Pulmonary Hypertension Association

Lung Transplantation:
Timing, Perioperative Considerations and Postoperative Outcome

Andrew Peacock, MD Edward Cantu III, MD, and R. Duane Davis, Jr, MD
Department of Surgery
Duke University Medical Center
Durham, North Carolina

Dr. Cantu was supported by a grant from the National Institutes of Health (1F32 HL 71457-01).

Lung transplantation has evolved over the past several decades in patients with end-stage lung disease. Single and bilateral lung as well as heart-lung transplantation has been utilized in the setting of severe pulmonary arterial hypertension (PAH) when all other therapeutic measures have been unsuccessful. While transplantation offers the prospect of improved survival and functional status, the potential consequences of lifelong immunosuppression and infection as well as chronic, refractory allograft rejection mandate careful patient selection and close follow-up prior to proceeding to transplantation. Pharmacologic therapy for severe PAH has evolved considerably as well, and survival with this disease in the setting of the best available treatment (continuous intravenous epoprostenol) appears to be approximately 88%, 76%, and 63% at 1, 2, and 3 years, respectively.¹ Because progressive right ventricular failure still occurs, transplantation must be considered in patients with end-stage disease who meet selection criteria. We will focus on timing of the referral and of the procedure, perioperative considerations, and postoperative outcome. Candidate selection, temporizing procedures such as septostomy, and immunosuppressive therapy are discussed in detail elsewhere in this issue.

Timing of Referral for Transplantation and of Procedure
The physician caring for the patient with PAH must be cognizant of three time-related variables: patient survival on current maximal medical management, approximate projected time on the waiting list, and patient survival after transplantation. Ideally, transplantation occurs when the clinically deteriorating patient has enough reserve to survive long enough to undergo transplantation but is not debilitated enough to jeopardize the graft (Table 1). With regard to this ideal there is significant uncertainty. All patients who are in World Health Organization (WHO) class III and IV with refractory right ventricular failure on presentation should be referred for transplantation,² as should those with progressive right ventricular failure on maximal medical therapy.³ Recent evidence from a prospective observational study¹demonstrated that patients receiving intravenous epoprostenol therapy who had not improved to functional class I or II should be listed because their mortality at 3 years was 38% and 100% for class III and IV, respectively. Patients with class I and II symptoms will likely have better survival with state-of-the-art medical therapy and referral should be deferred. However, patient characteristics with respect to blood type, size, and panel reactive antibodies should also be taken into account as these factors can significantly prolong time on the waiting list.⁴

Table 1. Pulmonary Arterial Hypertension: Guidelines for Lung Transplantation*
General Guidelines	Disease-Specific Guidelines

Age limits Single lung transplant ~65 years Bilateral lung transplant ~65 years Heart-lung transplant ~55 years Absolute contraindications Creatinine clearance <50 mg/mL/min HIV infection Active malignancy within 2 years† Hepatitis B antigen positivity Hepatitis C with positive liver biopsy Relative contraindications Symptomatic osteoporosis Severe musculoskeletal disease Body mass index >30 Hyperbilirubinemia >2.0 mg/dL Tobacco or substance abuse Psychosocial problems Invasive ventilator support Colonization with fungi or atypical mycobacteria	Management Treatment based on disease severity: Progression despite epoprostenol and standard supportive therapy‡ Hemodynamic predictors of poor outcome Cardiac index <2 L/min/m2 Mean right atrial pressure >15 mm Hg Mean pulmonary artery pressure >55 mm Hg§ Indications for transplant WHO class III or IV with progression on vasodilator therapy
* Modified from international guidelines⁴⁶ and Pielsticker et al.¹¹ † With exception of basal cell and squamous cell carcinoma of the skin. Further, 5-year waiting period is recommended for high stage renal, breast, and colon cancers as well as advanced melanoma (level III or greater). ‡ Patients often respond well to continuous intravenous epoprostenol even with severe abnormal hemodynamics as outlined here. Those not responding or with continued progression in spite of such therapy should proceed to transplant. § In patients with congenital heart disease, mean pulmonary artery pressure is often in excess of 55 mm Hg; this measurement in and of itself does not portend same poor prognosis as in other patients with pulmonary arterial hypertension. WHO=World Health Organization.

