E most common indication for bilateral lung transplantation.

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1 Double-Lung Transplantation in Mechanically Ventilated Patients With Cystic Fibrosis Gilbert Massard, MD, Hani Shennib, MD, Dominique Metras, MD, Jean Camboulives, MD, Laurent Viard, MD, David S. Mulder, MD, Christo I. Tchervenkov, MD, Jean-Francois Morin, MD, Roger Giudicelli, MD, and Michel Noirclerc, MD The Joint Marseille-Montreal Lung Transplant Program, Marseille, France, and Montreal, Quebec, Canada Many lung transplant programs consider ventilator dependence as a contraindication for transplantation. Among 54 patients in whom bilateral lung transplantations for cystic fibrosis were performed by the Joint Marseille-Montreal Lung Transplant Program, 10 were ventilator dependent. Three of them died in the early postoperative period (30%): 2 as a result of cerebral anoxia and sepsis, 1 of Pseudomonas cepacia pneumonia. Two patients died at 15 and 19 months after transplantation of obliterative bronchiolitis and secondary bacterial pneumonitis. Another 2 patients in whom obliterative bronchiolitis developed underwent retransplantation with a heart-lung block; 1 of those was operated on at 12 months and is well at 29 months after his initial transplantation; the second was operated on at 34 months and died of primary graft failure. Three other patients are alive and well at 3, 11, and 14 months after transplantation. Actuarial survival at 1 year was 70%. The postoperative course and the infectious and rejection complications were no different from those in patients who underwent transplantation while spontaneously breathing. Obliterative bronchiolitis developed in 66% of patients at risk (2 of 6 patients surviving more than 6 months). We conclude that transplantation in mechanically ventilated patients with cystic fibrosis is not associated with an increase in morbidity or mortality after bilateral lung transplantation. Long-term survival, as in patients who undergo transplantation while spontaneously breathing, is limited by the development of obliterative bronchiolitis. (Ann Thorac Surg 1993;55: ) nd-stage cystic fibrosis lung disease has become the E most common indication for bilateral lung transplantation. As transplantation waiting lists are expanding rapidly at a rate exceeding that of available donors, the duration of waiting on the transplant list is increasing. The condition of some patients will deteriorate to the extent that mechanical ventilation is required. Many centers perceived respiratory failure requiring mechanical ventilation to be a poor prognostic factor. Hence, mechanical ventilation was considered a contraindication for transplantation until recently [l, 21. As we have not been able to confirm this observation, we have elected to consider transplantation of mechanically ventilated patients provided they have been previously evaluated and accepted for transplantation before the need for mechanical ventilation. This article will review our experience in 10 patients with cystic fibrosis who required mechanical ventilation before bilateral lung transplantation. Presented at the Twenty-ninth Annual Meeting of The Society of Thoracic Surgeons, San Antonio, TX, Jan 2527, Address reprint requests to Dr Shennib, MontrCal Lung Transplant Program, 1650 Cedar Ave, Suite 9828, Montreal, Que H3G 1A4, Canada. Patients and Methods Recipient Population From May 1988 through June 1992, the Joint Marseille- Montreal Lung Transplant Program performed bilateral lung transplantations in 54 patients with cystic fibrosis. Ten double-lung transplantations for cystic fibrosis were performed in ventilator-dependent patients (18.5%). All had tracheal intubation with conventional mechanical respirators after unsuccessful trials of face or nasal mask ventilation. There were 9 children (3 boys and 6 girls) with a median age of 14 years (range, 8 to 19 years) and 1 adult woman. Severe malnutrition was an overall finding, with a mean percentile ideal body weight of 62%. All patients except 1 grew Pseudomonas aeruginosa in their sputum that was sensitive to at least one antibiotic. One patient had a multiresistant Pseudomonas cepacia infection. The median time spent on the waiting list was 3.5 months (range, 1 to 25 months). All 10 patients were regularly followed up at the transplant clinic, and 7 were actively listed before the development of respiratory failure. The median duration of pretransplantation artificial ventilation was 7.5 days (range, 3 to 42 days). Donor Population Recipients and donors were size matched based on measurement of submammary circumference, with an acceptable difference of 10%. In younger children, a 2-year by The Society of Thoracic Surgeons /93/$6.00

