Tag Archive for: cardiopulmonary bypass

Illustration showing phthalate exposure during cardiopulmonary bypass

Pediatric heart patients exposed to plastic chemicals during cardiopulmonary bypass

Children undergoing cardiac surgery using cardiopulmonary bypass are exposed to high levels of plastic chemical additives called phthalates, including DEHP, according to the largest single center study to date to measure this exposure. The findings were authored by a multi-disciplinary group from Children’s National Hospital and appear in the journal Transfusion.

What is it?

Di(2-ethylhexyl) phthalate (DEHP) is one of the most commonly used plasticizers in polyvinyl chloride (PVC) plastics, making up 40% to 80% of the finished weight of medical-grade tubing and blood storage bags. The study’s primary goal was to quantify three aspects of pediatric cardiac surgery: the phthalate exposure with and without cardiopulmonary bypass (the heart and lung machine), the time it takes for phthalates to clear after surgery and any correlations between higher phthalate exposures and postoperative complications.

The authors suggested that, like infants in the NICU exposed to various medical equipment, children on cardiopulmonary bypass are likely exposed to significant DEHP levels from blood products, bypass circuit components, and endotracheal tubes, potentially impacting postoperative outcomes.

Why does it matter?

Despite daily phthalate exposure in the general population, studies link high phthalate levels to developmental delays in language and motor skills. Phthalates accumulate in the hearts of infants undergoing umbilical catheterizations or blood transfusions. This is worrisome as even low-dose environmental exposure correlates with higher risks of overall and cardiovascular-related mortality.

Knowing these risks exist, it is important to understand these exposures, what causes them and implement measures to mitigate them, safeguarding medically fragile children. Regulatory actions in NICUs have reduced DEHP-containing plastics, yet no such efforts have been made for children on cardiopulmonary bypass.

The study also found some associations between postoperative complications and higher levels of phthalates, especially in younger children. They write, “it is plausible that a combination for risk factors (young age, longer CPB duration, increased phthalate exposure) collectively contribute to these complications.” More research is needed to understand the association and the impact of phthalates on how children recover from surgery.

Children’s National leads the way

The study involved 110 pediatric patients undergoing 122 cardiac surgeries at Children’s National, marking the largest single-center investigation into phthalate exposures in cardiac surgery. Led by a multidisciplinary team, including divisions of Transfusion Medicine and Cardiac Surgery, along with researchers from the Sheikh Zayed Institute for Pediatric Surgical Innovation, the study’s findings are some of the first to quantify that pediatric cardiac surgery patients are exposed to greater levels of these phthalate chemicals from plastic medical products, with increasing exposure the longer they require cardiopulmonary bypass. This is especially true when the bypass uses a prime based on red blood cells.

What’s next

The teams are exploring strategies to minimize chemical exposures, such as:

  • Using freshly donated blood products (made possible at Children’s National by the unique on-site Blood Donor Center).
  • Storing blood in DEHP-free storage bags prior to use when possible.
  • Increasing use of cell-saver equipment, which washes red blood cell products and removes extracellular contaminants.
  • At Children’s National, cardiac surgeons prioritize the use of recently collected, washed red blood cells in cardiopulmonary bypass cases, especially for younger and/or smaller patients.

“These exposures will affect patients undergoing pediatric cardiac surgery at any institution,” says first author Devon Guerrelli, M.S. “But we hope understanding what’s causing the exposures will help operating rooms around the United States take immediate small steps, like using washed red blood cells, to begin mitigating these exposures as soon as possible.”

Senior author Nikki Posnack, Ph.D., adds that the implications of phthalates on health are tremendous. “Studies have shown that heightened phthalate exposure increases your risk of all-cause and cardiovascular mortality,” she said. “Now is the time to support research efforts to understand how plastic chemicals damage the heart and to investigate strategies to reduce their overall impact.”

Read the study:
Prevalence and clinical implications of heightened plastic chemical exposure in pediatric patients undergoing cardiopulmonary bypass

Bone Marrow–Derived MSC Treatment Mitigates Structural Abnormalities Resulting From CPB

Cell therapy mitigates neurological impacts of cardiac surgery in pre-clinical model

Differences of cortical fractional anisotropy between cardiopulmonary bypass and control (left), cardiopulmonary bypass + mesenchymal stromal cells and cardiopulmonary bypass (center), and 3 groups (right).

