NHLBI Working Group on
Pediatric Heart Network/ Perioperative Working Group

Executive Summary

April 6-7, 2009

The NHLBI-funded Pediatric Heart Network (PHN) convened a Perioperative Working Group (WG) meeting on April 6 and 7, 2009, in Bethesda, MD, to help identify and define the areas where clinical studies may have the greatest impact on perioperative practice and outcomes in patients with congenital heart disease. This was in follow up of the PHN’s launch of a randomized trial in May 2005 comparing two surgical strategies for palliation of single ventricle physiology in neonates. This trial, the Single Ventricle Reconstruction (SVR) trial, randomized 555 infants in just over 3 years. Both the number of patients with single ventricle physiology recruited and the confirmation that certain clinical surgical questions are amenable to a multicenter randomized trial represent landmarks for the field. The WG wished to capitalize on this productive collaborative experience with the congenital cardiothoracic surgical community and recognized that a wide gap exists in our knowledge regarding the impact that everyday decisions have on the surgical management of patients with congenital heart disease.

Discussion

The Working Group consisted of experts in pediatric and adult cardiothoracic surgery, pediatric cardiology, pediatric cardiac critical care, pediatric cardiac anesthesiology, neurology, neuroradiology, genetics, bioinformatics, and neonatology. Four subcommittees were established with joint surgical and critical care leadership to focus on the following areas:

• The inflammatory effects of cardiopulmonary bypass and bypass strategies to ameliorate them
• Neurodevelopmental impact of perioperative management strategies, with particular emphasis on the neonate
• Novel surgical procedures
• Outcomes research, practice variation, and the influence of individual genomic variability on outcomes.

The subcommittees conducted literature reviews, assessed their sites’ current practices, and engaged in vigorous discussions, facilitated by NHLBI staff, before the April meeting via conference calls and e-mail exchanges. The WG identified gaps in current knowledge and potential opportunities for addressing these needs. Broadly, these problematic areas include the following:

• Major challenges for neonates undergoing surgery for congenital heart disease include both the short term impact from cardiopulmonary bypass and long term sequelae, such as neurodevelopmental deficits.
• The impact of genetic and epigenetic factors on outcome is likely significant but poorly understood.
• Technology advances in imaging, neuromonitoring, genotyping, devices, and database integration should be widely adapted or evaluated in the setting of pediatric cardiac surgical care.
• There is wide variability in individual practitioner and institutional perioperative management particularly of neonates undergoing surgery. Developing mechanisms for tracking this variability, evaluating its impact on outcomes, and disseminating relevant information is required.

Recommendations

Through much discussion and an iterative process, the WG made several recommendations to address the knowledge gaps. Recommendations included clinical trials, clinical studies as well as resource and data needs.

Clinical Trials

• Conduct a Phase II clinical trial of antithrombin III supplementation in neonates and infants less than 6 months of age undergoing cardiopulmonary bypass to determine if supplementation results in decreased bleeding and improved clinical outcomes.
• Conduct a Phase III clinical trial comparing regional cerebral perfusion versus deep hypothermic circulatory arrest to determine whether one of these techniques offers superior neuroprotection for children undergoing aortic arch reconstruction on bypass.
• Conduct a Phase III clinical trial to study the effects of remote ischemic preconditioning on ischemia-reperfusion injury in children undergoing cardiopulmonary bypass.

Clinical Studies

• Evaluate the neurologic outcome in children who undergo early repair of tetralogy of Fallot compared to those who undergo late repair to determine if avoiding the insult of cardiopulmonary bypass during the potentially vulnerable neonatal period may help improve neurodevelopmental outcome in these patients.
• Evaluate whether genetic variation impacts outcomes in patients with tetralogy of Fallot.
• Conduct a cross-sectional study linking existing MRI and other neuromonitoring information with existing neurodevelopmental assessments.
• Evaluate if nutritional status impacts outcome, including mortality, in infants and children undergoing cardiac surgery.
• Evaluate novel pediatric medical devices and adapt applicable adult devices in the setting of pediatric cardiac surgical care.

