By Robert M. Campbell, Jr., MD
The titanium rib, also known as VEPTR (Vertical Expandable Prosthetic Titanium Rib), was approved in 2004 by the Food and Drug Administration for the treatment of thoracic insufficiency syndrome in skeletally immature patients with potentially lethal spine and chest wall malformations. This marked the end of a 14-year FDA trial, known as the Titanium Rib project, which began in 1990 with a sole source FDA feasibility clinical trial in San Antonio, followed by a broader multi-center trial beginning in 1994 which included seven other prominent national children’s hospitals. The titanium rib device was approved as a Humanitarian Device Exemption (HDE) device which is an FDA means of approval when there are low patient numbers and no available controls, demonstrating proven safety and probable efficacy. The FDA mandated indication for the titanium rib is Thoracic Insufficiency Syndrome, defined as the inability of the thorax to support normal respiration or lung growth. This was a new disease described by the investigative team at CHRISTUS Santa Rosa Children’s Hospital which helped explain the lethal pulmonary component of many pediatric spine and chest wall syndromes. The titanium rib has made possible five new thoracic procedures to treat thoracic insufficiency syndrome which not only enlarge the constricted thorax in primary chest wall anomalies, but indirectly correct scoliosis in young children without stopping spinal growth. The story of its development in San Antonio is well known, but this article will examine the little-known story of how it was safely introduced into world-wide medical practice through a deliberate plan of stead medical mentorship that is now considered successful beyond all expectations.
Most “new” medical devices are just improvements of wellknown established devices. How and when to use them is usually not a problem since physicians learned the principles on older versions of the device during training. As an example, during my own training in the late 1970s and early 1980s I learned to treat scoliosis with Harrington rod instrumentation, a single stainless steel distraction rod dating back to the 1960s; it was attached posteriorly at the top and bottom of spinal curves. A shift in paradigm occurred in the mid-1980s when the Cotrel-Dubousset dual rod segmental spinal instrumentation was introduced and orthopaedists had to learn to attach two rods to the spine at multiple points, but the learning curve was not as steep as expected since the indications for spinal instrumentation remained the same, and dual rods were still based on core skills of posterior spinal exposure, fusion, and instrumentation. Most medical innovations, in fact, are incremental and are easily phased into practice.
The problem begins when there are radically new medical devices introduced with no precedent in their use or indications. For these, there are no core skills to build on, so training at all levels, beginning from established attendings to fellows and residents, has to start from the ground level. The challenge to teach the use of the titanium rib was especially formidable, since its indications for use, thoracic insufficiency syndrome, was poorly understood by both the orthopedic and general surgery community. Unfortunately, the first step in teaching something new is for the teachers to completely master the technique, and that can be a daunting task with revolutionary techniques.
The first titanium rib was implanted at CHRISTUS Santa Rosa Children’s Hospital in 1989 by its inventor, a pediatric orthopaedic surgeon, with co-surgeon Dr. Melvin D. Smith, a pediatric general surgeon (Fig.1). The devices were placed longitudinally to stabilize a chest wall defect of a ventilatordependent infant with severe respiratory insufficiency. Lay publicity ensued after this successful surgery, and we felt reasonably confident that we now had a practical prosthesis that would grow with the patient for rare chest wall deficiencies and we would probably, at most, see 2-3 children a year referred to us for surgery with this rare disorder. We also guessed that perhaps once or twice a year a surgeonmight visit us to learn the procedure. We had no idea what was really going to happen next.