A pre-clinical study in the journal JACC: Basic to Translational Science shows that infusing bone marrow-derived mesenchymal stromal cells (BM-MSCs) during cardiac surgery provides both cellular-level neuroprotection for the developing brain and improvements in behavior alterations after (or resulting from) surgery.

What this means

According to lead author Nobuyuki Ishibashi, M.D., Oxidative and inflammatory stresses that are thought to be related to cardiopulmonary bypass cause prolonged microglia activation and cortical dysmaturation in the neonatal and infant brain. These issues are a known contributor to neurodevelopmental impairments in children with congenital heart disease.

This study found that, in a pre-clinical model, the innovative use of cardiopulmonary bypass to deliver these mesenchymal stromal cells minimizes microglial activation and neuronal apoptosis (cell death), with subsequent improvement of cortical dysmaturation and behavioral alteration after neonatal cardiac surgery.

Additionally, the authors note that further transcriptomic analyses provided a possible mechanism for the success: Exosome-derived miRNAs such as miR-21-5p, which may be key drivers of the suppressed apoptosis and STAT3-mediated microglial activation observed following BM-MSC infusion.

Why it matters

Significant neurological delay is emerging as one of the most important current challenges for children with congenital heart disease, yet few treatment options are currently available.

Applications of BM-MSC treatment will provide a new therapeutic paradigm for potential MSC-based therapies as a form of neuroprotection in children with congenital heart disease.

Children’s National Hospital leads the way

The Ishibashi lab is the first research team to demonstrate the safety, efficacy and utility of using cardiopulmonary bypass to deliver BM-MSCs with the goal of improving neurological impairments in children undergoing surgery for congenital heart disease. In addition to this pre-clinical research, a phase 1 clinical trial, MeDCaP, is underway at Children’s National.

Recent additional funding from the NIH will allow the team to identify molecular signatures of BM-MSC treatment and mine specific BM-MSC exosomes for unique cardiopulmonary bypass pathology to further increase understanding of precisely how and why this cell-based treatment shows success.

x-ray of child with congenital heart disease

Cell therapy research for neuroprotection in congenital heart disease receives another $3.3 million from NIH

x-ray of child with congenital heart disease

Significant neurological delay is emerging as one of the most important current challenges for children with congenital heart disease, yet few treatment options are currently available.

The research lab of Nobuyuki Ishibashi, M.D., at Children’s National Hospital, recently received $3.3 million in additional funding for research into cell therapy for neuroprotection in children with congenital heart disease. The new support comes from the National Heart, Lung and Blood Institute (NHLBI) of the National Institutes of Health.

The research goal

The overarching goal of the award is to establish detailed molecular signatures from critical cell populations for tissue repair and regeneration at single cell resolution after bone marrow-derived mesenchymal stromal cell (BM-MSC) delivery. The team has shown cellular, structural and behavioral improvements in pre-clinical models after delivery of BM-MSCs through cardiopulmonary bypass for children with congenital heart disease. However, the mechanisms underlying the therapeutic action of BM-MSCs still remain largely unknown. This R01 renewal will address the key knowledge gap.

Why it matters

Significant neurological delay is emerging as one of the most important current challenges for children with congenital heart disease, yet few treatment options are currently available.

The Ishibashi lab has demonstrated the efficacy and utility of using cardiopulmonary bypass to deliver BM-MSCs  to improve neurological impairments in children undergoing surgery for congenital heart disease. Most notably, this included development of a phase 1 clinical trial, MeDCaP, at Children’s National.

The big picture

Together with the ongoing clinical trial established from the previous award, identifying molecular signatures of BM-MSC treatment and mining specific BM-MSC exosomes for unique cardiopulmonary bypass pathology will significantly improve understanding of this cell-based treatment. This work will also provide a new therapeutic paradigm for potential cell-free MSC-based therapies for neuroprotection in children with congenital heart disease.

