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Understanding Xenotransplantation’s Potential to Save Babies

The issue is simple: there are simply not enough hearts for all the children who need them. So 17% of all children who need a heart transplant die while waiting; this translates to 20% to 25% of infants.[1]

The University of Alabama at Birmingham (UAB) and Children’s of Alabama aim to change those dismal statistics with one of the most revolutionary approaches since the first heart was transplanted from one human to another in 1967 – xenotransplantation.  

Thanks to a $19.5 million grant from biotechnology magnate United Therapeutics Corporation, UAB and Children’s have launched one of the top programs in the world dedicated to developing genetically modified solid organs from pig models for transplantation.

The idea isn’t new. Pig tissue has been used to replace heart valves for years, said cardiothoracic surgeon David Cleveland, M.D., MBA, who leads the program at Children’s. The greatest challenge with solid organs, he said, is overcoming immunological and physiological barriers.

If they can do that, “We believe that there’s huge potential to improve the lives of children,” he said.  

Supporting Evidence

Earlier this year, Cleveland presented preliminary results from a study showing little reactivity in an infant’s blood to cells from a triple-knockout (TKO) pig. The pig had been genetically modified to delete the three major antigens that react with natural human anti-pig antibodies. Even those human cells that did react demonstrated a very mild reaction.

“We found that very promising,” Cleveland said.

Another area of interest is producing immune tolerance by transplanting porcine thymus tissue to “re-educate” the immune system to accept the pig heart, said cardiac intensivist Leslie Rhodes, M.D. The idea comes from the fact that children can develop an immune system via a human thymus transplant. “We wonder if we could we train their immune system to be tolerant to the pig thymus transplant,” she said.

Infants are the ideal starting place, Cleveland said, not only because they have the highest wait list mortality of any other demographic waiting for a solid organ transplant, but because their immune systems are still naïve. Indeed, they do not develop antibodies to pig glycans during at least the first three months of life, Cleveland and his team wrote in a recent journal article, providing a “window of opportunity” for the transplant.[2]

The next step is a transplant in a non-human primate. “The FDA won’t even consider it until we can prove consistent survival in a non-human primate,” Rhodes said. They hope to perform their first transplant later this year.

Societal Concerns Addressed

The team is also aware of the societal issues around xenotransplantation. To address that, they surveyed the families of patients on the transplant list and the nurses and physicians who will care for these children.

”I was surprised by how positive they were,” Cleveland said. “I thought there would be more pushback than there was.” Still, he said, “I think there has to be major education,” once xenotransplantation becomes a reality. “The idea of replacing a heart with a pig heart will take some people a little time to get over.”

He’s confident it will happen, though. “UAB is going to be one of the centers in the world with the potential to make this happen,” he said. “We have children living in our ICU because there’s not enough cardiac function; they are having their birthdays here. It totally changes entire families to have a child in the hospital forever. There has to be another way.“


[1] Dipchand AI. Current state of pediatric cardiac transplantation. Ann Cardiothorac Surg. 2018;7(1):31–55. doi:10.21037/acs.2018.01.07

[2] Cleveland D, Adam Banks C, Hara H, Carlo WF, Mauchley DC, Cooper DKC. The Case for Cardiac Xenotransplantation in Neonates: Is Now the Time to Reconsider Xenotransplantation for Hypoplastic Left Heart Syndrome? Pediatr Cardiol. 2019;40(2):437-444.

Cutting-Edge Research

Learn more about various research areas at the University of Alabama at Birmingham.

Cardiology

Children’s of Alabama CVICU Embraces Quality Improvement Projects

What if you could proactively identify patients who might go into cardiac arrest and intervene before the unthinkable happens? If you do what Children’s of Alabama did, you end up with fewer children having arrests and improved response times because of faster medication administration when an arrest does occur.

That’s all thanks to a multi-institutional quality improvement project — Cardiac Arrest Prevention (CAP) — centered around a resuscitation action plan, which focuses on rescuing patients before they arrest.

The project, led by cardiovascular intensive care unit (CVICU) Medical Director Santiago Borasino, M.D., and cardiac intensivist Hayden Zaccagni, M.D., is part of the Pediatric Cardiac Critical Care Consortium (PC⁴), made up of 52 of the country’s top children’s hospitals. The consortium maintains a focused CVICU registry designed to share real-time data and outcomes between institutions and participates in quality improvement projects to improve outcomes.

The CAP project is just one of the data-driven, collaborative learning initiatives the group has implemented.

