m2. Etiology for heart failure consisted of 4 viral, 3 congenital and 3 idiopathic cardiomyopathies. Before implant, all patients had evidence of progressive cardiac failure despite inotropic support, and 2 patients had been on extracorporeal membrane oxygenation (ECMO). Mean duration on the device was 34.3 days (8 to 107 days). Results: Two patients suffered stroke and recovered without sequelae. Two patients died of ischemic stroke and 1 of sepsis. Seven patients survived (6 transplanted and 1 weaned) for a survival rate of 70% compared with survival for ECMO as BTT, which was 40% to 50%. All survivors had complications related to bleeding, thromboembolic events and infections. Conclusions: The Thoratec VAD can be placed in small patients with large hearts that can accommodate the available cannulas. The Berlin Heart and the Medos VAD have a selection of ventricles with small stroke volumes. All 3 systems can be used successfully in the pediatric population as BTT with better survival than with ECMO. J Heart Lung Transplant 2006;25:16 –21. Copyright © 2006 by the International Society for Heart and Lung Transplantation.

It has been estimated that approximately 7,000 to 30,000 pediatric patients per year in the USA could benefit from bridge to transplantation (BTT).1 The most common etiologies of heart failure in this population are post-cardiotomy ventricular failure, viral myocarditis and idiopathic and congenital cardiomyopathies. Although a variety of ventricular assist devices (VADs) have been used successfully as BTT in adult patients, the experience in the pediatric population is limited, yet growing. It is evident that pediatric patients with

From the aDepartment of Cardiothoracic Surgery, University of Arizona Sarver Heart Center, Tucson, Arizona; bUniversity Medical Center, Tucson, Arizona; and cUniversity of Arizona College of Pharmacy, Tucson, Arizona. Submitted April 19, 2005; revised July 6, 2005; accepted July 13, 2005. Reprint requests: Francisco A. Arabía, MD, Department of Cardiothoracic Surgery, University of Arizona Sarver Heart Center, P.O. Box 245071, Tucson, AZ 85724-5071. Telephone: 520-626-6339. Fax: 520-626-4042. E-mail: [email protected] Copyright © 2006 by the International Society for Heart and Lung Transplantation. 1053-2498/06/$–see front matter. doi:10.1016/ j.healun.2005.07.003

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severe cardiomyopathies and heart failure can undergo successful BTT. The most widely used modality to support the failing ventricle in the pediatric population in the USA is extracorporeal membrane oxygenation (ECMO). In Europe, the Berlin Heart and the Medos VAD have been used as BTT with excellent results. The purpose of this study is to compare the survival of pediatric BTT with 3 different paracorporeal pneumatic systems to survival using ECMO. Studies of patients requiring ECMO for cardiac failure have shown that approximately 40% of patients recover adequate ventricular function and are able to be weaned off support and discharged from the hospital.2– 4 The ECMO experience as BTT is also well described, with success rates as high as 48%.5– 8 Although the use of ECMO has been associated with acceptable outcomes in this population, it is plagued with other complex problems.9 These include the need for patient sedation, immobility, bleeding, intense monitoring and length of support, which is further associated with a higher risk for complications. Another widely used device is the centrifugal pump, which also requires the patient to be continuously sedated

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Arabía et al.

and anti-coagulated. Early ambulation and mobilization in the pediatric population after placement of a VAD has been associated with faster recovery after transplantation.10 The intra-aortic balloon pump (IABP) has been utilized to provide cardiac and hemodynamic support in children. Pediatric series have shown that use of the IABP is feasible with survival rates ranging between 37% and 59%. However, it has not been successful in infants and small children.11 The Abiomed BVS 500012 has been utilized in large pediatric patients, although mobility is not optimal.13 The Novacor LVAS has been utilized in intermediate-sized pediatric patients with good results.14,15 Its most significant contribution is that it allows patients to be discharged home while waiting for heart transplantation. METHODS Ten children underwent placement of VADs between 1997 and 2004 with the intention of BTT (Table 1). The devices utilized were the Thoratec VAD (Thoratec Corp., Woburn, MA),16 the Berlin Heart VAD (Berlin Heart AG, Berlin, Germany) and the Medos VAD (Medos, Aachen, Germany). The last 2 devices are undergoing their first clinical use in the USA. The Food and Drug Administration approved their use on a compassionate basis.