Baby on ventilator

JAMA study shows no benefit to nitric oxide in cardiopulmonary bypass for young children

Baby on ventilator

An international clinical trial showed that nitric oxide doesn’t help kids recover faster from cardiac surgery with cardiopulmonary bypass.

A study published in JAMA finds that the practice of introducing nitric oxide into the gas flow of the cardiopulmonary bypass oxygenator does not improve recovery or reduce the amount of time a child under age 2 needs to be on a ventilator after cardiac surgery.

Children’s National Cardiac Surgery Chief Yves d’Udekem, M.D., Ph.D., co-authored the international study, which is already leading to changes in how hospitals around the world care for children with congenital heart disease (CHD).

The results are from a double-blind, randomized controlled trial with more than 1,200 participants across six centers in Australia, New Zealand and the Netherlands. The research team found that children under age 2 who had cardiac surgery with cardiopulmonary bypass spent about the same number of days on ventilators after surgery, whether nitric oxide was used during surgery or not.

“These findings do not support the use of nitric oxide delivered into the cardiopulmonary bypass oxygenator during heart surgery,” the authors conclude.

What this means

Previous smaller, single center studies had shown early indications that nitric oxide delivered during heart surgery could possibly improve recovery and shorten the need for respiratory support after surgery by reducing the occurrence of low cardiac output syndrome in children under age 2.

This large-scale international trial showed that this is not the case.

Why it matters

Based on these earlier studies, many hospitals in the United States and around the world who perform critical heart surgery on young children with congenital heart disease had already started to incorporate nitric oxide into cardiopulmonary bypass. This new, more robust data is helping hospitals reassess this practice. Many are stopping it altogether based on the findings.

This work is an important reminder of how valuable well-designed, large-scale, double-blind, randomized, controlled trials are to defining, improving and refining best practices in clinical care.

Also, trials of this size and significance in pediatrics generally, and CHD specifically, take a very long time to complete, if they are ever able to be completed at all. That’s because the number of children with these conditions is relatively small and spread out, even though CHD is the most common birth defect in the world. The authors say it is a major accomplishment to have completed a trial of this size and  in such a short time. Even better, the data gathered from this sample of patients from across international borders can be used to provide even more insights into how best to care for these children as they continue to grow and develop.

brain network illustration

Cardiopulmonary bypass may cause significant changes to developing brain and nerve cells

brain network illustration

Cardiopulmonary bypass, more commonly known as heart-and-lung bypass, has some unique impacts on the creation and growth of brain cells in the area of a child’s brain called the subventricular zone (SVZ), according to a study in the Annals of Neurology. The SVZ is a critical area for the growth and migration of neurons and nerve cells called neuroblasts, both of which ultimately contribute to the proper development of key brain structures and functions during the early years of life.

The findings, from a study conducted in the Cardiac Surgery Research Laboratory at Children’s National Hospital, provide new insight into the cellular impacts of the cardiopulmonary bypass machine on brain growth and development for newborn infants with congenital heart disease. They will have an important role in the refinement of strategies to help protect the fragile brains of children who require lifesaving cardiac surgery with cardiopulmonary bypass immediately after birth.

Specifically, the research team found that during cardiopulmonary bypass:

  • Creation of neurons (neurogenesis) in the neonatal and infant subventricular zone is altered.
  • Migration of nerve cells, called neuroblasts, to the frontal lobe is potentially disrupted.
  • Changes to the growth and movement of neurons in the SVZ are prolonged.
  • Cortical development and expansion is impaired.
  • Specific types of neurons found only in the brain and spinal cord, called interneurons, are also affected.

The study uses an innovative pre-clinical model of the developing brain that is more anatomically and physiologically similar to human neonates and infants than those used in prior studies and in most neurological laboratory-based research.

Cardiopulmonary bypass is one of several key factors thought to cause children with congenital heart disease to sometimes demonstrate delays in the development of cognitive and motor skills. These disabilities often persist into adolescence and adulthood and can ultimately represent long-term neurocognitive disabilities. It is also believed that genetic factors, abnormal blood flow to the brain while in utero or low cardiac output after surgical procedures on the heart may contribute to these challenges.

