Lung transplantation

Lung transplantation Analysis of thirty-six consecutive procedures performed over a twelve-month period A consecutive series of 36 lung transplant procedures in 35 patients, performed over a 12-month period, has been reviewed. There were 14 men and 21 women undergoing 23 single, 12 bilateral, and one en bloc double lung transplant. There were one hospital death and three late deaths in the series, giving a hospital survival rate of 97.2 % and a L-year actuarial survival figure of 91.7%. Airway complications occurred in six patients (17.2 %), one of whom died. Cytomegalovirus infection was demonstrated in 18 patients (51 %), but no deaths have resulted. The most common cardiac complication was an atrial tachyarrhythmia (nine patients, 25.7%) and three patients had a cardiac arrest, but all were successfully resuscitated. Twelve patients required a further 25 surgical procedures after transplantation; however, renal and hematologic complications were uncommon. The prevalence and management of the other associated complications is discussed. (J THoRAc CARDIOVASC SURG 1992;103:329-40)

David A. Haydock, MB, ChB, FRACS, * Elbert P. Trulock, MD, Larry R. Kaiser, MD, Neil A. Ettinger, MD, Anastasios N. Triantifillou, MD, Laura L. Ochoa, RN, Michael K., Pasque, MD, Simon R. Knight, FRACS,** Joel D. Cooper, MD, and the Washington University Lung Transplant Group, St. Louis, Mo.

Since the introduction oflung transplantation in 1983, 1 the technical aspects of the procedure have been refined and the success rate has steadily improved. Methods for replacement of either one or both lungs have been developed- and applied to individuals with end-stage lung diseases including idiopathic pulmonary fibrosis, emphysema, primary pulmonary hypertension, Eisenmenger's syndrome, cystic fibrosis, and a number of other conditions. This report reviews the consecutive lung transplants performed at our institution during a recent 12-month period, presents the details of patient management, and analyzes the results and the complications that occurred. To provide perspective, we will review the survival results in conjunction with those for the whole From the Divisionof Cardiothoracic Surgery, Washington University, School of Medicine, St. Louis, Mo. Received for publication Oct. 19, 1990. Accepted for publication Aug. 27, 1991. Address for reprints: J. D. Cooper, MD, Cardiothoracic Surgery, Washington University School of Medicine, Suite 3108 Queeny Tower, #1 Barnes Hospital Plaza, St Louis, MO 63110. *Current address: Green Lane Hospital, Auckland, New Zealand. **Current address: Austin Hospital, Victoria, Australia.

12/1/33853

program and those prevailing at the time for the world at large.

Methods and patients All patients receiving lung transplants at the Washington UniversityfBames Hospital during the l2-month period July 1, 1989, to June 30, 1990, are included. Thirty-six lung transplantations were performed in 35 patients (Table I). There were 14 men and 21 women with a mean age of 44 years (range 21 to 60). Organs were procured from 32 donors. The preservation technique used involvedthe administration of prostaglandin E] directly into the pulmonary artery and flushing with 3 L of modified Euro-Collins solution in conjunction with topical cooling and hypothermic transport. On eight occasions the donor lungs were shared between two recipients. Four of these 16 lungs were used at other institutions. Thirteen patients underwent bilateral lung replacement (12 bilateral replacements and one en bloc double lung procedure). The remaining 22 patients underwent 23 single lung transplantations (14 right and nine left). The diagnostic categories are listed in Table 1. Five patients had had prior thoracic surgery (two, previous transplants; three, previous lung biopsy with one of these patients having had bilateral pleurodesis). The criteria for recipient selection have been published.' These included individuals 60 years of age or younger, with chronic disabling and progressivepulmonary deterioration, with no other alternative therapy, whose disease severity and rate of progression suggests a life expectancy of less than 12 to 18 months. Cardiac assessment including cardiac catheteriza329

The Journal of Thoracic and Cardiovascular Surgery

3 3 0 Haydock et al.

