Indications

Lung transplantation is considered in selected children with end-stage or progressive lung disease or life-threatening pulmonary vascular disease for which there is no other medical therapy. Regardless of the underlying diagnosis, all candidates require (1) a clear diagnosis and well-delineated trajectory of illness such that the child is at high risk of death despite optimal medical therapy; (2) reliable access to transplant services and medications after transplantation; and (3) assurance that the patient and support system can and will adhere to the rigorous therapeutic plan before and after the transplantation.

Contraindications

Comorbid disorders can complicate the procedure and compromise the outcome. Box 57.1 includes several relative contraindications, though there is significant variability between centers. Most pediatric centers will use mechanical ventilation for patients who develop respiratory failure after listing despite the fact that mechanical ventilation is a risk factor for mortality. ^, More recently, extracorporeal support has been used to bridge pediatric and adult patients to transplant, including venovenous extracorporeal membrane oxygenation (VV ECMO) and pumpless, low-resistance membrane oxygenator devices. The early experiences for patients undergoing lung transplantation directly from ECMO had poor outcomes, with an overall survival rate of only 40%. Since then, single-center reports of outcomes after VV ECMO show that, with careful selection and emphasis on rehabilitation, the short-term survival is similar to those who were not supported pretransplant with VV ECMO. In an optimal setting that incorporates experienced physical therapists, following lung transplantation, these patients can be ambulatory less than 1 week posttransplantation. Some centers use central transthoracic placement of the ECMO catheters to allow patients to move their heads freely and ambulate more easily. Another advantage of this mode is that it prevents recirculation and minimizes damage to the tricuspid valve. Paracorporeal membrane oxygenation has been used in a subset of infants and children. The method entails use of a membrane oxygenator interposed between the pulmonary artery (PA) to left atrium (LA) that serves as a pumpless oxygenator to allow for extubation and rehabilitation while awaiting lung transplantation.

Survival and outcomes

Despite improvements in clinical outcome, morbidity and mortality associated with lung transplantation remains high. Mortality is greatest in the first year, with approximately 10% to 15% of all recipients dying owing to infection, cardiovascular failure, and/or multiorgan failure. Nevertheless, the overall median survival rate has improved over the past 30 years. Survival is similar between CF patients and children with other diagnoses ( Fig. 57.1 ). Survival is also similar among all pediatric recipients, including infants, when conditional survival to 1 year is considered ( Fig. 57.2 ). Before 2000, median survival was 3.3 years among all children but has improved substantially to 5.8 years after 2000. Upon conditional analysis limited to survival to 1 year, pediatric median survival surpasses that of adults to 8.9 versus 8.2 years ( Fig. 57.3 ). Single-lung transplantation has not been applied to the pediatric population for over a decade, as mortality is 40% in the first year and the survival of those few recipients was significantly decreased (median survival, 2.2 years) compared with patients who undergo bilateral sequential lung transplantation. ^,

Kaplan-Meier survival by diagnosis (transplantation performed January 1994 to June 2016). CF, Cystic fibrosis; ILD, interstitial lung disease; IPAH, idiopathic pulmonary arterial hypertension; non- Retx, non-retransplant; OB, obliterative bronchiolitis; PH, pulmonary hypertension.

Pediatric lung transplants (transplantation performed January 1994 to June 2016). Conditional Kaplan-Meier survival by recipient age group.

Conditional Kaplan-Meier survival to 1 year by pediatric lung transplant recipients compared with adults (transplantation performed January 1994 to June 2016).

Extended survival is compromised by chronic lung allograft dysfunction (CLAD), previously termed bronchiolitis obliterans syndrome (BOS). CLAD is thought to emerge as a result of various injuries to the graft that result in chronic active inflammation and a dysregulated injury response to various insults, including acute rejection and infection. The measured pulmonary mechanics of the graft encompasses a spectrum of phenotypes spanning between obstructive and restrictive phenotypes, as detected by pulmonary function testing (PFT). BOS is characterized by progressive airflow obstruction due to fibrotic obliteration of the small airways. Restrictive allograft syndrome (RAS) is characterized by restrictive lung function mechanics; studies may demonstrate elements of both. Within 5 years of transplantation, fewer than 50% of transplant recipients are free from BOS ( Fig. 57.4 ). Significant study has been applied to identify the etiologies of CLAD, yet the pathophysiology is not well characterized. Treatments are generally palliative rather than curative. ^,

Pediatric lung transplants freedom from bronchiolitis obliterans syndrome (transplantation performed January 1994 to June 2016).