Comprehensive Effort

“CAP is a joint effort with bedside nurses, respiratory therapists, administrative nursing staff and trainees, whether fellows or advanced practice practitioners, to not just identify at-risk patients but have a common mind-set and goals to prevent arrests,” Zaccagni said.

Once a patient meets certain criteria putting them at risk for cardiac arrest, the attending intensivist completes a paper report that remains bedside. Clinicians then round separately on these patients and, if warranted, give the bedside nurse the ability to start the treatment plan without waiting for separate orders. Resuscitation medications are kept at the bedside for immediate use if the patient demonstrates any danger signs. “The goal is to expedite interventions to prevent the arrest from occurring,” Zaccagni said.

Borasino, in collaboration with two former Children’s intensivists, Kimberly Jackson, M.D., and Jeffrey Alten, M.D., started the original resuscitation program. “Dr. Alten was our medical director and section chief until 2017 and he was instrumental in starting this project and then taking it to the national stage,” Borasino said, while Jackson coordinated the local effort when it began in 2013. Alten, now at Cincinnati Children’s Hospital Medical Center, is still the coordinating head of the national initiative, while. Jackson has moved to Duke University Medical Center in Durham, North Carolina, where she leads its initiative.

The official PC4 initiative began in October 2018, but Children’s had something similar in place for three years, Zaccagni said. However, because the PC4 initiative includes more than 10,000 patients, there is more data available on best practices. So, for instance, Children’s adjusted the bedside rescue medications so they are easier to deliver.

Although the new initiative had only been in place eight months when this article was written, “anecdotally, I’d say we’ve reduced the number of cardiac arrests,” Borasino said.

More Quality Improvement Initiatives

Two other quality improvement projects are also demonstrating results:

Star Track. Geared towards less-complicated patients who have cardiac surgery, this initiative involves standardizing patient care to remove unnecessary equipment sooner. This improves patient comfort and enables them to transfer soon out of the CVICU. “The patient comfort is our main goal,” Borasino said. “Patients undergoing these types of surgeries are older and don’t require the level of invasive monitoring our unit provides.”

A secondary benefit is patient flow. “We are a busy unit, so this allows us to care for more patients as needed,” Borasino said. In addition, removing devices reduces the risk of infection from invasive equipment like Foley catheters and central lines.   

Alarm reduction. This initiative is geared toward reducing the number of alarms in the unit in an effort to reduce “alarm fatigue” while improving the overall atmosphere. Alarm parameters are reviewed every 12 hours to ensure they are still accurate given the continually changing status of the patient. To date, the number of alarms has dropped by a third. “We’re trying to diminish that even more,” Borasino said. “We’d like all alarms to be meaningful alarms.”

Quality Improvement

Learn more about the cardiovascular intensive care unit at Children’s Alabama.

Cardiology

Taking a Multidisciplinary Approach to Congenital Heart Defects Months Before Birth

Congenital heart defects are the most common type of birth defect in the United States, affecting nearly 1% (about 40,000) births per year. Most are diagnosed early in pregnancy, leaving parents months to obsessively worry over their baby’s fate. But at the UAB Fetal Cardiac Diagnosis and Care Clinic, a collaboration between the University of Alabama at Birmingham and Children’s of Alabama, families can learn early on in their pregnancy what to expect prenatally, during delivery and in the postnatal period from a team of specialized physicians focused on their baby’s specific needs.

“Families get hit with the news that their baby has heart disease and it’s like a body blow,” said Children’s cardiologist Robb Romp, M.D. “We can demystify some of the scariness,” he said.

Clinic participants include pediatric cardiologists, cardiothoracic surgeons, maternal-fetal medicine specialists and a geneticist. “It is one of the quintessential multidisciplinary programs we run,” Romp said. “The goal is to recognize what the problems are prenatally and then ensure all the necessary resources are in place to care for the baby after birth.”

The half-day clinic meets monthly with between three to five families, about 50 a year, whose babies are known to have complex congenital heart disease. Patients come from throughout Alabama and surrounding states.

The clinic “helps families understand how many different providers are assisting in the care of their baby and that we are all working collaboratively,” Romp said. It also provides a very real perspective on how the team makes decisions, because the clinicians talk through the case with the family, he said. For instance, the issues the obstetrician focuses on may be different from those of the cardiologist. “The needs of both patients, mother and baby, need to be balanced to ensure both do well during and after the pregnancy,” he said.