Unlike heart or liver transplantation, the lung transplant allocation system does not take into account acuity of illness.⁵ The allocation algorithm in this system after matching size and blood group is entirely based on time accrued since listing. Organs are offered first locally then regionally in successive 500-mile increments.⁵ Since the clinical introduction of lung transplantation, the number of potential recipients has far outpaced the number of donors. This donor shortage has doubled the median time to transplant.⁶ There are currently 3937 patients awaiting lung transplantation and recent figures demonstrate that 33% will die on the waiting list.^5,6 Patient characteristics that can significantly prolong time on the waiting list are blood group antigen type, small patient size, and high panel reactive antibodies. The 1992-2001 UNOS registry demonstrated that blood type O patients waited an average of 11 months longer than blood type AB patients.⁵ In addition, small patients (those with a total lung capacity less than 4.5 L), wait an additional 60 days compared to recipients with a total lung capacity greater than 4.5 L..⁵ Lastly, Appel et al⁷ demonstrated that patients with high levels of panel reactive antibodies also waited significantly longer for transplantation and had higher mortality while waiting. Though no guidelines exist regarding these issues, our inclination is to refer class III and IV patients at the time of the initial evaluation. In the small group of patients with good functional status but with mitigating characteristics or history (ie, type O blood group or history of multiple previous transfusions) referral for listing is individualized and typically is reserved until some degree of disease progression has been demonstrated.

Operation
Historically, treatment for pulmonary hypertension required transplantation of a heart-lung block.⁸ This initial approach was consequent to the concern that right ventricular function would not improve sufficiently to prevent perioperative morbidity and mortality.⁹ In the current era of surgical therapy for PAH, isolated lung transplantation is now used in most cases except in instances where uncorrectable structural defects orleft ventricular dysfunction is present in the native heart.^9,10 Considerable variations in practice patterns have been reported with respect to single versus bilateral lung transplantation for pulmonary hypertension.¹¹

In a retrospective study of the University of Pittsburgh’s experience, both procedures resulted in similar length of mechanical ventilation, length of intensive care unit stay, and mortality.¹² Registry data from the International Society for Heart and Lung Transplantation have confirmed no significant differences in survival in patients with PAH.13 Despite no apparent differences in mortality, significant differences exist between those with single versus bilateral lung transplants with respect to blood flow, pulmonary artery pressure, and immediate cardiac index.

After single lung transplantation almost the entire cardiac output passes through the allograft while ventilation remains evenly distributed.^14-17 This is well tolerated provided that minimal allograft dysfunction is present. In the face of reperfusion injury, infection, or rejection, significant hypoxemia results from increased ventilation perfusion mismatch.^16,18 Single lung recipient outcomes are inextricably linked to the function of the single allograft. Unlike other recipients transplanted for other reasons, these recipients have no functional reserve from their native lung because pulmonary blood flow continues to be preferentially shunted through the allograft despite ineffectual ventilation.⁹ Additionally, an occasional complication of single lung transplantation for pulmonary hypertension is infarction of the native lung from hypoperfusion. Though rare, such situations require emergent reexploration and pneumonectomy.

Bando and colleagues¹⁷ further explored the postoperative hemodynamic results following single lung, bilateral lung, and heart-lung transplantation in a cohort of 57 consecutive patients with pulmonary vascular disease. They demonstrated that postoperative pulmonary artery pressures remained significantly higher in those with single lung transplants than in those with heart-lung or bilateral grafts; however, despite this difference, all groups experienced a significant decrease in pulmonary artery pressures. They further noted improvement in cardiac index in only the bilateral and heart-lung transplant recipients.