2 1088 MASSARD ET AL Ann Thorac Surg 1993;55: Table 1. Recipient and Donor Data Blood Age (Y) Sex Group CMV Weight (kg) Waiting Preoperative Patient Time Ventilation No. R D R D R D R D R D (mo) (days) F M F F A A -? F M A A F M A A F F 0 0 -? M M A A M M F F A A F F M M A A CMV = cytomegalovirus; D = donor; F = female; M = male; serodiagnosis for CMV;? = serodiagnosis for CMV unknown. R = recipient; + = positive serodiagnosis for CMV; - = negative difference in age between donor and recipient was generally accepted. There were 7 male and 3 female donors, with a median age of 14 years (range, 5 to 51 years) and a median weight of 37.5 kg (range, 17 to 80 kg). The cause of brain death was blunt trauma in 8 and a ruptured cerebral aneurysm in 2 donors. Three donor-recipient couples were male, 4 were female, and in 3 the donor was male and the recipient was female. Blood group matching was respected in all couples (6 A and 4 0). Despite a policy of accepting a mismatch of cytomegalovirus status between donors and recipients, 8 patients were retrospectively accurately matched (6 negative and 1 positive). Two recipients who were serologically negative for cytomegalovirus received lungs from donors whose cytomegalovirus status could not be determined (Table 1). Operative Procedure Donor lungs were preserved with modified Euro-Collins flush. All harvests but two were distant procurements. The median ischemic time was 288 minutes (range, 180 to 345 minutes). En bloc double-lung transplantation with cardiopulmonary bypass was performed in 6 patients. The airway was performed at the tracheal level in the first patient and was bibronchial in the subsequent 5 patients. The last 4 patients underwent bilateral sequential single-lung transplantation, which has been our current procedure of choice since June Cardiopulmonary bypass was required in 2 of the 4 patients who underwent bilateral sequential lung transplantation. Postoperative immunosuppression consisted of cyclosporine, azathioprine, steroids, and antithymocyte globulins. Results Immediate Postoperative Outcome There were three postoperative deaths (Table 2). A 19- year-old girl (patient 1) had brain damage, likely due to preoperative hypoxemia. This was compounded by the development of multibacterial pneumonia, septicemia, multiorgan failure, and death on the 24th postoperative day. A 9-year-old gxl (patient 4) also died of infectious complications and multiorgan failure on the 35th postoperative day. A 41-year-old patient (patient 9) was extubated 1 day after transplantation after 37 days of mechanical ventilation; however, a right lung abscess developed 23 days postoperatively due to Pseudomonas cepacia, and the patient died 41 days postoperatively of disseminated bilateral lung microabscesses. In general, weaning from the respirator for the survivors was slow. The median postoperative ventilation was 16 days (range, 1 to 56 days); a single patient (patient 7) required reintubation after extubation on the 4th postoperative day, when acute rejection developed; after a second attempt at extubation on day 10, a relapsing rejection required another intubation 2 days later. After extubation on day 22, a pulmonary edema related to a transient renal insufficiency necessitated a third reintubation; definite extubation was achieved on day 56 with improvement in renal function. Bronchial healing was uneventful in 6 recipients. One patient (patient 3) had partial dehiscence of the left bronchial, which was controlled with a Gianturco-type endobronchial stent. Two patients (patients 2 and 5) had minor bronchomalacia at the site