Lobar lung transplantation as a treatment for congenital diaphragmatic hernia

Lobar Lung Transplantation as a Treatment Diaphragmatic Hernia

for Congenital

By Krisa P. Van Meurs, William D. Rhine, William E. Benitz, Stephen J. Shochat, Gary E. Hartman, Arlene M. Sheehan, and Vaughn A. Starnes Stanford, California and Los Angeles, California 0 The mortality rate for infants severely affected with congenital dfaphragmatic hernia (CDH) remains high despite significant advances in surgical and neonatal intensive care including dobyed repair and extracorporeal membrane oxygenation (ECMO). Decause of the increasingly successful experience with dngle-lung transplantation in adults, this approach has been suggested as a potential treatment for CDH infants with unsalvageable pulmonary hypoplasia. The authors report on a newborn female infant who was the product of a pregnancy complicated by polyhydramnios. At birth, she was found to have a right-sided CDH and initially was treated with preoperative ECMO, followed by delayed surgical repalr. Despite the CDH repair and apparent resolution of pulmonary hypertension, the infant’s condition deteriorated gradually after decannulation, and escalating ventilator settings were required as well as neuromuscular paralysis and pressor support because of progressive hypoxemia and hypercarbia. A lung transplant was performed 8 days after decannulation, using the right lung obtained from a S-weekold donor. The right middle lobe was excised because of the size discrepancy between the donor and recipient. After transplantation, the patient was found to have duodenal stenosis and gastroesophageal reflux, which required duodenoduodenostomy and fundoplication. The patient was discharged from the hospital 90 days posttransplantation, at 3% months of age. Currently she is 24 months old and doing well except for poor growth. This case shows the feasibility of single-lung transplantation for infants with CDH, and the potential use of ECMO as a temporary bridge to transplantation. Lobar lung transplantation allowed for less stringent size constraints for the donor lung.

Copyright o 1994 by W.B. Saunders Company INDEX WORDS: Lung transplantation, pulmonary hypoplasia, congenital diaphragmatic hernia, extracorporeal membrane oxygenation.

T

HE MORTALITY RATE for infants with congenital diaphragmatic hernia (CDH) symptomatic in the first few hours of life remains high despite advances in surgical and neonatal intensive care.1,2 Extracorporeal membrane oxygenation (ECMO) increases the chance of survival; however, some infants do not respond to ECMO because of critical pulmonary hypoplasia. 3-5 Some ECMO centers do not provide ECMO for CDH infants with critical pulmonary hypoplasia. As a prerequisite for consideration for ECMO, Stolar et al require a preductal or postductal Paoz of more than 100 and a preductal or postductal Pacoz of less than 50 on 100% oxygen.6 Others have found that these predictors of survival are unreliable, and they offer ECMO to all CDH

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infants with respiratory failure.‘,* In utero surgery for CDH has also been reported, but results have been inconsistent.9-11 Because of the increasing experience with adult single-lung transplantation ait Stanford and other institutions, single-lung transplantation has become an option for CDH infants with “critical” pulmonary hypoplasia. 12-16We report on the first infant with CDH who underwent successful singlelung transplantation. CASE REPORT The infant was a full-term girl born to a ZO-year-old white woman via normal spontaneous vaginal delivery. The pregnancy had been complicated by polyhydramnios and suspected fetal intestinal obstruction, noted during the prenatal ultrasound examination. Amniocentesis had shown normal chromosomes. The baby’s birth weight was 4 kg, and the Apgar scores were 2 at 1 minute, 5 at 5 minutes, and 7 at 10 minutes. Because of severe respiratory distress at birth, she was intubated in the delivery room and transferred to the intensive care nursery, where a chest radiograph showed a right-sided diaphragmatic hernia. The first arterial blood gas readings on ventilator settings of PIP 24, PEEP 4, intermittent mandatoryventilation (IMV) 30, and FIO~1.0, were pH 6.89, Pacer 98, and Paor 58. Subsequently she was hyperventilated, paralyzed with pancuronium, and sedated with fentanyl. :She also received volume boluses, pressor support with both dopamine and dobutamine, and intravenous antibiotics. Because of progressive hypoxemia she was considered for ECMO. A cardiac ultrasound examination showed normal anatomy and evidence of severe pulmonary hypertension. Results of the head ultrasound examination were normal. She 1continued to have severe hypoxemia despite maximal medical therapy, with a pH of 7.53, Pacoz of 33, and Paoz of 30 on ventilator settings of PIP 35, PEEP 3, IMV 78, and FIO~ 1.0. The calculated oxygenation index was 53, and the decision was made to place her on venoarterial ECMO. Parental consent was obtained, and she was cannulated and placed on bypass at a flow of 90 ml/kg/mitt. After 4 days on bypass her chest radiograph showed improved left lung expansion. Results of a pulmonary function test at this time showed lung compliance of 0.17 ml/kg/cm Hz0 and resistance of 82 cm HrO/L/sec. Because of the apparent severity of the lung hypoplasia, lung transplantation was discussed with the parents as a