Evaluation of the donor

Criteria to assess the acceptability of lung donors have been developed. Box 57.2 describes the criteria used to define an ideal donor. These criteria have been developed largely from clinical experience rather than from large multicenter trials. Specific criteria for pediatric candidates have not been established. However, it is generally accepted that the ideal lung donor for children should be a nonsmoker of the same size (chest dimension measured from the diaphragm to the apex of the lung) and blood type or ABO compatible. Other than these basic criteria, the evaluation is relatively subjective and occurs at the time of retrieval. The general tenets followed include that the donor should have no significant history of lung disease, including asthma. There should be no pulmonary trauma or infections, gas exchange should not be impaired, and ischemic time should be minimal. Pediatric lung transplant centers may apply more stringent criteria if the candidate in question is reasonably stable. Donor offers from younger donors may be more desirable in some cases.

Depending on the need of the candidate, nonideal donors, also called extended or marginal donors, may be accepted. There is limited data to either support or prohibit the use of lungs from a nonideal donor. There is no evidence that a marginal donor will have any effect on either immediate or long-term morbidity or mortality except in egregious cases of the diagnosis of bronchopneumonia, the presence of purulent lower airway disease in the donor, or injury from contusions. It is shown that lungs obtained from donors older than 65 years who have a significant smoking history are at risk for developing malignancy in the setting of immunosuppression. As well, lungs from older donors have worse long-term graft survival.

Many factors stemming from donor cause of death and subsequent donor maintenance in the ICU can contribute to donor lung injury. The most common causes include ventilator-induced lung injury, atelectasis, oxygen toxicity, and volume overload. In addition, after brain death, a systemic inflammatory response known as a cytokine storm occurs. This predisposes to the development of lung injury that is similar to acute respiratory distress syndrome, (ARDS). A different type of cytokine storm that occurs following brain death is a catecholamine storm. In an attempt to protect cerebral perfusion during brain death, the body will release a large amount of catecholamines. This surge of catecholamines causes significant systemic hypertension, which results in elevated left-sided heart pressures and consequent interstitial edema and can sometimes cause alveolar hemorrhage, resulting in neurogenic pulmonary edema. This generally precludes the use of the lungs for transplantation because of poor oxygenation. However, neurogenic pulmonary edema is a leaky capillary syndrome that is fully recoverable. This is one area in which removal of the lung from the inflammatory milieu of the brain-dead donor and a period of time for recovery and removal of extravascular water with ex vivo lung perfusion (EVLP) has had a significant impact on donor lung utilization.

The process for donor lung preservation begins at the time of declaration of death and extends until the lungs are reperfused in the recipient. Prior to retrieval, fluids are managed to maintain euvolemia and barotrauma must be avoided. A 1-g bolus of methylprednisolone is given to the donor to mitigate brain death–induced systemic inflammation. At the time of retrieval, the lungs are prepared for transport, flushed vigorously with a preservation solution, and inflated with oxygen. An extracellular-type flush preservation solution with low potassium, coupled with glucose and dextran, has been established as best practice for prolonged cold preservation. Prostaglandin E ₁ (PGE ₁ ) is a vasodilator given before the dextran flush to reduce pulmonary vascular resistance and achieve a more complete flush. PGE ₁ also has antiinflammatory properties useful for lung preservation and prevention of reperfusion injury. A retrograde flush is subsequently performed with the same solution, again, to improve the homogeneity of the flush. The lungs are inflated with 50% oxygen before their removal from the body in order to maintain the alveolar structure and to provide oxygen for metabolism.

