Vol. 15, Issue 1 Jan 2015

Case Management: Making Lung Transplantation Available to More Patients

Contributing Author: Thomas Wozniak, MD

ACCREDITATION STATEMENT
Indiana University School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

DESIGNATION STATEMENT
Indiana University School of Medicine designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

FACULTY DISCLOSURE STATEMENT
In accordance with the Accreditation Council for Continuing Medical Education (ACCME) Standards for Commercial Support, educational programs sponsored by Indiana University School of Medicine (IUSM) must demonstrate balance, independence, objectivity, and scientific rigor. All faculty, authors, editors, and planning committee members participating in an IUSM-sponsored activity are required to disclose any relevant financial interest or other relationship with the manufacturer(s) of any commercial product(s) and/or provider(s) of commercial services that are discussed in an educational activity.

COMMITTEE AND AUTHOR DISCLOSURE
Statements of Disclosure of Relevant Financial Relationships have been obtained from Thomas Wozniak, MD. Dr. Wozniak has disclosed that he has no relevant financial relationships with any commercial interests.

OBJECTIVES
After reading this article, the reader should be able to:

  • Identify the system used to allocate donor lungs.
  • Describe why the majority of donor lungs are considered unacceptable for transplantation.
  • Summarize the rationale for and the technique used in ex vivo lung perfusion (EVLP).
  • Compare the clinical study results of lung transplantation with marginal lungs preserved with EVLP and ideal lungs preserved using cold storage techniques.
  • Discuss immunosuppression following lung transplantation.

Date of original release: January 2015
Date of expiration: January 2016


Note: While it offers CME credits, this activity is not intended to provide extensive training or certification in the field.

Overview of Lung Transplantation

The first human lung transplant was performed in 1963, with the recipient surviving for 18 days before succumbing to renal failure and malnutrition.1 Although this operation established the technical feasibility of lung transplantation, few others were performed until the mid-1980s, when advances in surgical techniques and the advent of cyclosporine immunosuppression made transplantation an accepted option for end-stage lung disease (Table 1). Since 2000, the number of lung transplants has increased annually. Slightly more than 1900 procedures were done in 2013, according to the US Organ Procurement and Transplantation Network, and approximately 1700 patients are currently on the lung transplant waiting list.2 The LAS system, implemented in 2005, is used to prioritize candidates aged ≥12 years. The complex calculation is based on a combination of waitlist urgency (one-year survival without a transplant) and predicted survival one-year post-transplant to produce a score ranging from zero (least ill) to 100 (most ill) that indicates the net benefit of lung transplantation.

Case Study

A 66-year-old woman with longstanding end-stage chronic obstructive pulmonary disease who requires supplemental oxygen (4 liters/minute) is referred to the Indiana University Health lung transplant program for evaluation. After completing the work-up, which includes radiographic and laboratory studies and functional and psychosocial assessments, she is listed for double-lung transplantation. Her lung allocation score (LAS) of 32.2995 places her below many individuals in more urgent need of transplant, and her time on the waiting list is prolonged.

A shortage of donor lungs is the major limiting factor to lung transplantation. Lungs are procured from just 15 percent of all multiorgan donors, as compared with an 88 percent rate for kidneys and livers and a 30 percent rate for hearts.3 These disparities largely reflect the vulnerability of the lung to potential complications arising before and after donor death, such as thoracic trauma, aspiration, ventilator-associated lung injury, pneumonia, and neurogenic pulmonary edema. As a result of such complications, more than 80 percent of donor lungs may be damaged and are generally considered unacceptable for transplantation (Table 2).4

"Lungs with suboptimal gas-exchange function or infiltrates visible on chest radiographs have been successfully transplanted," says Thomas Wozniak, MD, surgical director of the cardiothoracic transplant program at IU Health. "But an increased incidence of primary graft dysfunction—an acute lung injury that appears within 72 hours after transplantation and adversely affects outcomes—has been reported in some studies.5,6 Consequently, surgeons tend to be highly conservative when selecting donors."

Increasing the Pool of Donor Lungs with Ex Vivo Lung Perfusion

Cold flush with static cold storage is the accepted standard for preserving donor lungs. Provided ischemia times are not excessive and the initial quality of the organs is high, Dr. Wozniak says this technique is reasonably effective in maintaining lungs until transplantation. However, the inhibition of cellular metabolism caused by hypothermia makes it difficult to assess "marginal" lungs during the preservation period and eliminates any possibility for rehabilitating injured organs.

Because an estimated 10 to 20 percent of marginal lungs may actually be suitable for transplantation, there has been a pressing need for innovative interventions to accurately differentiate viable from nonviable donor lungs and improve the quality of substandard donor organs. An ex vivo lung perfusion (EVLP) system (XPS™, XVIVO Per fusion, Inc), approved last summer by the US Food and Drug Administration, may fill this critical need and allow more people with end-stage lung disease who have exhausted all other treatment options to receive lung transplants.

"When additional time is needed to determine if procured lungs satisfy the criteria for transplantation, the EVLP system is used to warm the donor organs to near-normal body temperature, ventilate them, and continuously flush the tissues with a sterile preservation solution (Steen™ solution) that provides nutrients and removes waste products and excess fluid."

"When additional time is needed to determine if procured lungs satisfy the criteria for transplantation, the EVLP system is used to warm the donor organs to near-normal body temperature, ventilate them, and continuously flush the tissues with a sterile preservation solution (Steen™ solution) that provides nutrients and removes waste products and excess fluid," Dr. Wozniak explains. "The four to six hours donor lungs can remain on the device for reconditioning gives the transplant team time to examine the organs, assess the airways with bronchoscopy, and evaluate lung function before deciding whether to proceed with surgery."