The team’s nurse practitioner, Laura Brasseale, coordinates all follow-up meetings and ensures the family tours areas of the hospital where their baby may require care.

Brian Casey, M.D., who directs the Division of Maternal-Fetal Medicine at UAB,spent 23 years at the University of Texas Southwestern in Dallas before moving to UAB in 2018. “After my arrival here, I was immediately impressed with this scheduled monthly meeting between the pediatric cardiologists and the Maternal-Fetal Medicine group at UAB,” he said. “This extraordinary collaboration allows for early discussions of prenatal treatment and delivery planning in order to optimize the baby’s outcome and  provides state-of-the-art care at a very high level for our patients.”

Fetal Diagnosis and Care

Learn more about the UAB Fetal Diagnosis and Care Clinic, a collaboration between the University of Alabama at Birmingham and Children’s of Alabama.

Cardiology

Thanks to Team-Oriented Approach, Heart Transplant Program Leads Country in Outcomes

transplant_team

The Pediatric Advanced Heart Failure and Transplant Team at Children’s Alabama, seated, left to right: Sally Smith, DNP, CRNP, CCTC; Meloneysa Hubbard, MSN, CRNP, CCTC; and Kimberly Sullivan, MSN, CCTC, CRNP. Standing, left to right: Mariah Strickland, MSN, CRNP; Waldemar F. Carlo, M.D.; David C. Mauchley, M.D.; F. Bennett Pearce, M.D; and Robert J. Dabal, M.D.

The numbers tell the story of the heart transplant program at Children’s of Alabama.

• 176 pediatric heart transplants since 1981
• 59 transplants since 2012
• Zero deaths since 2014
• A 97 percent one-year survival rate over the last decade — considerably higher than the national rate of 90.2 percent

One major reason? “We have a very cohesive, experienced, stable team,” said Medical Director F. Bennett Pearce, M.D. That team includes surgical director Robert J. Dabal, M.D., pediatric cardiologist Waldemar F. Carlo, M.D., and pediatric surgeon David C. Mauchley, M.D., as well as four cardiac nurse practitioners, three of whom are certified clinical transplant coordinators.

Until 2012, the pediatric transplant program was housed at the University of Alabama at Birmingham (UAB). But with the opening of the new children’s hospital that year, the transplant team was able to create a separate entity and move into a state-of-the-art cardiac care facility at Children’s. Today, it serves as a regional referral center and is the only pediatric heart transplant program in the state. The program also provides comprehensive care for patients with advanced heart failure using evidence-based medical management and mechanical circulatory support. Its surgeons also perform heart transplants, including ABO incompatible transplants, in infants.

Although the United Network of Organ Sharing (UNOS) considers the Children’s program to be a relatively young program, Pearce said, “the reality is far different” given the team’s depth and length of experience. The team is also diverse, he said, bringing different viewpoints and interests, which expands the program’s potential.

Moving to Children’s brought several advantages, he said, particularly access to pediatric specialists. “We can provide better multidisciplinary care for patients,” he said. The program also now has its own administrative structure and identity, providing families with a central place to call with questions or concerns.

The center also features dedicated social workers, child life therapists, physical/occupational therapists, dietary counselors, psychosocial counselors, specialty pharmacists and pastoral care. “We realize that when a patient is listed for transplant that you’re entering into a relationship the family as well as the patient,” Pearce said, “and we do all we can to optimize that relationship.”

Research is a major part of the program, he said, with ongoing studies on cardiomyopathy, pulmonary hypertension and heart transplantation. For instance, one major study is evaluating alternative immune suppression techniques for post-transplant children. The center also participates in numerous quality initiatives with other transplant programs around the country in order to identify best practices.

Largest Pediatric Heart Transplant Registry in the World

UAB houses the international Pediatric Heart Transplant Society, which maintains the largest registry in the world on heart transplantation. Data from the registry is used to encourage and stimulate basic and clinical research in the field of pediatric heart transplantation and to promote new therapeutic strategies. Since its founding in 1993, data from the registry has been used to produce more than 100 abstracts and presentations, and 87 publications. Today, 56 centers participate in the registry, which contains information on more than 6,542 transplants. James Kirklin, M.D., who was surgical director of Adult and Pediatric Heart Transplant program at UAB and Children’s until his retirement from clinical work in 2017, initiated the registry.

Cardiology Heart Transplant Chart

The Heart of It All
Visit www.childrensal.org/advanced-heart-failure-and-transplant to learn more about the Pediatric Advanced Heart Failure and Transplant team at Children’s of Alabama.