The superiority of bilateral versus single lung transplantation in patients with PAH remains a matter of debate. We prefer bilateral lung transplantation because it affords a greater reduction in pulmonary artery pressure, enhanced right ventricular protection and a larger effective pulmonary reserve. In addition, recent investigations have demonstrated a significant survival advantage of bilateral lung transplantation in patients with end-stage lung disease.^19-22

Perioperative Considerations
Worsening right ventricular failure is a substantial concern inPAH. Perioperative management requires the understanding of the multiple mechanisms that can lead to progressive ventricular dysfunction, such as inadequate preload, provoked increases in pulmonary resistance, fluid overload, systemic hypotension, and hypoxemia. Intraoperative management requires continuation of the optimized pharmacologic regimen (generally epoprostenol) through surgery because abrupt discontinuation can lead to profound pulmonary vasoconstriction, right heart failure, and death.²³ Typically, ascitic fluid is drained to allow for greater diaphragmatic excursion (sometimes requiring a temporary peritoneal catheter for intermittent decompression of the abdomen postoperatively). Additionally, the bypass is primed with fresh frozen plasma rather than isotonic crystalloid. Careful attention must be paid to volume status and diuretics must be used with caution based on hemodynamic monitoring. The prothrombin time, fibrinogen level, and a thromboelastogram should guide replacement therapy intraoperatively. Oxygen saturation should be kept greater than 90% to avoid unnecessary hypoxic vasoconstriction.²⁴ Normally, acidosis has minimal effect on pulmonary vascular resistance; however, in the presence of alveolar hypoxia its effect is considerably augmented. Rudolph et al²⁵ have demonstrated a decrease in pulmonary vascular resistance in patients with pulmonary hypertension by reducing the arterial carbon dioxide tension and hydrogen ion concentration. In the event that inotropic support is required in the face of euvolemia, dobutamine is the first agent of choice because of its pulmonary vasodilatory properties.²⁶ Milrinone can also be used, but its lack of pulmonary specificity can aggravate systemic hypotension.²⁷ If hypotension continues, norepinephrine and phenylephrine can be used to augment coronary perfusion by maintaining systemic pressures.²⁸

Postoperative management can be quite challenging. Patients may die suddenly in the immediate postoperative period from hemodynamic perturbations. Although single and bilateral lung transplantation results in immediate afterload reduction in the operating room, right ventricular function recovers more slowly.^10,29-31 Care must be taken to avoid pulmonary vasoconstriction and any therapy that decreases pulmonary vascular resistance should be weaned with caution.²³ Early extubation and mobilization of transplant recipients as well as negative fluid balance are the cornerstones of management. Loss of local defense mechanisms, consequent to denervation and reduction of mucociliary clearance, identifies why the allograft is more vulnerable to atalectasis and infection.³² Therefore, early extubation and mobilization of recipients augment lung reexpansion and recruitment of alveoli. Fluids are restricted and diuretics administered to achieve a negative fluid balance. Passive hepatic congestion from chronic right ventricular failure will likely have resulted in impaired liver synthetic function. Patients will be prone to coagulopathy and ascites. Intermittent drainage of ascites is indicated to augment ventilatory effort. Liberal use of vitamin K and fresh frozen plasma may be needed to prevent posttransplantion coagulopathy.

Outcomes
Reported cumulative world experience exceeds 13,000 lung transplants with 73% 1-year and 45% 5-year overall survival.³³ Patients with PAH, idiopathic pulmonary fibrosis, and sarcoidosis have higher early mortality rates than those with other diagnoses.³³ Patients with cystic fibrosis have 1-, 5-, and 10-year survival rates of 78%, 52%, and 37% while those recipients with PAH have survival rates of 64%, 44%, and 20%, respectively.³³ As noted, patients with PAH have the highest early hazard of all diagnoses. This can be explained by the complexity of the operation, the requirement for cardiopulmonary bypass, and the right ventricular dysfunction common in these patients.

The two most common causes of death after the first transplant year include bronchiolitis obliterans and infection.³³ Long-term success of lung transplantation is limited by chronic allograft dysfunction, thought to be primarily due to chronic allograft rejection. This injury has been characterized by scar formation and fibrosis of the small airways and is defined as bronchiolitis obliterans.³⁴ The diagnosis of bronchiolitis obliterans requires a histopathologic specimen that includes the small to medium sized airways. However, transbronchial biopsy specimens are insensitive for this diagnosis, since mostly alveolar tissue is obtained and bronchioles are infrequently sampled. The International Society for Heart and Lung Transplantation developed a reproducible and reliable surrogate marker for bronchiolitis obliterans that utilizes declining FEV₁.³⁵ The system has been widely adopted and validated as a useful surrogate for histological bronchiolitis obliterans.