Things began to get complicated within six months of the first surgery. The next referral to us was not a child with absent ribs, but rather an infant from Phoenix, Arizona, with severe rib fusion and associated scoliosis. Other surgeons in our shoes would probably have just thrown up their hands and said, “Well, we have a good way to treat absent ribs, but this is exactly the opposite, so we can’t help,” but we weren’t that type of surgeon. The first titanium rib procedure was based on the concept of prosthetic expansion and stabilization of the chest to enhance lung function and growth, so using those principles, they thought carefully about what might be accomplished by adapting the vertically placed chest wall prosthesis into a chest wall distractor. The device could be attached to proximal and distal ribs, and, with transverse osteotomies of the ribs, used to push the ribs apart, expanding the constricted hemi-thorax and correcting
the scoliosis (Fig. 2). The plan seemed logical to both surgeons, and the parents gave their permission to go forth with the surgery. It was successful, with the custom prosthesis titanium rib completely correcting the scoliosis and expanding the fused ribs with expansion of the underlying lung, but there was only one problem: the skin incisions could not be closed because of the massive expansion of the chest.
The solution was a practical one: the versatile custom device was shortened in the operating room with a sterilized hack saw and re-implanted with some decreased scoliosis correction so that there was enough skin flap length to close the incision at that point. This marked the second operation made possible by the titanium rib device. And there was also more to learn about regarding indications, techniques, and complications.
News spread about the new procedures and things soon got very busy. Referrals began to increase at CHRISTUS Rosa Children’s Hospital in the early 1990’s, and we organized ourselves into a tri-specialty team to both evaluate and care for patients, the team included a pediatric pulmonologist, Dr. Ricardo Pinero. While perfecting the first two titanium rib procedures, we found that new referral problems would necessitate the development of even more new operations.
The next big challenge was a referral from Birmingham, England, by the National Health Service of a girl with Jeune’s Asphyxiating Thoracic Dystrophy, a condition in which the rib cage was so narrow that there was virtually no room for lung growth. The 14-month-old child was full-time ventilator dependent and the National Health Service was desperate to find some kind of treatment for her. Medical records and glass slides were forwarded to San Antonio and a theoretical operation, to hopefully trigger lung growth by laterally expanding the chest through a custom curved titanium rib, was sketched out for Dr. Smith. The child, unfortunately, died before she could be transferred to the United States, but the plans were placed safely away for a future patient.
This soon occurred in 1991 when a child was born in San Antonio at Wilford Hall Medical Center with Jeune’s syndrome. The child was extremely fragile, with frequent respiratory arrests. Perfusion lung scan showed almost no blood flow to the lungs constricted by the extremely narrow chest.
I met with the mother of the child, along with Dr. Thomas Mayes, the child’s intensivist. Not knowing the possible outcome of the never-tried procedure, I bluntly told the mother that there was a 90 percent risk of death on the table. The mother incredibly did not change expression, but quietly turned to Dr. Mayes, and asked him what the risk of death was without the surgery. Dr. Mayes calmly responded “100 percent.”
The mother turned back to me, smiled, and said, “I’ll take 90 percent.” We performed the 5-hour operation soon afterwards and it went on to be successful. The patient is now a 17-year-old young man in high school and thriving.
During the San Antonio sole-source FDA clinical VEPTR study, two more procedures were also pioneered solely through surgeon intuition and all these techniques were refined and improved through experience and modified to minimize complications. Dr. Smith and I wanted to be absolutely sure we knew every aspect of these procedures before they were taught to other surgeons. We were often criticized for not publishing early, but the procedures were so new and radical, we felt long term experience was needed before placing results in the medical literature.
The administrative side of the Titanium Rib Project was without precedent, complex and a journey through uncharted territory; running a marathon without a finish line. After I designed the engineering blueprints for the titanium rib, I went on to many false starts and stops with several orthopaedic companies, finally persuading one, Techmedica Corporation of Camarillo, California, to make it as a custom prosthesis which did not require FDA oversight, but surgical volume soon became so heavy that a need, to approach the FDA personally to start an official FDA clinical trial, was felt. Soon, a meeting was set in Washington with Dr. Thomas Callaghan, chief of devices for FDA, and a champion for children, and they worked together to design the first titanium rib feasibility study. Things went well for a time, but Techmedica Corporation went out of business several years into the FDA study. A search quickly began for a new company to make the devices, and in 1994, the Synthes Spine Company of West Chester, Pennsylvania, assumed manufacture of the titanium rib. They began to organize a U.S. multi-center FDA VEPTR trial. Seven other children’s hospitals were chosen to participate, including Children’s Hospital of Pittsburgh, Boston Children’s Hospital, followed by Children’s Hospital and Regional Medical Center of Seattle, Washington, Children’s Hospital Los Angeles, Primary Children’s Medical Center of Salt Lake City, Children’s Hospital of Philadelphia, and Shriner’s Hospital for Children of Philadelphia. The next problem was how to train all these investigators, and bring them up to par with our seven years of experience. There were no “titanium rib” core skills available from residency and fellow- ship for these new investigators, so teaching the approach was going to be a complex task.