A novel strategy of perioperative lung preservation is being developed by the Toronto Lung Transplant Group. Using their technique, termed ex vivo lung perfusion (EVLP), lungs are continuously perfused anterograde with an acellular perfusate and ventilated with room air with an ICU ventilator at normothermia. A hypoxic air mix is bubbled into the perfusate to deoxygenate and add carbon dioxide (CO ₂ ) to the perfusate. This method, performed by a separate surgical team, allows for at least 12 hours of donor lung preservation. EVLP allows the team to further evaluate the donor lungs as to their suitability for transplantation. More important, the lungs can be treated actively to improve their performance. Marginal lungs can be resuscitated and rehabilitated using EVLP, expanding the donor pool.

Surgical approach

Bilateral sequential lung transplantation is the most frequently performed lung transplantation procedure in children and is performed most often via median sternotomy. The main stem bronchi and left and right pulmonary arteries are connected via end-to-end anastomoses. Two pulmonary veins with intact atrial connections are harvested from each donor lung. Each left atrial patch is sewn onto the recipient heart. This surgical approach minimizes cardiopulmonary bypass time, which reduces related complications.

Though combined heart-lung transplantation had initially been a favored surgical approach, improved surgical techniques as well as the profound scarcity of donor organs have led to a dramatic decrease in the frequency of heart-lung transplantation. Moreover, right-sided heart failure associated with pulmonary hypertension resolves following lung transplantation, which has obviated the need for heart and lung transplantation for primary pulmonary hypertension except in instances of severe, irreversible right heart failure. ^, There is no difference in survival between patients who undergo bilateral sequential lung transplantation compared with those who undergo heart-lung transplantation. Lung transplantation alone maximizes the distribution of organs from a single donor, benefiting more children.

In the 1990s, living donor lobar lung transplantation was developed as a strategy for transplantation in order to decrease waiting time of severely ill children awaiting lung transplantation, but with the adoption of a new lung allocation score in 2005 and improved peritransplant strategies, wait list deaths have decreased. The relative efficacy of the new lung allocation scoring system, combined with the technical and ethical challenges associated with living lobar transplantation, have prevented wider adoption of the procedure in the United States.

Presurgical management in the intensive care unit

Compared with the early era of lung transplantation, the number of patients receiving a transplant from the ICU and with mechanical respiratory support has increased recently. Thus, the incidence of bridging severe respiratory failure to lung transplant with ambulatory VV ECMO and mechanical ventilation is increasing. The risk of dying within 1 year of transplantation increases by 58% if the patient was bridged to transplant in the intensive care unit (ICU) with mechanical ventilation (MV) support before lung transplantation. Intubated patients who require heavy sedation and ventilation with high airway pressures are especially prone to ventilator-induced injury and ICU-related complications, including extrapulmonary organ failure. ICU-related complications—such as pressure ulcers, vascular complications, nosocomial infections, delirium, critical illness polyneuropathy/myopathy, and airway colonization—will increase wait list mortality and mortality after transplant. Candidates for lung transplant on MV support may have uncertain neurologic status. Thus, an approach with “awake” ventilation, even if supported with VV ECMO, is often pursued to obtain better short-term outcomes.

There have been substantial improvements in extracorporeal life support (ECLS) technology and many centers are increasingly using these devices. Bridge-to-recovery and bridge-to-transplant are the two basic indications for ECMO support. While the adult experience is quickly expanding, the pediatric literature is limited. A retrospective evaluation of the United Network for Organ Sharing database of pediatric transplantations between 2000 and 2013 in the United States determined that a small percentage (2.9%) of patients were bridged to transplant with ECMO and there was no statistically significant increase in hazard for death. Major advances in ECLS included use of heparin-coated circuits, development of polymethylpentene oxygenator membranes, introduction of centrifugal pumps, dual-lumen cannulas (important for small adults and the pediatric population), and miniaturized systems. For these reasons, VV ECMO as a bridge to transplant is considered carefully for a small percentage of critically ill children awaiting lung transplantation.