of, stented with a silicone device for a period of 4 weeks. All 3 patients eventually had good airway patency without stents. Acute rejection during the first postoperative month was noted in 6 patients: 5 (patients 2, 4, 5, 6, and 10) had one episode on days 5, 7, 13, 14, and 28, respectively; 1 patient (patient 7) had two episodes on days 6 and 12. Diagnosis was made on clinical grounds during the first 2 weeks and by transbronchial biopsies thereafter; all episodes of rejection resolved promptly with augmented steroid therapy. Long-Term Follow-up Three patients died during follow-up. Obliterative bronchiolitis developed in an 8-year-old girl (patient 2) at 12 months (documented by transbronchial biopsy); she had

3 Ann Thorac Surg 1993;55: 1087-Y2 MASSARD ET AL 1089 Table 2. Operative Details and Outcome Patient Graft Operative Postoperative Bronchial Immediate Late No. Ischemia (h) Procedure Ventilation (days) Healing Outcome Outcome DLT en bloc, tracheal 24 N Died day 24 of brain anoxia, sepsis, renal insufficiency DLT en bloc, bibronchial 18 Malacia, stent N BO at 12 mo, died at 15 mo (infection) 3 3 DLT en bloc, 16 Partial necrosis, N BO at 27 mo, died bibronchial stent during retx at 34 mo 4 5 DLT en bloc, bibronchial 35 N Died day 35 of brain anoxia, sepsis DLT en bloc, bibronchial 11 Malacia, stent N BO at 13 mo, died at 19 mo (infection) DLT en bloc, 22 N N BO at 8 mo, retransplanbibronchial tation at 12 mo, alive and well at 29 mo 7 5 Bilateral sequential DLT 56 N N Alive and well at 14 mo 8 5 Bilateral sequential DLT 4 N N Alive and well at 11 mo Bilateral sequential DLT 1 N Died day 41 of P cepuciu pneumonia Bilateral sequential DLT 2 N N Alive and well at 3 mo 80 = bronchiolitis obliterans; DLT = double-lung transplantation; N = normal fatal bronchial Aspergillus bronchopneumonia at 15 months. Another girl, aged 10 years (patient 5), experienced acute recurrent rejections during the 8th, 9th, 14th, and 18th months. A decrease in peak flow volumes suggested obliterative bronchiolitis at 8 months, which was proven on transbronchial biopsy at 13 months. Simultaneous acute rejection and bacterial pneumonitis caused death during the 19th postoperative month. Finally, obliterative bronchiolitis developed in an 18-year-old girl (patient 3) 27 months after transplantation. Her respiratory condition worsened after an episode of cytomegalovirus pneumonitis at 32 months; this patient underwent unsuccessful cardiopulmonary retransplantation at 34 months and died with primary graft failure. Bronchiolitis obliterans developed in 1 more patient. A 16-year-old boy (patient 6) had development of severe obliterative bronchiolitis during the 8th postoperative month. He underwent repeat transplantation 12 months after the initial procedure, while on a mechanical ventilator for 63 days. He had an unremarkable recovery and is well 17 months after the second transplantation. Three patients are alive and without apparent trouble 14, 11, and 3 months after transplantation (patients 7, 8, and 10). Actuarial survival, calculated with the Kaplan- Meier method, was 70% at 6 and 12 months, and 35% at 2 years (Fig 1). Survival after heart-lung or double-lung transplantation in this group of patients is in the range of 60% to 70% at 1 year [4-61. The most common cause of death during the first year, however, remains infection [6]. Many of the patients with cystic fibrosis awaiting transplantation are young adults or children who have severe bronchopulmonary infections resistant to conventional medical treatment and antibiotic therapy (71. Unfortunately, as the demand for lung transplantation increases, so does the number of patients and the duration of time on waiting list. Many patients will die awaiting the identification of appropriate donor lungs. An ethical ques- f months post-transplant Comment Despite an initial concern with the risk of postoperative infection, cystic fibrosis has become the most common indication for bilateral lung transplantation today [l, 3, 41. Monlhs I 0 I I 4 [ 12 I15 I 16 [ 20 I 30 Patlentsatrisk I10 9 I 7 I 6 I I 3 I 2 I 1 Fig 1. Probability of survivul ufter double-lung trunsplantution in patients with cystic fibrosis.