CHRISTUS Santa Rosa Children’s Hospital began to provide a hands-on course for the initial investigators from Pittsburgh and Boston at San Antonio, including multiple didactics, case presentations, andmost importantly, scrubbing in on actual cases. All other subsequent sites sent their operative teams to San Antonio to learn the new techniques – not only the orthopaedists, but also the pediatric general surgeons and the pulmonologists. Dr. David Skaggs, Associate Chief of Orthopaedics at Children’s Hospital Los Angeles, was awarded a traveling grant from the Pediatric Orthopaedic Society of North America and spent two weeks in San Antonio observing the operations so that he could perform them at his home institution. Home-site operating room table mentorship was the next logical step for the new U.S. investigative sites. Being chosen to spend several years traveling to each investigative site to assist the new titanium rib surgeons in their first cases was very complicated. The titanium rib was used in five new procedures; just initial experience in each of the procedures usually required five separate trips. The multicenter protocol was conservative in that all cases to be performed by investigators at other sites had to be approved by the staff of the Titanium Rib Project at CHRISTUS Santa Rosa Children’s Hospital. The hard work eventually paid off. All the other surgeons at other sites felt comfortable with these new operations, and the early multi-center FDA device trial results proved that these skills were exportable from San Antonio with the results of safety and efficacy readily duplicated by the other centers. Meanwhile, there was a new challenge for the San Antonio titanium rib mentors. Midway through the U.S. titanium rib multicenter FDA trial, the application for CE mark approval for the device in Europe was approved. Now a new continent needed training.
We first traveled to Basel, Switzerland in 2003 for the first international VEPTR course with many surgeons throughout Europe attending. They scrubbed in to assist Dr. Fritz Hefti, the Chairman of the Orthopaedic Department at the Kinder-Hospital in Basel. Dr. Hefti had a long standing interest in titanium rib technology since his associate, Dr. Anna Hell- Volcke, had previously spent 6 months in San Antonio as a fellow spending time learning the procedures and doing research. Her paper on growth of unilateral unsegmented bars of congenital scoliosis treated by the titanium rib won two science awards in Europe.
Next we went on to travel numerous times to Europe to visit hospitals, see patients, and assist surgeons who wished to learn how to use the titanium rib for their patients. These were very grueling trips; nothing is more stressful than operating in a strange land, with a strange surgeon, on a strange patient. The operative outcomes, however, were excellent. On one trip in England, in 2004, we, over a ten day period, visited a total of seven cities, giving courses at two institutions, and operating in four more hospitals. We visited Madrid first (Fig. 3), then went to the United Kingdom. After landing in London, we departed to Cardiff, Wales (Fig. 4) for the first British VEPTR procedure, then to Coventry, Nottingham, New Castle on Tyne, Bristol, and back again to London. The routine became standard: a procedure would be completed in one hospital at approximately 5:00 pm, then we’d jump into the car and be driven to another city, often arriving at 9:00 pm for a welcome banquet; we’d check into the hotel by midnight and check out at 5:00 am in order to go to the hospital to perform another case. All of the operating rooms around the world look pretty much alike. Foreign travel sounds exciting, but the VEPTR mentorship trips were an exhausting routine for many years. It was, however, the best way to introduce the device technology into other hands.