Bronchiolitis obliterans syndrome (BOS) is the most common cause of morbidity and mortality following lung transplantation. At 5 years, 50% of transplanted patients have developed BOS and of the survivors, more than 33% continue to carry this diagnosis. Quality of life is significantly reduced once BOS develops, and the risk for death due to infection may also be increased.^36-39

Kshettry and colleagues retrospectively analyzed 107 lung allograft recipients for the development of bronchiolitis obliterans to evaluate PAH as a potential risk factor. They demonstrated that patients with PAH developed bronchiolitis obliterans more often (39% vs 19%; P= .044) and more rapidly (12 vs 15 months; P = .05) than those with other diagnoses.⁴⁰ However, results from other investigators have not corroborated these findings. Sundaresan at Washington University, reported no significant tendency for development of BOS (surrogate for bronchiolitis obliterans) in patients with PAH.^41-42 At present there is no consensus as to whether PAH is a risk factor for the development of bronchiolitis obliterans.

The lungs are particularly vulnerable to infection after transplantation. This is likely the consequence of multiple factors that include constant exposure to potential inhaled pathogens, impaired local defense mechanisms (cough and mucociliary transport), and immunosuppression. Bronchoscopy is an invaluable adjunct for diagnosing pulmonary infection, because clinical or physiological parameters are often unable to distinguish between the two.⁴³ Non-CMV pneumonia is most commonly caused by gram-negative bacteria and Staphylococcus aureus early in the postoperative period. Viruses, fungi, and protozoa compose a set of more severe late infections that are more difficult to treat if prophylaxis is unsuccessful.⁴⁴

Table 2 - Common Morbidities 5 Years After Lung Transplantation

Outcome
Hypertension
Hyperlipidemia
Renal dysfunction
   Abnormal creatinine <2.5 mg/dL
   Creatinine >2.5 mg/dL
   Dialysis dependent
   Renal transplantation
Diabetes

Percentage
86.5
43.4
38.3
20.2
13.7
3.4
0.9
27.8

Adapted from Trulock.³³

Five years after transplantation, the most common morbidities excluding bronchiolitis obliterans include hypertension, hyperlipidemia, renal dysfunction, and diabetes (Table 2).³³ Osteoporosis can be prevented to some extent. All are a consequence of immunosuppressive therapy.

Despite all of these factors, more than 80% of 1-, 3-, and 5-year survivors reported no activity limitations on follow-up. In addition, at 5 years, 40% of patients reported they were working full or part time.³³ Further, Gross and colleagues⁴⁵ demonstrated significant improvement in health-related quality of life and satisfaction in about 80% of recipients interviewed.

Comment
Prior to the availability of epoprostenol, lung transplantation for PAH was indicated when mean right atrial pressure was >15 mm Hg, mean pulmonary artery pressure was >55 mm Hg, and cardiac index was <2 L/min/m2 and early survival was acceptable. Subsequent to the availability of medical therapy, the indications for transplantation have not changed but the patients are significantly more debilitated. Today, patients with pulmonary hypertension face a significant early hazard, with a 30-day survival of only 76%, while patients with CF and COPD have a survival of 91% and 93%, respectively.³³ Based on a conditional survival of 3 months, there is no difference between pulmonary hypertension, CF, and COPD, each with a 6-month survival of 96%.³³ This high early mortality seen after lung transplantation in patients with pulmonary hypertension likely reflects the ability of vasodilator therapy to prolong life despite significant pathophysiology. The advent of vasodilator therapy and the less than ideal results of lung transplantation for PAH have tempted clinicians to refer patients later when they have more advanced right ventricular failure. Despite these results, outcomes have improved since its original description and things must be kept in perspective.

With the significant medical advances in the treatment of PAH, transplantation should be reserved for those patients in whom pharmacologic therapy has failed. In this subset of patients whose condition does not respond, and which deteriorates with pulmonary vasodilator therapy, significant improvement in hemodynamics, functional class, actuarial survival, and quality of life has been demonstrated with isolated lung transplantation. Candidate selection and timing of referral to transplant centers is critical for ultimate success, particularly with current allocation protocols that do not take into account the severity of illness. Though long-term success is tempered by chronic allograft dysfunction and infection, significant improvements in outcomes have established lung transplantation for PAH as an efficacious and life-prolonging treatment.

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