Table I. Diagnoses and procedures performed in this group ofpatients Diagnosis

Single

Bilateral double

Emphysema ai-Antitrypsin deficiencyemphysema Lymphangioleiomyomatosis* Idiopathic pulmonary fibrosis Cystic fibrosis Primary pulmonary hypertension Atrial septal defect and Eisenmenger's syndrome Obliterative bronchiolitis Eosinophilicgranuloma Early graft failure

9 3 1 2 0 5 I 0 I I

2 6 0 I 3 0 0 I 0 0

'In addition to a left single lung transplant, this patient had a left free wall accessory pathway divided by the epicardial approach.

tion study was performed on all patients over 40 years of age. The average waiting time to transplantation was 56.7 days (median of 51 days and range of 2 days to 5 months). In general, single lung transplantation was performed on those patients with primary pulmonary hypertension, Eisenmenger's syndrome, pulmonary fibrosis, and those patients with chronic obstructive pulmonary disease who were over the age of 50 years. In the case of a single lung procedure the side to be transplanted was determined primarily by quantitative ventilationperfusion scintigraphy; the lung with the poorer ventilation and perfusion was usually replaced. Bilateral lung replacement was used in patients with cystic fibrosis and in patients with chronic obstructive pulmonary disease who were less than 50 years of age. Preoperatively the patients were expected to move to St. Louis to await transplantation and to participate in a daily supervised pulmonary rehabilitation program. Postoperative management. Routine intensive care unit management was undertaken. Careful attention to fluid balance and renal function was maintained to prevent fluid overload and renal failure. Weaning from the ventilator was initiated as early as a few hours after the operation, but it was unusual to extubate a patient within 12 hours of the operation. Infection. The standard prophylactic antibiotic used was cefazolin (I gm every 8 hours intravenously) for several days. ~dditional an~ibiotics were used in response to cultures of significant orgamsms from each the donor or the recipient. Viral prophylaxis. All patients received 200 mg of acyclovir every 12 hours by mouth as herpes prophylaxis. An effort was made to match for cytomegalovirus (CMV) status in the CMV-negative recipient. For the majority of patients in this series who were CMV negative and received an organ from a CMV-positive donor, ganciclovir (5 mg/kg intravenously every 12 hours for 2 to 3 weeks) was administered and weekly immunoglobulin infusions (15 gm immune globulin [Gamimmune] average dose) were given to maintain titers. More recently, high-dose acyclovir (800 mg every 6 hours by mouth) has been given to this group of patients. Each patient had weekly buffy coat analysis for CMV, and samples were sent for CMV detection at the time of bronchoscopic examination and biopsy. Biopsy-proved CMV infection was managed with ganciclovir. Pneumocystis prophylaxis. If there was no allergy to sulfo-

namides, then double-strength trimethoprim/sulfamethoxazole was ?iven twice ~ day 3 days a week. In those allergic to sulfonarnides, aerosolized pentamidine was given once a month. C:andida. Oral nystatin "swish and swallow" was given to all patients. . Immunosuppr~ssi~n. Preoperatively the patients were given mtr~venous a.zathlOpnne2 mg/kg. Postoperatively the patients received antilymphoblast globulin (Minnesota, equine) 15 mg/kg intravenously via a central line over 6 to 24 hours each day for 7 days. Azathioprine was administered at a dose of 2 rug/kg each day, either intravenously or by mouth, and the dose was reduced if the white count fell below 6.0. Cyclosporine was started at a dose of 3 to 4 mg/hr intravenously and adjusted according to the cyclosporine level. Intravenous cyclosporine was tapered and then stopped when adequate levels were achieved by oral dosing. The target cyclosporine levels in the first month were 400 to 500 ng/rnl (radioimmunoassay on whole blo~). Steroids we~e avoided in the iinmediate perioperative penod but oral steroids were given at a dose of 10 mg/day from the fifth postoperative day, increased to 0.5 rug/kg/day on the twenty-first postoperative day, with a taper starting from the third month. The dose was gradually reduced to 0.15 to 0.20 rug/kg/day at the I-year mark. . Rejection. Rejection was diagnosed on a clinical basis within the first few weeks. Clinical features are variable and include one or more of the following: raised temperature; decreased oxygen tension or oxygen, desaturation with exercise; a hilar flare on the chest x-ray film. The usual response to a presumed r~jection. episode was to administer 500 mg of methylprednisolone intravenously and to follow that with two further daily doses (each of 250 to 500 mg) if the response to the first dose confirmed the diagnosis. Bronchoscopy. The first bronchoscopic examination was performed in the operating room, the second before extubation ~nd the third before discharge. Otherwise bronchoscopic stud~ tes were performed when clinically indicated. Transbronchial biopsies were performed in response to clinical situations in the first 3 weeks but thereafter at regular intervals unless otherwise indicated. Usually the first biopsy tissue was obtained at 3 weeks and then at 3, 6, and 12 months after transplantation. Physiologic evaluation Pulmonary function testing. Pulmonary function tests were done during pretransplantation evaluation and at routine intervals thereafter in the preoperative and postoperative periods. Six-minute walk. Each patient underwent a standardized 6-~i~~te walk t~t with pulse oximetry monitoring at the time of IOltIaI evaluation and at regular intervals during the preoperative and postoperative periods. The oxygen saturations were maintained at greater than 90% by supplemental oxygen if necessary. The distance walked, the number of stops, and the amount of supplemental oxygen used were recorded. Statistics. Means ± 95% confidence limits are quoted unless otherwise stated. For comparison of groups before and after transplantation, 95% confidence limits of the mean were used to det.er~~e signifi~nt ~iff~rences. For comparison of changes in an individual patient, significant differences were determined by use .of the paired t ~est. Survival was estimated by the KaplanMeier method and IS quoted in conjunction with standard errors of the mean. Results There have been one hospital death and three late deaths among the 35 patients. The mean length of