Numerous surgeons continued to come to San Antonio during this time period. Dr. Noriaki Kawakami of Nagoya, Japan, president of the Japanese Scoliosis Society, took two separate trips to San Antonio to learn the procedures and introduce them in Japan (Fig. 5) in 2004. Numerous surgeons continued to come to San Antonio for onsite training, many Europeans from England, Germany, Scandinavia, and other countries. Surgeons also came from South America and Canada. The titanium rib operative population in San Antonio continued to skyrocket through the years and provided a ready source of teaching material for these visiting surgeons.
With approval of the Titanium Rib in 2004 in the United States, additional training requirements were now placed on the San Antonio mentors. Numerous U.S. surgeons went on to visit San Antonio for hands-on experience, and another round of training trips began. We traveled to many prominent children’s hospitals that were not in the original investigative study in order to help them begin their programs. The most successful part was teaching the multi-specialty approach (Fig.6), which emphasized not only pediatric orthopaedics, but also the general surgery, intensive care, post-operative rehabilitation, pulmonary care and other patient matters. Through these mentorship efforts, the other hospitals were able to offer titanium rib technology to their local patients.
With FDA approval, the Titanium Rib Project was successfully concluded, and a new “sponsoring entity” was needed to continue research and treatment of thoracic insufficiency syndrome in San Antonio. Approaching the CEO of CHRISTUS Health, Dr. Thomas Royer, and Dr. Rick Wayne, CEO of CHRISTUS Santa Rosa Children’s hospital, with a proposal for the founding of a national organization based in San Antonio was the start. Studying thoracic insufficiency syndrome diseases and continuing to develop advances in treatment were continuations. With CHRISTUS’ backing, the Thoracic Institute of CHRISTUS Santa Rosa Children’s Hospital went on to be established. Yearly national courses have been given by the Thoracic Institute in San Antonio on thoracic insufficiency syndrome and its treatment with the titanium rib with contributions by many physicians and staff.
Lori Buegeler, RN, nursing case manager, taught visiting surgeons how to manage insurance company inquiries and special needs such as oxygen for transport and scheduling special air ambulances for these unique patients. Ms. Hope Treviño, administrative assistant of the Thoracic Institute, in addition to her overwhelming duties of coordinating patient inquiries, national patient visits for evaluation, and referrals, handled all of the complex arrangements for bringing the surgeons to San Antonio. Research continued to be published by the Institute with the aid of Charmaine Grohman, the research associate for the Institute. The number of children evaluated in San Antonio over the years for thoracic insufficiency syndrome now numbers over 1,000 and the patient population continues to grow. The successful development of the titanium rib, approved only after what is rumored to be the longest FDA device trial in U.S. history, has helped spur national reform in general pediatric device development. After testifying in 2007, before the Senate Committee on Health about pediatric devices, a new bill, to help nurture pediatric device innovation, was signed into law as The Pediatric Device Safety and Improvement Act of 2007. My goal is to continue to serve on an NIH intra-agency working group to help implement the provisions of the new pediatric device bill.
The 14-year titanium rib technology master mentorship plan, set in motion in 1994, has just been completed and has succeeded beyond expectations. This new complex, radical technology, now established around the world to treat the most fragile of pediatric patients, has been safely introduced in over 30 countries. This San Antonio mentorship philosophy, borrowing from both classic and innovative principles in surgical and medical training, will prove to be an important model in the future for other introductions of paradigm-shift technologies. All it takes is hard work, planning, and relentless perseverance. The children who benefit are worth it.
Acknowledgement
This article honors the memory of Dr. Melvin D. Smith who passed away January 14th, 2008, after a ten year battle with prostate cancer. Robert M. Campbell, Jr., MD is a professor of orthopaedics at UTHSCSA and holds the President’s Council/Dielmann Chair in Pediatric Orthopaedic Surgery. He moved to San Antonio in 1986 after completing a pediatric orthopaedic fellowship at the Alfred I. DuPont Institute in Wilmington, Delaware. After six years in private practice, working with Dr. Kaye Wilkins and Dr. Earl Stanley, he joined the Health Science Center in 1992.