Data and Resources

• Leverage clinical trial data sets, such as the SVR trial data set, and large clinical registries and administrative data sets, such as the Society of Thoracic Surgeons (STS) National Congenital Database, the Pediatric Health Information System (PHIS) database, and others, to evaluate practice variation and its impact on outcome.
• Develop a biorepository and clinical registry to allow for the efficient, prospective collection of data on patients with congenital heart disease. The clinical registry should be linked to the biorepository to allow for a multisystem evaluation of clinical outcomes.
• Create a bioinformatics infrastructure, modeled on the National Cancer Institute’s cancer Biomedical Informatics Grid, to allow all PHN constituencies to share data and knowledge.

Publication Plans

The working group committee will develop a report of the meeting for publication in an appropriate professional cardiovascular journal.

Staff Contacts / E-mail

Jonathan Kaltman, MD, NHLBI, NIH
kaltmanj@nhlbi.nih.gov

Gail Pearson, MD, NHLBI, NIH
pearsong@nhlbi.nih.gov

Participants

Working Group Chairs:

• Pedro del Nido, MD, Children’s Hospital Boston
• Gil Wernovsky, MD, Children’s Hospital of Philadelphia

Speakers:

• Kenneth Buetow, PhD, National Cancer Institute
• David Bull, MD, University of Utah Health Sciences Center
• Patrick McQuillen, MD, University of California, San Francisco Medical Center
• Richard Prager, MD, University of Michigan
• Roger Simon, MD, Dow Neurobiology Laboratories
• Aoy Tomita-Mitchell, PhD, Medical College of Wisconsin
• Hector Wong, MD, Cincinnati Children’s Hospital Medical Center
• Ajit Yoganathan, PhD, Georgia Institute of Technology

Inflammation/Bypass Strategies Subcommittee:

• Ronald Bronicki, MD, Children’s Hospital of Orange County
• Paul Checchia, MD, Washington University in St. Louis, Co-chair
• James Jaggers, MD, Duke University
• Francis McGowan, MD, Children’s Hospital Boston
• Tim McQuinn, MD, Medical University of South Carolina
• Richard Ohye, MD, University of Michigan, Co-chair
• J. Philip Saul, MD, Medical University of South Carolina
• Steven Schwartz, MD, The Hospital for Sick Children

Neurodevelopmental Outcomes and Neuroprotection Subcommittee:

• Dean Andropoulos, MD, Baylor College of Medicine, Co-chair
• Nancy Ghanayem, MD, Children’s Hospital of Wisconsin
• Jane Newburger MD, MPH, Children’s Hospital Boston
• Frank Pigula, MD, Children’s Hospital Boston, Co-chair
• Ann Stark, MD, Baylor College of Medicine
• Ismee Williams, MD, MS, Columbia University
• Robert Zimmerman, MD, Children’s Hospital of Philadelphia

Novel Surgical Procedures Subcommittee

• Christopher Caldarone, MD, The Hospital for Sick Children
• George Hoffman, MD, Children’s Hospital of Wisconsin
• Aditya Kaza, MD, University of Utah Health Sciences Center
• Peter Laussen, MBBS, Children’s Hospital Boston, Co-chair
• William Mahle, MD, Emory University
• James Tweddell, MD, Children’s Hospital of Wisconsin, Co-chair

Outcomes Research/Genomics Subcommittee

• J. William Gaynor, MD, Children’s Hospital of Philadelphia, Co-chair
• Bruce Gelb, MD, Mount Sinai School of Medicine
• Timothy Hoffman, MD, Nationwide Children’s Hospital, Co-chair
• Richard Prager, MD, University of Michigan
• Debra Schwinn, MD, University of Washington
• Karen Uzark, PhD, Cincinnati Children’s Hospital Medical Center

Pediatric Heart Network

• Lynn Mahony, MD, University of Texas Southwestern
• Lynn Sleeper, ScD, New England Research Institutes
• Thomas Travison, PhD, New England Research Institutes

June 2009