17

In contrast to the Thoratec VAD, the Berlin Heart and the Medos systems have several prosthetic ventricle sizes that allow their use in small children. A wearable driving unit is also available to provide more ambulatory capacity.17 The Medos left ventricular chamber is available in 3 sizes, with stroke volumes of 10, 25 and 60 ml. When bi-ventricular support is required, the right ventricular chambers are 10% smaller (9, 22.5 and 54 ml, respectively).18 The pediatric population included 7 males and 3 females, ranging in age from 4 months to 16 years. The admitting diagnoses included 3 patients with dilated idiopathic cardiomyopathy, 3 with congenital cardiomyopathy and 4 with a viral cardiomyopathy. The 2 patients with congenital cardiomyopathy had undergone previous open heart procedures. The mean age of the group was 7.42 years (median 8.50 years), the mean weight was 25.8 kg (median 17.65 kg) and the mean body surface area was 0.88 m2 (median 0.82 m2). Pre-operatively all patients were in the pediatric intensive care unit. Although none of the patients had altered renal function by elevation of creatinine, all had hyponatremia, except for Patients 7 and 9. Hyponatremia was a reflection of the severity of fluid overload and heart failure. Seven patients had abnormal liver function as demonstrated by an elevated international normalized ratio (INR). All patients re-

Table 1. Pediatric Demographics for Bridge to Heart Transplantation Agea Patient (years) Gender Diagnosis 1 8 M Congenital (TGV) 2 11 M Dilated cardiomyopathy 3 16 M Dilated cardiomyopathy 4

9

M

5

14

F

6

12

F

7

0.9

M

8

1

F

9

0.3

M

2

M

10

Congenital (tricuspid regurgitation) Dilated cardiomyopathy Viral cardiomyopathy Viral cardiomyopathy Viral cardiomyopathy Viral cardiomyopathy Congenital (aortic stenosis)

Body Pre-operative inotropic Weightb surface support (␮g/kg/min) (kg) area (m2)c 34 1.1 Dopamine 6, dobutamine 15 17 0.77 Dopamine 5, dobutamine 10 64

1.66

18.3

0.86

54

1.52

35

1.22

8

0.4

11.6

0.51

7

0.34

9

0.45

Fractional shortening (20% to 44%) Not available 10%

Dopamine 2, dobutamine 20, milrinione 1, epinephrine 4.5 ␮g/min Dopamine 2, dobutamine 13

10%

124

1.2

15%

125

1.8

133

1.4

130

4.4

145

1.3

133

1.3

142

1

126

2

Dopamine 3, dobutamine 15, 17% milrinone 0.4 Dopamine 3, dobutamine 10, 5% milrinone 0.5 ECMO for 7 days, dopamine 15% (left ventricular 2, dobutamine 5 ejection fraction) ECMO for 5 days, dobutamine 14% 15, epinephrine 0.1 Dobutamine 15, nitroglycerine 13% 2.5 Dobutamine 20, epinephrine 7% 0.5, milrinone 0.5

INR, international normalized ratio; TGV, transposition of the great vessels; ECMO, extracorporeal membrane oxygenation. a Mean 7.42 years, median 8.50 years, SD 5.94 years, range 15.70 years. b Mean 25.79 kg, median 17.65 kg, SD 20.26 kg, range 57.00 kg. c Mean 0.88 m2, median 0.82 m2, SD 0.48 m2, range 1.32 m2.

Pre-operative serum Na (mEq/dl) INR 122 2.1 128 1

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Arabía et al.