4 1090 MASSARD ET AL Ann Thorac Surg 19!33; tion frequently encountered is the decision as to whether a patient with cystic fibrosis in whom respiratory failure develops should be supported with mechanical ventilation until a suitable donor is found or not. Most centers would choose to provide palliative therapy and avoid mechanical ventilation with the concern that a donor lung may not be found promptly and before other organ failures develop. Many centers have advocated the use of ventilatory support methods that avoid endotracheal intubation such as face and nasal bipap masks [8,9]. Unfortunately, not all patients would respond properly to such a modality, and some of them would definitely require intubation and mechanical ventilation to achieve acceptable respiratory physiological parameters. The choice of proceeding with mechanical ventilation or not thus becomes unavoidable. In our program, we have adopted a policy in which we would be reluctant to accept patients who have never been previously evaluated by our team when they are presented to us for the first time on a mechanical ventilator. We would, however, consider transplantation for patients whose condition has deteriorated and who require mechanical ventilation if they have been previously accepted for transplantation and are awaiting the availability of suitable donor lungs. This series presents our experience with patients who have been on mechanical ventilation for periods of up to 42 days. Our early results indicate that survivals comparable with those of patients who undergo transplantation while spontaneously breathing can be achieved [5, 61. It would appear that the postoperative recovery is likely to be slightly extended. Nevertheless, we have failed to identify mechanical ventilation on its own as a risk factor for an increased mortality during the first year. The preoperative evaluation of these patients must be thorough and continuous. At any time, if any deterioration of other organs is evident, the patient should be withdrawn from the transplantation list unless this organ dysfunction is mild and likely to be reversible. The neurological examination is of utmost importance and should be a major determining factor in deciding to pursue transplantation. We have been disappointed in identifying that at least 1 of our patients had severe cerebral anoxia with irreversible brain damage. Most of these patients will have severe right ventricular dysfunction with liver congestion and gastrointestinal malfunction. Right ventricular dysfunction associated with severe pulmonary disease is likely to be reversible by the implantation of well-preserved and functioning lungs. Particular care should be directed toward nutritional support, perhaps through intravenous methods, which we have found mechanically ventilated patients will tolerate much better than enteral routes. It has been gratifying to see that liver function tests normalize early after transplantation and that intestinal absorption improves remarkably, which would allow early use of enteral feeding methods after successful transplantation. The technique of bilateral lung transplantation is quite challenging. We currently believe that sequential bilateral single-lung transplantation is the procedure of choice [ 10, 111. We have been able to perform the latter procedure safely in some patients who had marginally abnormal coagulation profile, without the need for use of cardiopulmonary bypass. Nevertheless, we remain cautious in avoiding cardiopulmonary bypass as prolonged periods of circulation on one-lung ventilation in a freshly implanted lung can result in an exaggerated reperfusion injury [5]. The choice of going on cardiopulmonary bypass or not will have to be based on an estimate of how long it would require to remove the contralateral native lung and implant the second allograft. Our postoperative mortality has been due to multiorgan failure from sepsis in 2 patients, and to colonization with Pseudornonas cepacia, which resulted in an aggressive bronchopneumonia of the transplanted lungs, in 1 patient. We now consider infection with Pseudomonas species that has no antibiotic coverage a contraindication to transplantation. Such a resistance can only be determined by culture and sensitivity tests of a variety of antibiotics in a synergistic manner. The choice of pursuing a policy of accepting mechanically ventilated patients should not be based exclusively on the fact that survival of mechanically ventilated patients can be equal to that of spontaneously breathing patients with cystic fibrosis. An important factor is the availability of donor organs and their way of allocation, which varies from one country to another. The general policy applied in Canada and in France is based on the physiologic status of the recipient, giving priority to intubated patients. This allows for some flexibility in the choice of the recipient. However, our approach would be difficult