Kristine J. Guleserian

Berlin Heart EXCOR Pediatric Ventricular Assist Device for Bridge to Heart Transplantation in US Children

Background— Recent data suggest that the Berlin Heart EXCOR Pediatric ventricular assist device is superior to extracorporeal membrane oxygenation for bridge to heart transplantation. Published data are limited to 1 in 4 children who received the device as part of the US clinical trial. We analyzed outcomes for all US children who received the EXCOR to characterize device outcomes in an unselected cohort and to identify risk factors for mortality to facilitate patient selection. Methods and Results— This multicenter, prospective cohort study involved all children implanted with the Berlin Heart EXCOR Pediatric ventricular assist device at 47 centers from May 2007 through December 2010. Multiphase nonproportional hazards modeling was used to identify risk factors for early (<2 months) and late mortality. Of 204 children supported with the EXCOR, the median duration of support was 40 days (range, 1–435 days). Survival at 12 months was 75%, including 64% who reached transplantation, 6% who recovered, and 5% who were alive on the device. Multivariable analysis identified lower weight, biventricular assist device support, and elevated bilirubin as risk factors for early mortality and bilirubin extremes and renal dysfunction as risk factors for late mortality. Neurological dysfunction occurred in 29% and was the leading cause of death. Conclusions— Use of the Berlin Heart EXCOR has risen dramatically over the past decade. The EXCOR has emerged as a new treatment standard in the United States for pediatric bridge to transplantation. Three-quarters of children survived to transplantation or recovery; an important fraction experienced neurological dysfunction. Smaller patient size, renal dysfunction, hepatic dysfunction, and biventricular assist device use were associated with mortality, whereas extracorporeal membrane oxygenation before implantation and congenital heart disease were not.

Bone marrow as a cell source for tissue engineering heart valves

BACKGROUNDnThis study was designed to assess the feasibility of using ovine bone marrow-derived mesenchymal stem cells to develop a trileaflet heart valve using a tissue engineering approach.nnnMETHODSnBone marrow was aspirated from the sternum of adult sheep. Cells were isolated using a Ficoll gradient, cultured, and characterized based on immunofluorescent staining and the ability to differentiate down a specific cell lineage. Two million cells per centimeter squared were delivered onto a polyglycolic acid (PGA), poly-4-hydroxybutyrate (P4HB) composite scaffold and cultured for 1 week before being transferred to a pulse duplicator for an additional 2 weeks. The tissue-engineered valves were assessed by histology, scanning electron microscopy, and biomechanical flexure testing.nnnRESULTSnCells expressed SH2, a marker for mesenchymal stem cells, as well as specific markers of smooth muscle cell lineage including alpha-smooth muscle actin, desmin, and calponin. These cells could be induced to differentiate down an adipocyte lineage confirming they had not fully committed to a specific cell lineage. Preliminary histologic examination showed patchy surface confluency confirmed by scanning electron microscopy, and deep cellular material. Biomechanical flexure testing of the leaflets showed an effective stiffness comparable to normal valve leaflets.nnnCONCLUSIONSnMesenchymal stem cells can be isolated noninvasively from the sternum of sheep and can adhere to and populate a PGA/P4HB composite scaffold to form tissue that has biomechanical properties similar to native heart valve leaflets. Thus, bone marrow may be a potential source of cells for tissue engineering trileaflet heart valves, particularly in children with congenital heart disease.