quired cardiac support with inotropic agents. Dopamine and dobutamine were administered to all patients. Dopamine was used at a minimum of 2 ␮g/kg/min (range 2 to 6) and dobutamine at a minimum dose of 5 ␮g/kg/min (range 5 to 20). Four patients required addition of milrinone and 3 patients required intravenous epinephrine. Fractional shortening, as determined by echocardiography before device implant, ranged between 5% and 17%. Patient 1 had transposition of the great vessels and had undergone a Senning procedure with pulmonary artery banding. He developed progressive systemic ventricular dysfunction during the next 6 months and presented with cardiac failure. Patient 2 had developed progressive heart failure during the previous 4 to 6 weeks. Initial presentation revealed significant cardiac enlargement. Patient 3 had progressive shortness of breath and decreased physical tolerance for 4 months before presentation. Patient 4 had undergone a tricuspid valvuloplasty for insufficiency. He had been diagnosed with restrictive cardiomyopathy and right heart failure over the course of the previous 3 years. Patient 5, a female from Central America with idiopathic cardiomyopathy, was initially suspected to have Chagas disease. This was eventually ruled out as an etiology. Patient 6 had had progressive viral-type syndrome associated with shortness of breath and abdominal symptoms. The symptoms had lasted ⬍2 months by the time of presentation in cardiac failure. Patient 7 was presumed to have a viral cardiomyopathy and had suffered a cardiorespiratory arrest. He had been on ECMO for 7 days before transfer. Patient 8 had been transferred in cardiac failure, suffered a cardiorespiratory arrest, and was placed on ECMO for 5 days without improvement in cardiac function. Patient 9 had a mild Ebstein’s anomaly but had suddenly deteriorated during a viral syndrome. He did not respond to inotropic support and required placement of a Medos LVAD. He continued in failure with low VAD output requiring placement of a right VAD (RVAD) the next day. Patient 10 had an atrial septal defect, ventricular septal defect, aortic stenosis, coarctaction of the aorta and was pacemaker-dependent. He was already in failure when he underwent a percutaneous aortic valvuloplasty as last resort. He did not improve and had placement of an LVAD requiring an RVAD the next day because of insufficient LVAD output and right ventricular failure. All patients had been accepted and listed for heart transplantation before implantation of the device. The devices were implanted in different configurations (Table 2) depending on evidence of right ventricular failure, size of the patient and surgeon’s choice. The Berlin Heart and the Medos VAD were obtained from the manufacturers with special permission from the Food and Drug Administration (FDA). Internal review

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Table 2. Devices Patient 1 2 3 4 5 6 7 8 9 10 a

Device Thoratec VAD Thoratec VAD Thoratec VAD Berlin Heart Thoratec VAD Thoratec VAD Medos VAD Medos VAD Medos VAD Medos VAD

Cannulation and configuration Apical LVAD Apical LVAD Bi-apical BVAD Bi-atrial BVAD LV apical and right atrial BVAD Bi-apical BVAD Bi-atrial BVAD Apical LVAD LV apical and right atrial BVAD Bi-atrial BVAD

Days on VADa 11 22 49 40 46 105 20 8 22 20

Mean 34.3 days, median 22.0 days, SD 28.5 days, range 97 days.

board (IRB) approval was obtained for the Berlin Heart and Medos VAD. A Thoratec LVAD with apical cannulation was utilized in Patients 1 and 2. Three patients had bi-ventricular Thoratec VADs, 2 of which had left ventricular apical cannulation.19 Patient 4 had a Berlin Heart in the bi-ventricular configuration with atrial cannulations. Patients 7 and 10 had a Medos VAD, also in the bi-ventricular configuration with atrial cannulation. Patient 8 had a Medos VAD in the LVAD configuration with apical cannulation, and Patient 9 had a Medos bi-ventricular device in a left ventricular apical right atrial configuration. All patients received anti-coagulation after implantation that consisted of heparin, aspirin, dipyridamole and pentoxifylline.20 The doses were modified on a weight basis. Once the patients were stable, heparin was exchanged for coumadin. Thromboelastography, bleeding time, platelet count and INR (range 2.5 to 3.5) were used frequently and as necessary to monitor the adequacy of the anti-coagulation. An in-depth discussion of the adult protocol has been described elsewhere.21 The anticoagulation protocol utilized in this population was the same as that for adults. Intravenous prophylactic antibiotics were used at the time implantation and oral antibiotics for the duration of the implant. The patients were re-listed for heart transplantation once they were hemodynamically stable, ambulatory, and had achieved adequate nutritional status. They were encouraged to take short trips around the hospital and participate in the pediatric recreation room. Interaction with parents and siblings was encouraged as they provided emotional and psychologic support. RESULTS The children were supported for a mean of 34.3 days (median 22 days). In Patient 1, support was discontinued after 12 days upon finding that he suffered irreversible brain damage when he failed to awaken after implantation. This patient had also suffered cardiac arrest in the operating room before implantation, which