Volume 103 Number 2

Lung transplantation

February 1992

~l~~,========~~=C===J 1 I

1

0.8 S U R

33 1

v, '--.____

I

.....

-. -._--_. - --~- ------------- -_.- ---- ----------~ --- ---------- ------_. ~-- --~-- -----.- ----------------'.

0.6

f-

V

I

V A L

0.4 0.2 0

~

0

I

I

I

I

I

I

I

I

I

50

100

150

200

250

300

350

400

450

500

DAYS POST TRANSPLANT -

35 PATIENTS

-

WASH.U.(n=63)

------ WORLD (n=171)

Fig. 1. The Kaplan-Meier survivalcurves for the 35 patients in this series (35 PATIENTS), all patients from The Washington University Lung Transplant Group (WASH. U.), and all patients in the world experience during the period July 1, 1989, to June 30, 1990 (WORLD). FEET

2500,.----------------------------,

2000

1500

1000

500

N-23

N-30

N-27

OL----------------------------l EVALUATION PREOP 3 WEEKS 3 MONTHS 6 MONTHS MEAN AND 95% CONFIDENCE LIMITS

Fig. 2 The mean 6-minute walk distance (± 95% confidencelimits) before transplantation and at each follow-up period. follow-up is 482 days with a range of 319 to 660 days for surviving patients. This gives a 97.2% ± 2.7% hospital survival rate and a l-year actuarial survival rate of 91.7% ± 4.6%. The survival rate for all patients receiving

lung transplants at The Washington University Medical Center from the commencement of the program in 1988 to December 31, 1990, inclusive is 77.3% ± 5.3% at 1 year. For those patients in whom the lung transplant

332

The Journal of Thoracic and Cardiovascular

Haydock et al.

Surgery

Table II. The diagnosis for the patients in each group Pathology

No.

Group I Emphysema Cystic fibrosis Lymphangio1eiomyomatosis Obliterative bronchiolitis Eosinophilic granuloma Group 2 Pulmonary fibrosis Group 3 Primary pulmonary hypertension Atrial septal defect and Eisenmenger's syndrome

20 3 I I I 3 5 I

Table III. Mean FEV1 for the group ofpatients with obstructive physiology at the time of evaluation and at 1, 3, and 6 months postoperatively FEV, (L)

Evaluation I mo 3 mo 6 mo

No.

Total (n = 24

Single (n = 14)

Bilateral (n = 10)

24 24 18 10

0.52 1.84* 1.91* 1.52*

0.50 1.29 1.37 1.21

0.54 2.68 3.04 3.37

Two patients have been excluded from this table. One died perioperatively and one required a second transplant operation. *p < 0.05 (paired t test) when compared with evaluation FEVI for each individual.

operation was done by means of currently used techniques (i.e., not en bloc double transplants), the I-year actuarial survival rate is 84.9% ± 4.9%. The survival curves are shown in Fig. I. A review of The International Lung Transplant Registry revealed that during the same time frame as the series under review 171 transplants were performed worldwide with a 30-day survival rate of 86.5% ± 2.6% and a l-year survival rate of 70.2% ± 3.6%. Stay in the intensive care unit ranged from 1 to 36 days with a median of 4 days and a mean of 7 days. Hospital stay ranged from 15 to 66 days with a median of 24 days and a mean of 25.8 days. Satisfactory oxygen saturations with the patient breathing room air (oxygen tension >60 mm Hg) were attained as early as 2 days and as late as 40 days after transplantation. The median was 7 days. No recipient is oxygen dependent. Five patients required reintubation during their postoperative period. Functional status Six-minute walk. When compared with pretransplantation values, the distances walked over a 6-minute period significantly improved at 3 months (p < 0.05) but not