The use of the Berlin heart EXCOR in patients with functional single ventricle

INTRODUCTIONnThe frequency and successful use of pediatric ventricular assist devices (VADs) as a bridge to cardiac transplantation have been steadily increasing since 2003, but the experience in patients with complex congenital heart disease has not been well described. Using a large prospectively collected dataset of children supported with the Berlin Heart EXCOR VAD, we have reviewed the experience in children with single ventricular anatomy or physiology (SV), and compared the results with those supported with biventricular circulation (BV) over the same time period.nnnMETHODSnThe EXCOR Investigational Device Exemption study database was retrospectively reviewed. VAD implants under the primary cohort and compassionate use cohort between May 2007 and December 2011 were included in this review.nnnRESULTSnTwenty-six of 281 patients supported with a VAD were SV. The most common diagnosis was hypoplastic left heart syndrome (15 of 26). Nine patients were supported after neonatal palliative surgery (Blalock-Taussig shunt or Sano), 12 after a superior cavopulmonary connection (SCPC), and 5 after total cavopulmonary connection (TCPC). Two patients received biventricular assist devices, 1 after stage I surgery and 1 after stage II. SV patients were supported for a median time of 10.5 days (range, 1-363 days) versus 39 days (range, 0-435 days) for BV (P = .01). The ability to be bridged to transplant or recovery in SV patients is lower than for BV patients (11 of 26 [42.3%] vs 185 of 255 [72.5%]; P = .001). Three of 5 patients with TCPC were successfully bridged to transplant and were supported with 1 VAD. Seven of 12 patients with SCPC were bridged to transplant, and only 1 of 9 patients supported after a stage I procedure survived.nnnCONCLUSIONSnThe EXCOR Pediatric VAD can provide a bridge to transplant for children with SV anatomy or physiology, albeit less successfully than in children with BV. In this small series, results are better in patients with SCPC and TCPC. VAD support for patients with shunted sources of pulmonary blood flow should be applied with caution.

Outcomes of pediatric patients supported with continuous-flow ventricular assist devices: A report from the Pediatric Interagency Registry for Mechanical Circulatory Support (PediMACS)

BACKGROUNDnContinuous-flow (CF) ventricular assist devices (VADs) have largely replaced pulsatile-flow VADs in adult patients. However, there are few data on CF VADs among pediatric patients. In this study we aimed to describe the overall use, patients characteristics and outcomes of CF VADs in this population.nnnMETHODSnThe Pediatric Interagency Registry for Mechanical Circulatory Support (PediMACS) is a national registry for U.S. Food and Drug Adminstration (FDA)-approved VADs in patients <19 years of age. Patients undergoing placement of durable CF VADs between September 2012 and June 2015 were included and outcomes were compared with those of adults from the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS).nnnRESULTSnCF VADs were implanted in 109 patients at 35 hospitals. The median age at implantation was 15 years (2.8 to 18.9 years) and median weight was 62 kg (range 16 to 141 kg). The underlying disease was cardiomyopathy in 89 (82%) patients. The INTERMACS level at time of implant was Level 1 in 20 (19%), Level 2 in 64 (61%) and Levels 3 to 7 in 21 (20%) patients. Most were implanted as LVADs (n = 102, 94%). Median duration of support was 2.3 months (range <1 day to 28 months). Serious adverse event rates were low, including neurologic dysfunction (early event rate 4.1 per 100 patient-months with 2 late events). Competing outcomes analysis at 6 months post-implant indicated 61% transplanted, 31% alive with device in place and 8% death before transplant. These outcomes compared favorably with the 3,894 adults supported with CF VADs as a bridge to transplant.nnnCONCLUSIONSnCF VADs are commonly utilized in older children and adolescents, with excellent survival rates. Further study is needed to understand impact of patient and device characteristics on outcomes in pediatric patients.

Management of Single‐Ventricle Patients With Berlin Heart EXCOR Ventricular Assist Device: Single‐Center Experience