Postsurgical management

Immediate postoperative care is focused on respiratory and hemodynamic management. In the perioperative period, pulmonary care emphasizes reestablishment of functional residual capacity. Mechanical ventilation is generally necessary for less than 48 hours but may be prolonged in the event of primary graft dysfunction. There is a wide variation in MV strategies among lung transplant centers. In general, lung protective approaches using low tidal volumes based on recipient’s characteristics are preferred. However, in a retrospective study on patients receiving a transplant between 2010 and 2013 among three transplant centers, low tidal volume ventilation was not shown to have an effect on length of ICU stay, forced expiratory volume (FEV ₁ ) at 3 months postsurgery, or survival to 6 months. Conversely, poor outcomes have been associated with injudicious use of higher-pressure ventilation strategies. To minimize hyperoxic-related injury to the lungs, the fraction of inspired oxygen is maintained at less than 60% while maintaining systemic arterial saturation at 94% to 95%. Ventilator strategy uses 5 to 7 mL/kg tidal volumes and an inspiratory plateau pressure of less than 30 cm H ₂ O. Sufficient positive end expiratory pressure is used to fully recruit and maintain the functional residual capacity of the newly transplanted lungs. Once the patient is extubated, aggressive tracheobronchial toilet, chest physiotherapy, and bronchoalveolar lavage can mobilize secretions to ensure patency of the airways.

Hemodynamic status must be closely monitored though data on hemodynamic management are limited. Vascular permeability and myocardial function may be adversely affected by cardiopulmonary bypass, necessitating inotropic support in the perioperative period. Usually, restrictive fluid support (0.9–1.0 × maintenance) is encouraged. Central venous pressure monitoring is beneficial in order to optimize cardiac output. Central venous pressure alone may be unreliable to guide volume status. Hemodynamic instability may be exacerbated by diminished intravascular volume. Early recognition of compromised renal function is essential, as the prescription of all medications excreted and metabolized by the kidneys will need to be promptly altered. Additionally, clinical and ultrasound observations may be helpful.

The most common causes of hypotension in the immediate posttransplantation period include hypovolemia from overly aggressive diuresis, systemic inflammatory response syndrome from surgical insult causing low systemic vascular resistance, medication-induced hypotension (including sedatives/analgesics), lung hyperinflation, hemorrhage, tamponade, or heart failure. ^, Management should be causally determined, generally requiring a combination of fluid volume management, transfusion of blood products, administration of vasopressors or inotropes, correction of bleeding diatheses, chest tube drainage, and, when indicated, surgical revision.

Recipients may experience early severe graft dysfunction as a result of lung injury incurred during or prior to organ harvest. The occurrence of primary graft dysfunction (PGD) is between 10% and 35% of all patients. The clinical presentation of PGD is entirely consistent with ARDS as manifested by elevated alveolar-arteriolar gradient, compromised pulmonary compliance, poor ventilation and perfusion matching, and impaired diffusion. PGD refers to acute respiratory failure defined by reduced oxygenation index and pulmonary infiltrates within 72 hours of lung transplantation ( Table 57.2 ). In most patients, a mild and transient course is observed, but 10% to 20% of patients will be affected by a severe form (partial pressure of arterial oxygen/fraction of inspired oxygen [Pa o ₂ /F io ₂ ] <200). Secondary causes of hypoxemia—such as volume overload, pneumonia, acute rejection, atelectasis, or pulmonary venous outflow obstruction—should be excluded. Severe PGD is associated with high hospital mortality rates of 30% to 40%, prolonged ICU stay, and impaired long-term graft function and survival. It is the leading cause of mortality in the perioperative period. In a multicenter study from 10 US centers, increased oxygen fraction levels at the time of graft reperfusion was associated with increased risk of subsequent PGD. Severe PGD is associated with donors with any smoking history, PAH, the use of cardiopulmonary bypass, large-volume blood product transfusion, elevated pulmonary arterial pressures, or obesity. Improved surgical techniques and organ perfusate have diminished the severity of early graft dysfunction over the last decade.

TABLE 57.2

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