Approval for the EVLP system was based on the results from two clinical trials—the HELP study from Canada7,8 and the NOVEL study conducted at IU Health and seven other US centers.9 Both trials compared outcomes for lung transplant patients who received marginal lungs preserved using the EVLP system (n=90) with controls given ideal donor lungs preserved using conventional cold storage techniques. Up to 12 months post-transplantation, survival and organ rejection rates for the two groups were comparable. As a condition of device approval, the manufacturer is continuing the NOVEL study (ClinicalTrials.gov identifier: NCT01365429) to evaluate long term efficacy and identify adverse events associated with EVLP.

"Twenty to 25 percent of patients on the lung transplant waiting list die because organs are not available," Dr. Wozniak emphasizes. "Ex vivo lung per fusion is a unique way to significantly expand the donor pool and give more patients, including high-risk patients who are unlikely to undergo transplantation, the opportunity to receive this potentially lifesaving surgery."

Case Study (cont.)

After spending two years on the lung transplant waiting list, the patient elects to participate in the NOVEL study. Less than eight weeks after enrolling in the trial, a set of non-standard lungs that would normally have been declined are procured for the patient and placed on the EVLP system. Following four hours of reconditioning, the lungs meet the criteria for transplantation. A bilateral lung transplant is performed through bilateral thoracotomy incisions, which provide excellent exposure of the pleural space. The lungs are implanted separately and sequentially without the use of cardiopulmonary bypass. After completion of the anastomoses, two chest tubes are placed in each pleural space, and the chest is closed. The airway is inspected endoscopically, anesthesia is reversed, and the patient is transferred to the intensive care unit.

The immunosuppressive regimen is started immediately before surgery, consisting of loading doses of tacrolimus and mycophenolate mofetil. A bolus of methylprednisolone is given intraoperatively before graft perfusion. Administration of all three drugs continues postoperatively; the patient also receives a single dose of alemtuzumab.

The patient's recovery is prolonged due to kidney and gastrointestinal issues that ultimately resolve. She is discharged home on postoperative day 79.

Less than eight weeks after enrolling in the trial, a set of non-standard lungs that would normally have been declined are procured for the patient and placed on the EVLP system.

Immunosuppressive Therapy

Graft failure, a form of acute respiratory disease syndrome/diffuse alveolar damage, is the leading cause of death during the first 30 days after transplantation. Chronic allograft rejection or graft dysfunction, which manifests as bronchiolitis obliterans syndrome, is a leading cause of late mortality. Because immune reactivity and graft rejection are highest in the first six post-transplant months and declines with time, the intensity of the immunosuppressive regimen decreases over the first year, eventually settling on the lowest maintenance levels capable of preventing graft rejection. Whenever feasible, lower doses of multiple drugs with non-overlapping toxicities are preferable to higher—and more toxic—doses of fewer drugs. Combination immunosuppressant regimens also help block the many components of the complex immunologic cascade leading to graft rejection.

"The immunosuppressive strategies used in lung transplantation have capitalized on the experiences with transplantation of other solid organs," Dr. Wozniak points out. "Nonetheless, there is no consensus regarding the optimal regimen."

A retrospective cohort study was conducted using United Network for Organ Sharing data on 4805 adults who received lung transplants between 2005 and 2009.10 Overall, transplantation had a positive and durable effect on physical function for both older (≥65 years) and younger (18 to 64 years) recipients. Ninety percent survived the first 12 months post-transplant (Table 3), and these individuals were predicted to experience relatively good function for some years thereafter. Even older patients with very severe functional debility at the time of transplantation rarely become disabled within the first four years after receiving new lungs.

Case Study (cont.)

The patient returns to IU Health for routine follow-up weekly for one month, then biweekly for three months, then monthly for one year. Monitoring consists of clinical examination, chest radiographs, spirometry, bronchoscopy, and blood tests to regulate immunosuppressive therapy. Her lung function gradually improves after surgery and plateaus at six months posttransplant. Nine months after receiving her donor lungs, she is doing well and continues immunosuppression with oral cyclosporine, mycophenolate mofetil, and prednisone. Her functional status is normal, and she does not require supplemental oxygen.

IU Health Lung Transplant Program

IU Health performs nearly 500 solid-organ transplants each year, making it the fourth largest solid-organ transplant center in the nation, according to the Organ Procurement and Transplantation Network. IU Health Methodist Hospital is home to the lung transplant program, the only such program in Indiana. In 2014, Dr. Wozniak and his colleagues performed 58 lung transplants, making the IU Health program one of the largest in the United States. Forty percent of these recipients were enrolled in the phase 4 NOVEL study.

Thomas Wozniak, MD

Surgical Director Thoracic Transplantation & MCS
IU Health Physicians Cardiovascular Surgery
twozniak@iuhealth.org

Dr. Wozniak received his medical degree from the IU School of Medicine, did a residency in general surgery at IU Health Methodist Hospital, and completed fellowships in cardiothoracic surgery at St. Louis (Missouri) Health Sciences Center and cardiothoracic transplantation at IU Health Methodist Hospital. He specializes in cardiothoracic surgery and has subspecialties in heart and lung transplantation, mechanical circulatory support, and high-risk cardiac surgery.

Dr. Wozniak is certified by the American Board of Surgery and the American Board of Thoracic Surgery. A Fellow of the American College of Surgeons, he is also a member of several other professional organizations, the author of more than a dozen journal articles and book chapters, and the principal investigator for four ongoing clinical trials.

Dr. Wozniak was the first surgeon in Indiana to perform robotic-assisted, minimally invasive mitral valve repair and replacement and to implant the Heartmate II and Heartware ventricular assist devices. Additionally, he was a member of the surgical team that performed the world's first bilateral lung-pancreas transplant.

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