There are minimal data regarding chronic management of single-ventricle ventricular assist device (VAD) patients. This study aims to describe our centers multidisciplinary team management of single-ventricle patients supported long term with the Berlin Heart EXCOR Pediatric VAD. Patient #1 was a 4-year-old with double-outlet right ventricle with aortic atresia, L-looped ventricles, and heart block who developed heart failure 1 year after Fontan. She initially required extracorporeal membrane oxygenation support and was transitioned to Berlin Heart systemic VAD. She was supported for 363 days (cardiac intensive care unit [CICU] 335 days, floor 28 days). The postoperative course was complicated by intermittent infection including methicillin-resistant Staphylococcus aureus, intermittent hepatic and renal insufficiencies, and transient antithrombin, protein C, and protein S deficiencies resulting in multiple thrombi. She had a total of five pump changes over 10 months. Long-term medical management included anticoagulation with enoxaparin, platelet inhibition with aspirin and dipyridamole, and antibiotic prophylaxis using trimethoprim/sulfamethoxazole. She developed sepsis of unknown etiology and subsequently died from multiorgan failure. Patient #2 was a 4-year-old with hypoplastic left heart syndrome who developed heart failure 2 years after bidirectional Glenn shunt. At systemic VAD implantation, he was intubated with renal insufficiency. Post-VAD implantation, his renal insufficiency resolved, and he was successfully extubated to daytime nasal cannula and biphasic positive airway pressure at night. He was supported for 270 days (CICU 143 days, floor 127 days). The pump was upsized to a 50-mL pump in May 2011 for increased central venous pressures (29u2003mmu2003Hg). Long-term medical management included anticoagulation with warfarin and single-agent platelet inhibition using dipyridamole due to aspirin resistance. He developed increased work of breathing requiring intubation, significant anasarca, and bleeding from the endotracheal tube. The family elected to withdraw support. Although both patients died prior to heart transplantation, a consistent specialized multidisciplinary team approach to the medical care of our VAD patients, consisting of cardiothoracic surgeons, heart transplant team, hematologists, pharmacists, infectious disease physicians, psychiatrists, specialty trained bedside nursing, and nurse practitioners, allowed us to manage these patients long term while awaiting heart transplantation.

Ten yr of pediatric heart transplantation: a report from the Pediatric Heart Transplant Study

The PHTS was founded in 1991 as a not‐for‐profit organization dedicated to the advancement of the science and treatment of children during listing for and following heart transplantation. Now, 21 yr later, the PHTS has contributed significantly to the field, most notably in the form of outcomes analyses and risk factor assessment, in addition to amassing the most detailed dataset on pediatric heart transplant recipients worldwide. The purpose of this report is to review the last decade of pediatric patients listed for heart transplantation (January 1, 2000–December 31, 2009) and summarize the changes, trends, outcomes, and lessons learned.

Surgical aortic valvuloplasty in children and adolescents with aortic regurgitation: acute and intermediate effects on aortic valve function and left ventricular dimensions.

OBJECTIVEnSurgical aortic valvuloplasty is increasingly employed in the management of children and adolescents with aortic regurgitation, but the durability of this approach and factors associated with outcome are not well defined.nnnMETHODSnFrom 1989 to 2005, a total of 81 patients younger than 19 years with moderate or severe aortic regurgitation underwent surgical aortic valvuloplasty. Aortic regurgitation was congenital in 20 cases, after treatment of aortic stenosis in 30, from other injuries to the aortic valve in 12, and from other causes in 19. Eighteen patients had moderate or severe aortic stenosis. Preoperative left ventricular end-diastolic dimension z score was 4.9 +/- 2.7.nnnRESULTSnAfter surgical aortic valvuloplasty with various techniques, including pericardial leaflet augmentation in 80%, aortic regurgitation was improved in 77 patients and was mild or less in 68. Ten of 18 patients with moderate or severe aortic stenosis before repair had a decrease to mild, whereas 2 had progression from mild to moderate. Left ventricular end-diastolic dimension z score decreased by 2.9 +/- 2.1 (P < .001). During follow-up (median 4.7 years), 33 patients underwent aortic valve reinterventions, including aortic valve replacement in 25. Estimated freedoms from aortic valve replacement were 72% +/- 6% at 5 years and 54% +/- 9% at 7.5 years and were shorter in patients with moderate or severe aortic stenosis before surgical aortic valvuloplasty. Among surviving patients who did not undergo aortic valve replacement, aortic regurgitation at follow-up was moderate in 21 and trivial or mild in 34; left ventricular and aortic root dimensions were preserved.nnnCONCLUSIONnSurgical aortic valvuloplasty is a valid option with good intermediate results for children and adolescents with aortic regurgitation from a variety of causes, particularly for patients with less than moderate aortic stenosis.