to apply in the United States, where the priority is defined by the date of inscription on the waiting list. Another important consideration is the likelihood of obtaining organs at an appropriate time before failure of other organs. This is particularly important in the pediatric population, in which we found that approximately 40% of our patients on the waiting list would die before a suitable donor can be identified. Nevertheless, as the techniques of pneumoreduction and lobar implantation improve, size limitation may not become an important issue [12]. The weak point in any lung transplantation continues to be the development of bronchiolitis obliterans [13]. This is true irrespective of whether or not the patients are mechanically ventilated before transplantation. The appropriate timing of transplantation in patients with cystic fibrosis is controversial. This is usually based on several criteria including a rapid overall decline of the health status of the patient, frequent and prolonged periods of hospitalization, increasing hypercapnia, and weight loss despite maximum nutritional support [14]. We have always estimated that those patients were unlikely to survive more than a year but have been surprised to see that some of them will stabilize and live for periods even longer than 2 years. On the other hand, we have evaluated patients and deferred consideration for transplantation on the assumption that they were not yet sick enough to undergo transplantation, and found later that they had a rapid decline in their health status and had died within

5 Ann Thorac Surg 1993;55: 1O87-Y2 MASSARD ET AL 1091 a few weeks or months. Perhaps the only unquestionable condition that a patient is unlikely to survive without transplantation is dependency on mechanical ventilation. A successful transplantation in this group of patients is most gratifying. In summary, we conclude that lung transplantation in ventilator-dependent patients with cystic fibrosis is a reasonable therapeutic approach with a life expectancy similar to that of patients who are spontaneously breathing. Provided that other organs are not affected, these patients should be considered for transplantation. Longterm success in this category of patients, as in any other recipients of lung transplants, is limited by the development of bronchiolitis obliterans. References 1. Egan TM, Trulock EP, Boychuk J, Ochoa L, Cooper JD. Analysis of referrals for lung transplantation. Chest 1990;99: Low DE, Trulock EP, Kaiser LR, et al. Lung transplantation of ventilator-dependent patients. Chest 1992;101:& Jones K, Higenbottam T, Wallwork J. Successful heart-lung transplantation for cystic fibrosis. Chest 1988;93: De Leva1 MR, Smyth R, Whitehead B, et al. Heart and lung transplantation for terminal cystic fibrosis. J Thorac Cardiovasc Surg 1991;101:63+Q.. 5. Shennib H, Noirclerc M, Ernst P, et al. Double-lung transplantation for cystic fibrosis. Ann Thorac Surg 1992;54: Ramirez JC, Patterson GA, Winton TL, Hoyos AL, Miller JD, Maurer JD. Bilateral lung transplantation for cystic fibrosis. J Thorac Cardiovasc Surg 1991;103: Colten HR, Wilson JD, Brawnwald E, et al. Cystic fibrosis. In: Harrison's principles of internal medicine, 12th ed. New York: McGraw Hill, 1991: Groth 5, Stafangor G, Dirksen H, Anderson JB, Falk M, Kelstrup M. Positive expirating pressure physiotherapy improves ventilation and reduces volume of trapped gas in cystic fibrosis. Bull Eur Physiother Respir 1985;21: Hymeyr YL, Webber BA, Hudson ME. Evaluation of PEEP as an adjunct to chest physiotherapy in the treatment of cystic fibrosis. Thorax 1986;41: Kaiser LR, Pasque MK, Trulock EP, et al. Bilateral sequential lung transplantation: the procedure of choice for double-lung replacement. Ann Thorac Surg 1991;52: Bisson A, Bonnette P. A new technique for double-lung transplantation: bilateral single lung transplantation. J Thorac Cardiovasc Surg 1992;103: Noirclerc M, Shennib H, Giudicelli R, et al. Size matching in lung transplantation. J Heart Lung Transplant 1992;ll: s Burke CM, Glanville AR, Theodore J, Robin ED. Lung immunogenicity, rejection and obliterative bronchiolitis. Chest 1987;92: Shennib H, Adoumie R, Noirclerc M. Current status of lung transplantation for cystic fibrosis. Arch Intern Med 1992;152: DISCUSSION DR G. ALEXANDER PATTERSON (St. Louis, MO): Doctor Shennib, how many of those patients had had a tracheostomy at the time of transplantation? DR SHENNIB: I think most of them were intubated orally. There were about 3 patients, 3 of 10, who were intubated through a tracheostomy. DR PATTERSON Were the six en bloc procedures all done through median sternotomies? DR SHENNIB: Two of the six en bloc procedures were done through a sternotomy. Neither of the patients had a tracheostomy. DR FRANK C. DETTERBECK (Chapel Hill, NC): Over the last 3 years we have performed 29 transplantations in patients with cystic fibrosis, 6 of whom were on ventilators. They were ventilated