From the Departments of Pediatrics and Pediatric Surgery, Lucile Salter Packard Children’s Hospital, Stanford University Medical Center, Stanford, CA, and the Department of Pediatric Cardiovascular Surgery, Children’s Hospital of Los Angeles, University of Southern California, Los Angeles, CA. Address reprint requests to Krisa P. Van Mews, MD, Department of Pediatrics, 750 Welch Rd, Suite 315, Palo Alto, CA 94304. Copyright o 1994 by W. B. Saunders Company 0022-341%194/2912-0018$03.0010

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potential experimental treatment for CDH. On day 6, an off-bypass trial was attempted; pH was 7.44, Pace? was 44, and Paoz was 113 on PIP 27, PEEP 5, IMV 50, and F102 40%, and an echocardiogram showed minimal signs of pulmonary hypertension. The off-bypass trial was repeated 24 hours later, after 7 days on bypass, and findings were similar. Repair of the CDH was performed after 180 hours on bypass. During surgery, the right lobe of the liver and the small intestine and colon were found to be in the right side of the chest, and only an anterior rim of diaphragm was observed. The right lung was noted to be severely hypoplastic. A patch repair of the diaphragm was performed using Gore-tex (W.L. Gore and Associates, Inc, Flagstaff, AZ), and a ventral hernia was created with a SILASTIC@ patch (Dow Corning, Midland, MI) because of the inability to close the abdomen. A right chest tube was placed. The infant remained on ECMO for 20 hours after the CDH repair, without incident. Subsequently she was decannulated, after 203 hours on ECMO, and placed on ventilator settings of PIP 27, PEEP 5, IMV 60, and F102 50%. She required slow but progressive increases in the ventilator settings as well as neuromuscular paralysis and pressor support with dopamine. She was listed for lung transplantation after parental consent. Eight days after discontinuation of ECMO, a lung became available from a 6-week-old donor. She was placed on cardiopulmonary bypass; the right lung was excised, and the donor lung anastomosed at the right atrium, right main-stem bronchus, and right pulmonary artery. The patient was weaned easily from operative bypass. Because the graft was too large to be accommodated in the right hemithorax, the right middle lobe was resected. The chest was closed, and the infant returned to the intensive care nursery. Her initial immunosuppression consisted of cyclosporin, azathioprine, prednisone, and OKT3 antibodies. The posttransplant course was complicated by respiratory distress, infection, intestinal obstruction, and supraventricular tachycardia. Her ventral hernia was closed 4 days posttransplant. Bronchoscopy with bronchoalveolar lavage was performed on two occasions to exclude infection, and pulse solumedrol was given once for suspected rejection. A pulmonary function test performed on postoperative day (POD) 7 showed marked improvement, with compliance of 0.6 ml/kg/cm Hz0 and resistance of 51 cm HzO/L/sec. A ventilation/perfusion scan performed on POD 39 showed approximately equal ventilation and perfusion bilaterally. Initially she was extubated on POD 15, but reintubation was required. Low ventilator settings were maintained, and several extubations were attempted; successful extubation was achieved on POD 45. She was weaned to room air on POD 57 (Fig 1). Attempts at feeding were repeatedly unsuccessful, with increased gastric residuals and occasional bilious vomiting. An exploratory laparotomy on POD 40 showed duodenal stenosis, which required duodenoduodenostomy, Thal fundoplication, and revision of the Gore-tex patch of the diaphragm. Repeated episodes of supraventricular tachycardia were managed with adenosine and digoxin. She was discharged at 3% months of age, 90 days posttransplantation, on cyclosporin, azathioprine, prednisone, digoxin, reglan, aldactazide, and several electrolyte supplements. She was receiving Pregestimil feedings (Mead Johnson Nutritional, Evansville, IN) via a gastrostomy tube. At age 24 months she has failure to thrive; her weight, length, and weight/length are below the fifth percentile. Her current medications are cyclosporin, azathioprine, prednisone, digoxin, metaclopramide, and trimethoprim-sulfamethoxazole.

Fig 1. tion.