at 2 to 3 weeks (p = NS*) after transplantation (Fig. 2). There was no significant change between the walk at 3 months and that at 6 months (p = NS). Supplemental oxygen was required to maintain saturations above 90% in 89.3% of those patients performing the 6-minute walk test (n = 28) at evaluation, in 95.5% of patients (n = 22) just before the operation, in 22.2% of patients (n = 27) at 2 weeks postoperatively, and in 0% of patients (n = 22) at 12 weeks postoperatively. Physiologic testing. The patients have been divided into three separate groups according to their disease process (Table II), namely, those with obstructive physiology (group 1), those with restrictive physiology (group 2), and those with pulmonary hypertension (group 3). GROUP 1 (OBSTRUCTIVE PHYSIOLOGY). The measurement of forced expiratory volume in 1 second (FEV\) improved significantly from before transplantation to all periods offollow-up in group 1 patients (Table III). The mean values of the percent predicted FEV 1 attained by patients receiving one and two lung transplant(s) are illustrated in Fig. 3. Lung transplantation is associated with a significant improvement in percent predicted FEV I in the postoperative period (p < 0.05), and this improvement is greater in those undergoing a bilateral replacement. GROUP 2 (RESTRICTIVE PHYSIOLOGY). In the three patients in group 2 (Table 11), the total lung capacity and arterial blood gases with the patient breathing room air have improved in the postoperative period for each individual (Table IV). . GROUP 3 (PULMONARY HYPERTENSION). The patients (n = 6) in group 3 all had pulmonary hypertension, either primary or the result of Eisenmenger's syndrome (Table 11). Follow-up right heart catheterization studies and radionuclide ventriculograms have been performed in all patients to determine right heart and pulmonary pressures and right ventricular ejection fractions (Fig. 4). The mean pulmonary artery pressure was 55.7 ± 5.8 mm Hg and fell to 19.2 ± 6.6 mm Hg at postoperative catheterization (p < 0.05). The mean right ventricular ejection fraction was 27.8% ± 11.0% and increased to 48.8% ± 11.3% at postoperative radionuclide ventriculography (p < 0.05). Mortality. The one hospital death occurred in the only patient in the series who underwent the original en bloc double lung replacement procedure. This patient had a global myocardial infarction during the operation and died 3 days after the operation despite massive inotropic support and use of an intraaortic balloon pump. His preoperative coronary anatomy was normal and there was no *NS

= Not significant.

Volume 103 Number 2

Lung transplantation

February 1992

333

120.---------------------------,

100 % p r

e

d i

80 60

c t

e

d

40 20 N-10

EVALUATION

1 MONTH

3 MONTHS MEAN AND 96'1 CONfiDENCE LIMITS

Fig. 3. The percentpredicted FEY I for twogroups of patientswithchronic obstructive pulmonary disease. Group I comprises 10 patientsundergoing bilaterallungtransplantation and group 2 comprises 14 undergoing single lung transplantation.

evidence of coronary occlusion at autopsy. We subsequently abandoned the concept of en bloc double lung replacement and developed the sequential bilateral lung transplantation procedure." This operation is considerably simpler and safer than the original double lung procedure. The second death in this series occurred in a 55-year-old patient who had undergone a right single lung transplant for ai-antitrypsin deficiency emphysema and was discharged well on postoperative day 25. On postoperative day 48 a sudden fatal bronchial anastomosis-right pulmonary artery fistula developed. For the bronchial anastomosis in this case we had used interrupted PDS sutures (Ethicon, Inc., Somerville, N.J.) (not our usual technique). The autopsy demonstrated that the PDS knot ends had made two puncture wounds in the adjacent pulmonary artery and that the fatal hemorrhage had occurred through a small defect in the airway anastomosis.The third death in the series occurred in a 55-year-old man who died 205 days after transplantation as a result of hepatic carcinoma. The final death occurred at 368 days. The patient was a 38-year-old woman who had undergone retransplantation after her initial graft (performed in 1988) had failed because of obliterative bronchiolitis. A lymphoproliferative disorder developed (discussed later) and her agonal event was the development of fulminant pancreatitis.

Table IV. Mean total lung capacity (TLC) and room air arterial partial pressure ofoxygen (RA Paos} at evaluation and at 1, 3, and 6 months postoperatively in those with restrictive physiology RA Pa02 TLC(L)

Evaluation 1 rna 3 rna 6 rna

1.95 (n 2.84 (n 3.00 (n 2.75 (n

= 3) = 3) = 2) = I)

(mm Hg)

41 (n 62 (n 91 (n 73 (n

= 2) = 3) = 2) = 1)

One patient at evaluation was too oxygen dependent for us to attempt measuring a room air arterial blood gas level.