Factors affecting interest in cardiothoracic surgery: Survey of North American general surgery residents

BACKGROUNDnApplications to cardiothoracic surgery (CTS) training programs have declined precipitously. The viewpoints of potential applicants, general surgery residents, have not yet been assessed. Their perceptions are crucial to understanding the cause and formulating appropriate changes in our educational system.nnnMETHODSnAn initial survey instrument was content-validated, and the final instrument was distributed electronically between March 24 and May 2, 2008 through 251 general surgery program directors to all Accreditation Council for Graduate Medical Education-accredited general surgery residents (7508).nnnRESULTSnThe response rate was 29% (2153 residents; 89% programs). Respondents demographics matched existing data; 6% were committed to CTS, and 26% reported prior or current interest in CTS. Interest waned after postgraduate year 3. Interest correlated with CTS rotation duration. Of the respondents committed to CTS, 76% had mentors (71% were cardiothoracic surgeons). CTS had the most shortcomings among 9 subspecialties. Job security and availability accounted for 46% of reported shortcomings (3 to 14 times higher than other subspecialties). Work schedule accounted for 25%. Length of training was not a very important factor, although it was identified as an option to increase interest in CTS. Residents who were undecided or uninterested in CTS were twice as likely to cite the ability to balance work and personal life as important than residents who chose CTS.nnnCONCLUSIONSnThe dominant concern documented in the survey is job security and availability. The importance of mentorship and exposure to CTS faculty in promoting interest was also evident. Decision makers should consider these findings when planning changes in education and the specialty.

Factors Dominating Choice of Surgical Specialty

BACKGROUNDnThere has been much focus on factors influencing medical students career choice, prompted by such concerns as a sufficient future surgical workforce, declining applicant pool, changing gender composition, and a cultural shift in values and priorities. Once in a surgical residency, there are little data on factors influencing general surgery (GS) residents final specialty choice.nnnSTUDY DESIGNnA survey instrument was developed and content validated in conjunction with the Association of American Medical Colleges Center for Workforce Studies. The final instrument was distributed electronically between March 24 and May 2, 2008, through 251 GS program directors to all ACGME-accredited GS residents (n = 7,508).nnnRESULTSnResponse rate was 29% (2,153 residents; 89% programs). Half of GS residents remained undecided about specialty choice through the 2(nd) year, declining to 2% by year 5. Of the two-thirds who decided on a specialty, 16.5% chose to remain in GS, 14.6% chose plastics, 9.3% cardiothoracic, and 8.5% vascular. The specialty choice factors most likely to be very important were type of procedures and techniques, exposure to positive role model, and ability to balance work and personal life. Relative importance of factors in specialty choice varied by gender and chosen specialty. Mentors play a key role in specialty choice (66% decided had mentors versus 47% undecided). Work schedule was the most frequently selected shortcoming in every specialty except plastics. Cardiothoracic surgery followed by GS had the highest shortcomings.nnnCONCLUSIONSnThe majority of GS residents plan to subspecialize. Three factors dominate specialty choice. Faculty need to understand their impact potential to modify or change perceptions of their specialty.

Citric-acid-derived photo-cross-linked biodegradable elastomers.

Citric-acid-derived thermally cross-linked biodegradable elastomers (CABEs) have recently received significant attention in various biomedical applications, including tissue-engineering orthopedic devices, bioimaging and implant coatings. However, citric-acid-derived photo-cross-linked biodegradable elastomers are rarely reported. Herein, we report a novel photo-cross-linked biodegradable elastomer, referred to as poly(octamethylene maleate citrate) (POMC), which preserves pendant hydroxyl and carboxylic functionalities after cross-linking for the potential conjugation of biologically active molecules. Pre-POMC is a low-molecular-mass pre-polymer with an average molecular mass between 701 and 1291 Da. POMC networks are soft and elastic with an initial modulus of 0.07 to 1.3 MPa and an elongation-at-break between 38 and 382%. FT-IR–ATR results confirmed the successful surface immobilization of type-I collagen onto POMC films, which enhanced in vitro cellular attachment and proliferation. Photo-polymerized POMC films implanted subcutaneously into Sprague–Dawley rats demonstrated minimal in vivo inflammatory responses. The development of POMC enriches the family of citric-acid-derived biodegradable elastomers and expands the available biodegradable polymers for versatile needs in biomedical applications.