“Unraveling cellular and molecular events during surgery using this preclinical model will allow us to design therapeutic approaches that can be restorative or reparative to the neurogenic potential of the neuronal stem precursor cells found in the subventricular zone of the neonatal or infant brain,” says Nobuyuki Ishibashi. M.D., Foglia-Hills Professor of Pediatric Cardiac Research, director of the Cardiac Surgery Research Laboratory at Children’s National and senior author on the study. “In particular, previous studies in our laboratory have shown improvement in the neurogenic activities of these precursor cells when they are treated with mesenchymal stromal cells (MSCs).”

The findings from this study further support the work already underway in the NIH-funded MeDCaP clinical trial for neonates and infants undergoing cardiac surgery using the cardiopulmonary bypass machine. That trial uses the heart and lung machine itself to deliver MSCs directly into the main arteries that carry blood to the brain.

Yves d'Udekem

Yves d’Udekem, M.D., Ph.D., joins Children’s National as Cardiac Surgery Chief

Yves d’Udekem, M.D., Ph.D., a pediatric cardiac surgeon recognized for expertise in the most challenging procedures for newborns and children with complex congenital heart disease, has joined Children’s National Hospital as chief of Cardiac Surgery and co-director of the Children’s National Heart Institute.

“Children’s National has the cases and expertise I was looking for,” he says. “Even better, when you visit it’s clear that the entire Heart Institute team is energetic about working together. They’re constantly seeking better ways to do this work and improve how we care for children and their families.”

Dr. d’Udekem comes to Children’s National from The Royal Children’s Hospital in Melbourne, Australia, an institution that has led the advancement of congenital heart disease care and research, performing more than 500 surgical procedures with cardiopulmonary bypass each year.

He has a broad spectrum of pediatric cardiac surgery expertise, with special emphasis in single ventricle congenital heart defects, when one lower chamber of the heart does not develop. One area of his research portfolio includes clinical research into long-term quality of life for people who had Fontan procedures — a critical surgical approach to adapt blood flow for people born with single ventricle heart disease. He has additional expertise in valve repair, artificial hearts and other cardiac assist devices.

“Sometimes it seems like I’ve been born and put on this earth for that single purpose — I have to bring life to patients with single ventricle hearts or assist devices,” he says. He describes his path to pediatric cardiac surgery as serendipity, “It’s more like pediatric cardiac surgery chose me.”

“It is an honor to welcome Yves d’Udekem to the Children’s National Heart Institute,” says David Wessel, M.D., executive vice president and chief medical officer of Hospital and Specialty Services at Children’s National. “He is a surgeon, physician and leader of the highest caliber. I can say without hesitation that Yves’ leadership of our cardiac surgery team will change the lives of hundreds, if not thousands, of children and adults with congenital heart disease.”

In preparation for Dr. d’Udekem’s arrival, the Children’s National Heart Institute and hospital leadership created a framework plan for success that will build on the legacy of excellence established by Richard Jonas, M.D. Dr. Jonas, a world leader in congenital heart surgery who has made significant clinical and academic advances in the field, will continue his award-winning laboratory-based research at Children’s National on neurodevelopmental outcomes for children with congenital heart disease.

Dr. d’Udekem is Belgian-born with Canadian and Australian citizenship. He received his early training in Belgium and Toronto. As an attending cardiac surgeon in Belgium, he operated on both adults and children with congenital heart disease. Dr. d’Udekem then worked with internationally recognized heart surgeon Marc de Leval, M.D., FRCS, and others in London to train in congenital heart surgery at the Great Ormond Street Hospital for Children. From there, he was recruited to The Royal Children’s Hospital in Melbourne, Australia, where he has been ever since.

Dr. d’Udekem has more than 350 research publications and has obtained more than $7 million in grant funding in the past five years for work to create the first research network of Australian children and adults who have undergone the Fontan procedure.

He started seeing patients at Children’s National in mid-September.

Dr. Jonas and research collaborator Nobuyuki Ishibashi in the laboratory.

Cardiac surgery chief recognized for studies of surgery’s impacts on neurodevelopment

Dr. Jonas and research collaborator Nobuyuki Ishibashi in the laboratory.

Dr. Jonas and research collaborator Nobuyuki Ishibashi in the laboratory.