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required cardiopulmonary resuscitation. Patient 7 developed seizure activity after 20 days. Computerized tomography of the brain confirmed the presence of multiple strokes. Support was terminated after discussing the findings with the family. Patient 10 developed bowel ischemia followed by sepsis. The family requested that support be terminated. This patient was also known to have untreated coarctation of the aorta that may have contributed to his death. Patient 8 developed fever and was thought not to be a transplant candidate. A repeat echocardiogram revealed improvement in left ventricular contractility. He underwent successful removal of the LVAD at 8 days with eventual complete return of left ventricular function. Patients 2, 3, 4, 5, 6 and 9 continued to improve and were bridged to transplantation. The heart transplant procedure was performed in the usual manner. Mean ischemic time of the donor heart was 244 minutes. The most common complication during the peri-operative period was bleeding as a result of the anti-coagulation needs for the devices. This was treated with aminocaproic acid or aprotinin infusion as well as blood products. These patients were discharged home after a mean post-transplant hospital stay of 19 days. All patients achieved normal pulmonary, renal and hepatic function. No isolated right ventricular failure was seen in the 1 patient who received a Thoratec LVAD. The group had 20 adverse events during the time of support, with 2 complications/patient. The thromboembolic rate was 40%. Three patients suffered strokes and Patient 4 had evidence of splenic infarcts on computerized tomography of the abdomen. Patient 2 experienced a right middle cerebral artery occlusion that resulted in an initial left-sided hemiparesis. This patient recovered with minimal sequelae. Complications related to bleeding occurred in 40% of patients. Two patients had upper gastrointestinal bleeding that required decreased anti-coagulation for several days. The change in the anti-coagulation consisted of decreasing dipyridamole and discontinuing aspirin. Patient 3 had several episodes of epistaxis that resolved spontaneously. Patient 6 developed cardiac tamponade 8 days after implantation, which required mediastinal re-exploration. The source of the bleeding was not identified. It appeared that this was the result of excessive anticoagulation. The infection rate was 30%. Three patients underwent local infections at the level of the skin where the cannulae exited. Patient 3 initially developed Candida albicans that was treated with oral fluconazole. This patient also eventually developed a skin infection with Staphylococcus epidermidis. Patient 5 developed a similar infection; both were treated with intravenous vancomycin. Patient 5 also developed what appeared to be thrombus formation in the right-sided

Arabía et al.

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Table 3. Complications and Outcomes Patient 1 2 3

4

5 6 7 8 9 10

Complications Ischemic stroke Ischemic stroke Epistaxis, Candida and Staphylococcus epidermis drive-line infection, hemolysis Left lower-lobe pneumonia, splenic infarcts, upper gastrointestinal (GI) bleed Gastritis, RVAD clots, drive-line infection Tamponade, upper GI bleed, systemic hypertension Ischemic stroke Fever, right middle lobe collapse BVAD replacement secondary to thrombi Ischemic bowel

Outcome Died Alive—transplanted Alive—transplanted

Alive—transplanted

Alive—transplanted Alive—transplanted Died Alive—weaned Alive—transplanted Died

VAD. This finding prompted VAD replacement. Small plaques were identified on the inner wall of the VAD that appeared insignificant. Patient 9 also developed slight thrombus formation in both VADs, requiring them to be changed despite what was considered adequate anticoagulation. Post-operative evaluation in these 2 patients showed no clear thrombus and minimal white thrombus. One patient had a transient deterioration of renal function at the time of implantation of the device and after cardiac transplantation, which did not require treatment. The patient who was bridged with the Berlin Heart was known to have an elevated pulmonary vascular resistance (22 Wood units). He underwent right ventricular dysfunction in the peri-operative period and required inhaled nitric oxide for 3 days. This patient underwent right-heart catheterization 1 year after transplantation that showed normal pulmonary vascular resistance. There were no device-malfunction adverse events in this series. The overall survival rate for this group was 70% (Table 3). DISCUSSION All 3 devices utilized in this series are well known and their function is very similar. The Thoratec VADs have been used worldwide while the Berlin Heart and Medos VADs have been used in Europe. The Thoratec VAD system has been utilized in over 800 patients worldwide with 58% to 74% of the patients surviving to transplantation, along with a hospital discharge rate of between 81% and 89%.22 Infections have been the most common complication associated with this device. The most common cause of death has been multiple-organ failure. This is very similar to most commonly available devices. The Thoratec VAD has

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Arabía et al.