Chest radiograph taken after right lobar lung transplanta-

DISCUSSION

This case report shows the clinical advantages of several novel approaches: lobar lung transplantation for CDH, ECMO as a bridge to transplantation, and organ transplantation as a bridge to recovery of normal function in paired organs. Lobar Lung Transplantation for CDH

Over the last decade, the approach to the severely affected infant with CDH has changed from the traditional emergency surgery to incorporate new approaches such as preoperative stabilization with delayed surgical repair, ECMO used both pre- and postoperatively, high-frequency ventilation, and the administration of exogenous surfactant. Although these strategies have offered some advantages, all have failed to significantly lower the high mortality rates for infants with severe cases of CDH. The Neonatal ELSO Registry has reported a progressive decrease in survival rates for CDH infants treated with ECM0.l’ This could be attributable to the increased frequency of prenatal diagnosis of CDH. Infants who in the past would died at the referring hospitals or during transport are now often born at ECMO centers and included in the statistics.18 In addition, more liberal criteria for ECMO may result in its use in infants whose conditions are destined to deteriorate from lethal pulmonary hypoplasia. Most recently, the Fetal Treatment Program at the University of California, San Francisco, has pioneered the use of fetal surgery for CDH diagnosed before 30

LUNG TRANSPLANTATION

FOR CDH

weeks’ gestation. 9-11Clearly, this approach is novel and its ultimate utility remains to be determined. Whether prenatal findings such as polyhydramnios are good markers for the severity of pulmonary hypoplasia is still questionable. The use of heart-lung transplantation for adult pulmonary vascular disease was first reported by Reitz et al in 1982.12 Avoidance of airway complications was made possible in part by the use of cyclosporin, permitting the deletion of corticosteroids from the early postoperative immunosuppressive regimen. Subsequently, the Toronto Lung Transplant Group reported the results of single-lung transplantation for pulmonary fibrosis with concomittant pulmonary hypertension.‘” Presently, the indications for single-lung transplantation have been extended to include primary and secondary pulmonary hypertension.14J5 Single-lung transplantation has several potential advantages over heart-lung transplantation. The first is a lower operative mortality rate because of reduced bleeding complications and better operative exposure with posterolateral thoracotomy, when compared with median sternotomy and avoidance of cardiopulmonary bypass. Second, there is a significant advantage with regard to donor organ availability; there are potentially three recipients per donor. A major restriction to the expansion of heart, heart-lung, and lung transpIant programs continues to be donor shortage. Finally, with single-lung transplantation the native lung is parallel to the transplanted organ, and thus postoperative problems such as pulmonary reimplantation response and rejection episodes are better tolerated. Single-lung transplantation as a treatment for CDH is appealing because of the predominantly unilateral pulmonary airway and vascular changes occurring in these patients. In addition, experience has suggested that transplantation in the newborn period may be associated with less rejection because of the immature immune system. Starnes et al reported that the linearized rejection rate was lower for patients under I year of age than for older children.16 Selecting the potential CDH candidates for lung transplantation remains difficult because of the absence of clear physiological measurements of the severity of pulmonary hypoplasia. The decision for this infant was easier because all the available strategies had failed. Clearly, it would be advantageous to be able to identify these children prospectively. Lobar lung transplantation has been suggested as a potential method to expand the donor pool for pediatric lung transplantation.i9 Subtotal, lobar, or segmental lung transplantation permits the use of larger donor organs and of living related donors, with

the associated immunologic advantages. At our institution, two other patients had been treated successfully with these techniques. A 12-year-old child with end-stage bronchopulmonary dysplasia received the right upper lobe from her mother. The other patient, a 3.5kg infant with idiopathic pulmonary hypertension unresponsive to ECMO, received the left upper lobe from a 2-year-old 15-kg donor after 28 days on bypass. In the present case, the infant described received the right upper and lower lobes from a 6-week-old donor. Excision of the right middle lobe was necessary to accommodate the size discrepancy.

ECMO as a Bridge to Transplantation

The use of ECMO as a bridge to transplantation has increased, influenced by the success of pediatric heart and heart-lung transplantation and the ongoing donor shortage. The number of children being bridged to transplantation is small and therefore it is difficult to draw conclusions regarding its utility. Delius et al reported on three children who received ECMO for a mean of 212 hours and who had contraindications to transplantation before a donor could be obtained.20 Galantowicz and Stolar reported on four children who had ECMO for a mean of 60 hours, all of whom survived to transplantation.21 Only one ECMO complication was noted. In both of these studies there was a short waiting period for organs. ECMO is effective as a bridge to transplant, but potential problems are the uncertainty of the waiting period and the increasing number of ECMO complications8 accruing over time, many of which are contraindications to transplantation.