for an average of 11 days before transplantation and were intubated for an average of 7 days afterward, roughly similar to your experience. Somewhat in contrast, obliterative bronchiolitis occurred in only 2 of those patients. One of them underwent a second transplantation and the other 1 is getting along, not well, but getting along with obliterative bronchiolitis. We have only had two deaths in this group of patients. I am amazed at your short average waiting time, and I wonder what your explanation for that is. I think waiting time is one of the factors that really precludes performing transplantation in patients on ventilators currently unless they are really way up at the top of the list. What is the maximum amount of time that you would be willing to have a patient be on a ventilator and still perform transplantation? How long would you wait before you would say, "I am afraid the patient is colonized and too debilitated, and this is not reasonable anymore"? DR SHENNIB: I think you answered my question. One has to recognize that there are differences in allocation of organs in France, Canada, the United Kingdom, and the United States of America. In Canada, any patient who is on a ventilator becomes a priority if the program wishes to put that patient at the top of the list. The patient acquires a category of 3 or 4. Any patient who is in this category gets priority nationwide, and I believe this applies the same in France. So perhaps this explains why some of those patients have undergone transplantation very expeditiously. I think transplantation can be done as long as the patient's condition is maintained-you have to remember that our psychological barrier was a patient on a ventilator. We now have numerous patients who are on home ventilation. They put their nasal mask on and switch the machine on at night; in fact, we have a patient who drives a car with a mechanical ventilator on his side. So I think then the question becomes, should we deny those patients transplantation simply because they are admitted to the hospital? I think we have made a decision that we should not do that. The only criterion that would preclude transplantation in those patients is the development of multiorgan failure. I think if renal failure or systemic sepsis or coagulopathy develops, notwithstanding the fact that liver congestion due to right ventricular failure is something that we can accept, in the rest of the cases we would not perform transplantation in those patients.

6 1092 MASSARD ET AL Ann Thorac Surg 1993;55: DR ROBERT L. HARDESTY (Pittsburgh, PA): I would like to follow up with just one comment. I think one of the smartest things that we have done in pulmonary transplantation in the United States is to have time waiting as the only criterion for distribution of the organ. Our personal approach is very similar to what you recommended in your summary. We will perform transplantation in a ventilated patient provided that the waiting time indicates to us that we are going to get that donor relatively shortly. I have one question. Unless you tell me otherwise, my conclusion from your experience is that the high incidence of obliterative bronchiolitis is due to less immunosuppression be- cause these patients were on ventilators before transplantation. Am I correct or not correct? DR SHENNIB: We looked at that. I do not think that they were over- or under-immunosuppressed or that their treatment was different. This series consists mostly of children. I suspect that here we are facing the same problem with trying to maintain adequate immunosuppression in children. Our experience in general with children is that somehow they have a higher incidence of bronchiolitis obliterans. The Society of Thoracic Surgeons: Thirtieth Annual Meeting Mark your calendars for the Thirtieth Annual Meeting of The Society of Thoracic Surgeons, which will be held at the New Orleans Convention Center in New Orleans, Louisiana, January 31-February 2, Members may register for the Scientific Sessions at no charge. There will be a $250 registration fee for nonmember physicians except for Scientific and Poster Session presenters and residents. Registration for the Postgraduate Course is separate from the Annual Meeting. There will be a $65 registration fee for attendees of the Postgraduate Program, which will he held Sunday, January 30. The Postgraduate Course will provide in-depth coverage of thoracic surgical topics selected to enhance and broaden the knowledge of practicing thoracic and cardiac surgeons. Advance registration forms, hotel reservation forms, and details regarding transportation arrangements, as well as the complete meeting program, will be mailed to Society members this fall (1993). Nonmembers wishing to receive information on attending the meeting should write to the Society s Secretary, Richard P. Anderson. Richard P. Anderson, MD Secretary The Society of Thoracic Surgeons 401 N Michigan Ave Chicago, IL (312)