now been utilized successfully in children with a body surface area (BSA) of ⬍1.3 m2. In this series, survival was better for patients with the diagnosis of cardiomyopathy/myocarditis vs congenital disease: 72% vs 14%.23 Furthermore, a multicenter experience with the Thoratec device in children with a BSA of 0.7 to 2.1 m2 has shown 60% survival to transplantation and 10% survival after recovery of the native heart.24 Five patients in this series received the Thoratec VAD, 4 of whom survived. This device was utilized in the larger patients. The Berlin Heart has been utilized as bridge to recovery and transplantation. Over 350 Berlin Heart devices had been implanted by 1999, and it has been used in patients as small as 4 kg. Duration of support has ranged from 12 hours to 114 days, with a mean duration of 17.3 ⫾ 24.2 days. Thromboembolic complications have been identified in patients with septic infections. Minor infections have been observed at cannulae exit sites.25 Only 1 patient received this device in the present series. Survival rates have been published in the literature for these 3 devices. Overall survival rates in the pediatric population were as follows: Thoratec VAD, 68.8%; Berlin Heart VAD, 48.9%; and Medos VAD, 36.2%.26 Excellent results have also been described with 72% survival at 1 month, 1 year and 5 years for children who underwent BTT. Furthermore, survival was better for children with cardiomyopathy as compared with congenital heart defects.27 The current anti-coagulation protocols available at different institutions may be adequate for medium- to large-size/ almost-adult patients. Such protocols may not be adequate for neonates or small children. It has been suggested that a technique to decrease the risk of thromboembolic events in this population when utilizing these devices is to use apical cannulation as opposed to atrial inflow into the device. This could provide better washing of the ventricle and possibly better output from the device. Infections remain a concern and better management of the exit cannulae will help with this complication. An in-depth discussion of anti-coagulation is beyond the scope of this study. There is no doubt that the availability of these 3 devices gives hope for this population. However, it should be kept in mind that the devices are different in some ways and the appropriate device and configuration should be selected for proper application and accommodation of the patient’s size. One of the major factors that made this population different from adults is the need to clearly communicate to the patient’s family the obstacles to be encountered, because it is they who provide consent for the intervention. Expectations must be realistic and outcome possibilities clearly presented.

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The number of pediatric patients assessed herein was small (n ⫽ 10). Physical size of the patients ranged from infant to adult. The Thoratec VAD system is adequate for small- to intermediate-size children, depending on the anatomy. Neonates and small children remain a challenge with regard to use of VADs. In this patient sub-population, the Berlin Heart and Medos VADs are the best option as the cannulae and pumps come in a variety of sizes. The device must to be tailored to each patient’s needs. More clinical experience is required to make a definitive statement about which device should be used and under which configuration. Further investigation is needed to develop appropriate anti-coagulation protocols. Although ECMO has been adequate as a BTT in some cases, waiting times for organs have increased in the last few years. The difference in survival between pediatric VADs and ECMO as BTT is not statistically significant at this time as a larger population is required for data assessment. We hope that this study shows a positive trend with VADs in this population. Complications related to the use of ECMO are known to increase the longer the patient is on support.28 This may exclude ECMO as the best option. VADs have shown that they can provide long-term support in adults and children. In addition, they allow mobility to the point that patients may be able to return home one day, increase their level of physical activity, and potentially may be able to return to school, at home or while in the hospital, while waiting for a suitable donor. The cost of this technology has proven to be very expensive in the adult population, adding significant expense to the total cost of transplantation. The cost might even be higher in the pediatric population as more support is likely to be required. A return to a normal quality of life is impossible while on a device, regardless of whether it is bridge to recovery or bridge to transplantation. Emotional support among family members is essential to encourage a child who has been ill to undergo a major surgical intervention and rehabilitation, and then undergo a second operation. The support of several medical specialties, including social workers and child psychologists, is required to provide successful outcomes for patients who receive a VAD. It is our hope that management of the pediatric population with VADs will be easier than with ECMO. Proper management of outpatient children with a VAD will prove to be a challenge. REFERENCES 1. Spray TL. Demographics of heart failure in the pediatric population. Paper presented at the 47th annual ASAIO Conference, June 2001, New York. 2. Ibrahim AE, Duncan BW, Blume ED, Jonas RA. Longterm follow-up of pediatric cardiac patients requiring

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