Cardiology

‘Not-So-Stressful’ Stress Testing Evaluates Pediatric Congenital Heart Disease and Exercise-related Complaints

exercise_labPut a seemingly timid child with congenital heart disease (CHD) on a treadmill, attach electrodes to their chest and place a mask over their mouth and nose to measure gas exchange, and it’s amazing what you can learn about their cardiovascular and pulmonary health.  That’s the premise behind Children’s of Alabama’s new Cardiometabolic Exercise Testing Lab, which opened this summer. The lab was made possible through the generosity of Gene and Leslie Cash in loving memory of their daughter Kelly Cash.

“Exercise capacity can be highly predictive of the risk of complications related to CHD, including developing heart failure,” said pediatric cardiologist Camden Hebson, M.D., who runs the lab. “Given that the heart and lungs are usually the limiting factors on the extent of exercise capacity, stress testing is a wonderful way to evaluate how well patients are supported.”

In contrast, evaluating a child at rest, as with an EKG and echocardiogram, “is like evaluating the quality of a car when it’s in the shop versus taking it out on the road and seeing how well it drives,” he said.

While the test mimics the traditional stress test, the use of the mask to measure oxygen consumption (VO2) and CO2 elimination is particularly important, Hebson said.

“These become the key variables to say from a quantitative standpoint how well the heart and lungs support you as you exercise,” he said.

Children who have been living with a heart condition for years may underappreciate the severity of their symptoms, he said. The exercise test, however, provides objective data that can demonstrate problems and allow intervention.

“Many patients become accustomed to how they feel with exercise, yet with stress testing we can identify limitations early on and thus intervene in a timelier manner,” he said.

The test also enables serial assessments to assess function over time.

In some instances, he said, a patient’s symptoms are attributed to cardiovascular function, but the stress test can show it was related to pulmonary function instead.

“Sometimes that’s hard to tease out because we’re always focused on the heart,” he said. “Exercise testing offers a way to make that connection.”

Children as young as 7 years old can complete the test, he said, and those that can’t walk or run on the treadmill can use a bike. The key point is that “they need to be comfortable enough to come in and wear a mask, EKG leads, etc., while exercising,” he said.

To take some of the fear and anxiety out of the experience, the team has decorated the room to look more inviting with posters of sports figures and decals. They even added a scoreboard where kids can write their “code name” and see how they compare to others taking the test. The goal,  Hebson said, is to make the lab look less like a clinic or hospital setting and more like a place to have fun.

The test itself takes about 15 minutes, with another 30 minutes for the setup and explanations. It is typically covered by insurance.

Hebson, nursing staff, and parents are always in the room. As he noted, “We try to make it the least stressful as possible, even though it’s a stress test.”

Interested in a Pediatric Cardiology Fellowship at Children’s of Alabama?
Learn more at childrensal.org/pediatric-cardiology-fellowship.

Cardiology

Kylin’s Brave Heart

kylin_heart

Hearts are full at Children’s of Alabama because Kylin Harris’ heart is well. Inside a hospital conference room in June 2018, the banner was hung, the tablecloth was draped and the cake was cut in celebration of Kylin, the first-ever patient at Children’s to be successfully weaned from a pediatric ventricular assist device without the need for a heart transplant. The 1-year-old guest of honor arrived in what is by far Children’s most popular mode of transportation – a red Radio Flyer wagon – a stark contrast from her arrival just four months prior.

Kylin was flown by helicopter to Children’s after her mother, Keianna Harris, came home to find her daughter uncharacteristically lethargic. Kylin hadn’t slept well the past two nights and a startled Harris, a nurse by trade, took Kylin to their local emergency room. While en route to the hospital, Kylin had a seizure and fell limp.  Doctors at Children’s intubated Kylin and later diagnosed her with advanced heart failure due to myocarditis. Kylin experienced cardiac arrest while being transferred to the Cardiovascular Intensive Care Unit. Doctors performed chest compressions and CPR, and placed her on extracorporeal membrane oxygenation therapy (ECMO), which pumps and oxygenates a patient’s blood outside the body allowing the heart and lungs to rest for a limited time.