Lung Transplantation as a Bridge

Single lung transplantation may be viewed as a temporary, palliative treatment for infants with CDH. Theoretically, single-lung transplantation may act as a bridge to a point where gas exchange may be sufficient with a single organ, becausu adults generally tolerate unilateral pneumonectomy without adverse sequelae. Long-term immunosuppression, with its attendant risks, may not be mandatory if growth of the contralateral endogenous organ is sufficient. This remains a theoretical alternative for the present patient. The future of single-lung transplantation in infants with CDH will depend on the long-term morbidity and mortality rates associated with heart-lung and single-lung transplant recipients. Infection, rejection, and obliterative bronchiolitis are all significant life-

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time risks for these patients. Optimal immunosuppression requires further study. Infection and lymphoproliferative syndrome are the result of excessive immunosuppression, and rejection and obliterative bronchiolitis are seen in patients with inadequate immunosuppression. Determination of the ultimate

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ET AL

utility of this novel approach to CDH awaits further experience. ACKNOWLEDGMENT The authors thank Dr Jack Cahill (of Kaiser Permanente, Santa Clara) for referring this patient.

REFERENCES 1. Reynolds M, Luck SR, Lappen R: The “critical” neonate with diaphragmatic hernia: A 21-year perspective. J Pediatr Surg 19:364-369, 1984 2. Weiner ES: Congenital posterolateral diaphragmatic hernia: New dimensions in management. Surgery 92:670-681,1982 3. .Van Meurs KP, Newman KD, Anderson KD, et al: Effect of extracorporeal membrane oxygenation on survival of infants with congenital diaphragmatic hernia. J Pediatr 117:954-960, 1990 4. Weber TR, Conners RH, Pennington G, et al: Neonatal diaphragmatic hernia: An improving outlook with extracorporeal membrane oxygenation. Arch Surg 122:615-618,1987 5. Heiss K, Manning R, Oldham KT, et al: Reversal of mortality for congenital diaphragmatic hernia with extracorporeal membrane oxygenation. Ann Surg 209:225-230,1989 6. Stolar C, Dillon P, Reyes C: Selective use of extracorporeal membrane oxygenation in the management of congenital diaphragmatic hernia. J Pediatr Surg 23:207-211,1988 7. Walker LK, Jones DJ, Jato N, et al: Pre-operative use of extracorporeal membrane oxygenation for stabilization of neonates with congenital diaphragmatic hernia. First World Congress of Pediatric Intensive Care, Baltimore, MD, June 1992 8. Newman KD, Anderson KD, Van Meurs KP, et al: Extracorporeal membrane oxygenation and congenital diaphragmatic hernia-should any infants be excluded? J Pediatr Surg 25:1048-1053, 1990 9. Harrison MR, Langer JC, Adzick NS, et al: Correction of congenital diaphragmatic hernia in utero, V. Initial clinical experience. J Pediatr Surg 25:47-57, 1990 10. Harrison MR, Adzick NS, Longaker MT, et al: Successful repair in utero of a fetal diaphragmatic hernia after removal of herniated viscera from the left thorax. N Engl J Med 322:15821584,199O

11. Lorenz HP, Adzick NS, Harrison MR: Open human fetal surgery. Adv Surg 26:259-273,1993 12. Reitz BA, Wallwark JL, Hunt SA, et al: Heart-lung transplantation: Successful therapy for patients with pulmonary vascular disease. N Engl J Med 306:557-564,1982 13. The Toronto Lung Transplant Group: Experience with single lung transplantation for pulmonary fibrosis. JAMA 259:22582262,1988 14. Starnes VA, Stinson EB, Oyer PE, et al: Single lung transplantation: A new therapeutic option for patients with pulmonary hypertension. Transplant Proc 23:1209-1210,199l 15. Maurer JR, Winton TL, Patterson GA, et al: Single lung transplantation for pulmonary vascular disease. Transplant Proc 23:1211-1212, 1991 16. Starnes VA, Oyer PE, Bernstein D, et al: Heart, heart-iung and lung transplantation in the first year of life. Ann Thorac Surg 53:306-310, 1992 17. Neonatal ECMO Registry of the Extracorporeal Life Support Organization (ELSO), Ann Arbor, MI, January 1993 18. Harrison MR, Bjordal RI, Langmark F, et al: Congenital diaphragmatic hernia: The hidden mortality. J Pediatr Surg 13:227230,1979 19. Crombleholme TM, Adzick NS, Hardy K, et al: Pulmonary lobar transplantation in neonatal swine: A model for treatment of congenital diaphragmatic hernia. J Pediatr Surg 25:11-18, 1990 20. Delius RE, Zwischenberger JB, Cilley R, et al: Prolonged extracorporeal life support of pediatric and adolescent cardiac transplant patients. Ann Thorac Surg 50:791-795,199O 21. Galantowicz ME, Stolar CJH: Extracorporeal membrane oxygenation for perioperative support in pediatric heart transplantation. J Thorac Cardiovasc Surg 102:148-152,199l