Richard Jonas, M.D., is this year’s recipient of the Newburger-Bellinger Cardiac Neurodevelopmental Award in recognition of his lifelong research into understanding the impact of cardiac surgery on the growth and development of the brain. The award was established in 2013 by the Cardiac Neurodevelopmental Outcome Collaborative (CNOC) to honor Jane Newburger and David Bellinger, pioneers in research designed to understand and improve neurodevelopmental outcomes for children with heart disease.

At Children’s National, Dr. Jonas’ laboratory studies of neuroprotection have been conducted in conjunction with Dr. Vittorio Gallo, director of neuroscience research at Children’s National, and Dr. Nobuyuki Ishibashi, director of the cardiac surgery research laboratory. Their NIH-supported studies have investigated the impact of congenital heart disease and cardiopulmonary bypass on the development of the brain, with particular focus on impacts to white matter, in people with congenital heart disease.

Dr. Jonas’s focus on neurodevelopment after cardiac surgery has spanned his entire career in medicine, starting with early studies in the Harvard psychology department where he developed models of ischemic brain injury. He subsequently undertook a series of highly productive pre-clinical cardiopulmonary bypass studies at the National Magnet Laboratory at MIT. These studies suggested that some of the bypass techniques used at the time were suboptimal. The findings helped spur a series of retrospective clinical studies and subsequently several prospective randomized clinical trials at Boston Children’s Hospital examining the neurodevelopmental consequences of various bypass techniques. These studies were conducted by Dr. Jonas and others, in collaboration with Dr. Jane Newburger and Dr. David Bellinger, for whom this award is named.

Dr. Jonas has been the chief of cardiac surgery and co-director of the Children’s National Heart Institute since 2004. He previously spent 20 years on staff at Children’s Hospital Boston including 10 years as department chief and as the William E. Ladd Chair of Surgery at Harvard Medical School.

As the recipient of the 2019 award, Dr. Jonas will deliver a keynote address at the 8th Annual Scientific Sessions of the Cardiac Neurodevelopmental Outcome Collaborative in Toronto, Ontario, October 11-13, 2019.

What rare diseases teach us about common ones

Think of the urea cycle as a river. A normal river flows to where it empties, similar to the process the body uses to rid itself of harmful ammonia via the urea cycle.

Think of the urea cycle as a river. A normal river flows to where it empties, similar to the process the body uses to rid itself of harmful ammonia via the urea cycle.

I recently presented at Spotlight Health 2016, the health-focused portion of the Aspen Ideas Festival, about how studying and treating rare diseases can inform innovative treatment approaches for more common medical conditions. Our Division of Genetics and Metabolism sees more than 8,000 patients a year with rare conditions, such as urea cycle disorders and Down syndrome. Through decades of analyzing these diseases and treating children who have them, we have developed therapies that apply not only for the small numbers of patients who have rare diseases but also for more common conditions caused by environmental factors leading to a similar physical response.

For instance, we’ve demonstrated that the stress of cardiopulmonary bypass during surgery to correct congenital heart disease creates conditions similar to a critical blockage in the urea cycle, specifically the biochemical creation of citrulline, a key biochemical.

When that cycle is unable to flow, or continuing the river analogy, becomes dammed up due to a genetic defect, as in urea cycle disorders, or an environmental factor, such as the extreme stress of cardiopulmonary bypass, the body is unable to make enough citrulline which is critical for maintaining normal blood pressure. We’ve shown that replacing that citrulline can correct a lot of these problems whether caused by rare genetics or the cardiac OR.

Applying rare disease treatment approaches to more common diseases is not limited to urea cycle disorders. Work by my colleague Carlos Ferreira, MD, demonstrates how a rare genetic calcifying arterial disease (generalized arterial calcification in infancy, GACI) causes the same calcium buildup and blockages as chronic kidney disease. Dr. Ferreira hypothesizes that life-saving drugs developed for use in GACI could help patients with long-term kidney disease by averting organ damage and eventual failure caused by the buildup of calcium crystals.

The more we learn about these rare diseases, the more we come to appreciate the tremendous implications our findings have for patients with the rare disorders and potentially hundreds of thousands of others.

About the Author

Marshall Summar, MD
Research interests: The interactions between common genetic variations and the environment.