The Pediatric Advanced Heart Failure and Transplant Team at Children’s discussed every detail of Kylin’s care with Harris. It was apparent ECMO would not provide long enough support for Kylin’s heart. First, doctors would convert Kylin from ECMO to the Berlin Heart® EXCOR, a long-term cardiac assist device that functions as a heart outside of the body. The Berlin Heart acts as a bridge to transplantation for children in heart failure, allowing the patient mobility and freedom to rehabilitate in preparation for transplant surgery. Available in several sizes, the Berlin Heart is not totally implanted inside the body. Doctors insert cannulas, or flexible tubes, in the heart and they extend through the skin and connect to a small pump located outside the body. That pump, along with its computerized drive unit, maintains blood flow.

“It was a lot to take in … It all happened so fast,” Harris said. “My biggest fear was losing her. It was scary not knowing whether she was going to make it through.”

The Pediatric Advanced Heart Failure and Transplant Team, a partnership between Children’s and the University of Alabama at Birmingham (UAB),  is among the first in the U.S. to use the Berlin Heart in children and reported the first successful Berlin Heart bridge to transplantation for a child with a single ventricle. Children’s and UAB first used the device in 2005, when UAB was home to the pediatric cardiac unit. The following year, the team weaned its first patient, now an adult, from the Berlin Heart without the need for transplant at UAB. In 2012, with the opening of the Benjamin Russell Hospital for Children and Bruno Pediatric Cardiac Unit, all pediatric cardiac care to relocated to Children’s.

The team’s success with the Berlin Heart led to a landmark study published in the New England Journal of Medicine in 2012 featuring two team members as co-authors – pediatric cardiologist F. Bennett Pearce, M.D., and David Naftel, Ph.D, professor in the UAB Division of Cardiothoracic Surgery. The research team, known as the Berlin Heart Study Investigators, evaluated ECMO and the Berlin Heart to see which offered children the best chance of survival until they could receive a new heart or recover enough heart function not to need a support device or transplant.

Pearce says 46 percent of children diagnosed with heart failure die or receive a heart transplant within the first five years after diagnosis. A heart transplant is a child’s best hope of survival, with the survival rate after a transplant estimated at 83 percent at three years. However, with limited donor hearts available, the wait is often long.

“Children on waiting lists for heart transplants experience the highest waiting-list mortality for any age or organ,” Pearce says. “This research demonstrates that the Berlin Heart, available in variety of appropriate sizes for children, has the potential to effectively and safely bridge children from diagnosis to transplantation or in some cases recovery, for long periods of time.”

Before the study and subsequent approval of the Berlin Heart by the U.S. Food and Drug Administration, ECMO was the mainstay for mechanical circulatory support as a bridge to transplantation. The effective period of support with ECMO is typically limited to 10 to 20 days before serious complications such as bleeding and major organ system failure, often prohibiting transplantation. The short duration of support afforded by ECMO is often inadequate, the study reads, citing only 40 to 60 percent of children requiring support with ECMO survive long enough to undergo heart transplantation. Researchers found that the longest duration of support for the younger, smaller children was 174 days for the Berlin Heart and 21 days for ECMO therapy. The longest duration of support for the larger, older children was 192 days for the Berlin Heart and 28 days for ECMO.

“The Berlin Heart provided better survival over longer support periods than ECMO therapy,” Pearce says. “These longer support periods on the Berlin Heart allow for patient rehabilitation, improved nutrition and weaning from ventilator support to use of the patient’s own respiratory system so that the children may be better candidates for successful transplantation or so that long-term cardiac recovery can occur.”

Kylin lived with the Berlin Heart for 83 days. In that time span, doctors noted signs of cardiac recovery and further testing gave doctors the green light to again operate on Kylin to remove the device. Pearce credits fellow pediatric cardiologist Waldemar F. Carlo, M.D., who was the first to see hints of Kylin’s recovery.

“He was the strongest advocate for us to explore whether her degree of recovery was enough for her to be off the device,” said Pearce, adding Kylin’s echocardiogram and catheterization data yielded positive results. “We followed the protocol of the Berlin Heart Clinical Support Team. We were in daily communication with the team from the moment we considered weaning her off.

“She has continued to show us normal cardiac function. We removed her from the transplant list because she had improved so much. We’re following her closely, but our hope is she won’t require a heart transplant,” Pearce said.

And much to Harris’ delight and relief, her baby girl did make it through. Kylin is her old self again, she says, smiling from ear to ear.

“When Kylin was in the hospital, she wouldn’t smile. She felt miserable,” Harris said. “But now her personality is back. She’s been grinning ever since we left.”

Joseph S. Bruno Pediatric Heart Center
Learn more about the services provided by the Bruno Pediatric Heart Center at Children’s of Alabama at https://www.childrensal.org/heart-inpatient-services.