Complications. The major complications are listed in Table V and summarized as follows. Surgical complications. Nine intraoperative complications occurred in seven patients. These included two myocardial infarctions, two phrenic nerve injuries, and two recurrent laryngeal nerve injuries. The pulmonary venous anastomosis was narrowed on two occasions, and one of these patients required extracorporeal membrane oxygenation (ECMO) and reexploration for bleeding. These complications are discussed in more detail in the following paragraphs. Airway complications. In total, six patients (17.2%)

334

The Journal of Thoracic and Cardiovascular Surgery

Haydock et al.

MEAN PULMONARY ARTERY PRESSURES -,-

70r;.m"~Hg::...

BEFORE TRANSPLANT

.......,

RIGHT VENTRICULAR EJECTION FRACTION 'llo

70......------------------...., MEAN AND left CONFIDENCE LIMIT'

ME• • • •0 . . . CD.FlDE.CE LIMITS

80

80

50

50

40

40

30

30

20

20

10

10

AFTER TRANSPLANT

oL-----------------~

AFTER TRANSPLANT

BEFORE TRANSPLANT

oL-----------------~

Fig. 4. Pulmonary hypertension (n = 6). The mean pulmonaryartery pressureand right ventricular ejection fraction (%) before and after lung transplantation.

Table V. List of complications incurred by the 35 transplant recipients Description of complication Biopsy-confirmed CMV infection Hematologic Requirement for another operation Bacterial pulmonary infection Supraventricular arrhythmia Severe persistent donor lung dysfunction Airway healing deficits Prolonged ileus Wound complications Fungal infection Cardiopulmonary arrest Other nerve injuries Deep venous thrombosis Myocardial infarction Intraperitoneal hemorrhage Grand mal convulsions Phrenic nerve palsy Recurrent laryngeal nerve palsy Cholecystitis Hospital death Late death Miscellaneous

No. oj patients

18 16

12 II 9

7 6 6 6

3 3

3 3 2 2 2 2 2

I I 3

7

had detectable deficiencies in airway healing. Of these six defects, three consisted of noncircumferential areas of airway necrosis and slough that were detected on routine bronchoscopic examination and healed with no clinical significance. Three patients had airway healing complications of clinical significance (8.6%). One patient died as a result of a fatal bronchus-pulmonary artery fistula (see Mortality). Two patients had significant management

problems and required the use of airway stents (one temporary and one still in place). Details of their management have previously been presented.' Both patients are functioning well 12 and 14 months after the transplant operation.

Postoperative dysfunction of the transplanted lung. Seven patients (20%) had prolonged periods of donor lung dysfunction that included abnormally high inspired oxygen fraction requirements, prolonged need for ventilation, persistent infiltrates on chest x-ray films, and evidence of severe diffuse alveolar damage on lung biopsy (open lung biopsy on three occasions). In three of the seven patients there was. no obvious explanation for the poor early function of the graft (mean ischemic time for these patients was 282 ± 92 minutes as compared with 322 ± 28 minutes for the group without donor lung dysfunction). In the other four the development of dysfunction was more clearly related to a proved complication. In one patient donor lung dysfunction developed after a cardiac arrest that involved a prolonged resuscitation period (postoperative day 2), and another patient had the same problem after an airway complication (postoperative day II). The two other patients with this problem had technical problems related to the pulmonary venous anastomosis. In one patient (primary pulmonary hypertension) the pulmonary veins of the graft were damaged when the heart was harvested. Narrowing of what was a difficult pulmonary venous anastomosis occurred, with the diagnosis being made when she could not be weaned from cardiopulmonary bypass. A pericardial patch was applied to the venous anastomosis but significant lung injury had occurred at this stage. She required ECMO for 3 days postoperatively from which she was successfully weaned. The second patient had delayed recognition of a faulty

Volume 103

Lung transplantation

Number 2 February 1992

venous anastomosis, when the posttransplantation perfusion scan revealed only 6% flow to the transplanted lung. The area was reexplored and the anastomosis patched, which resulted in an increased flow to the lung. However, lung function failed to recover sufficiently and the patient subsequently underwent successful retransplantation (postoperative day 11). This was the only one of the seven patients with posttransplantation lung dysfunction to require retransplantation. The remaining six patients were treated conservatively. This latter group of patients have all been discharged from the hospital and do not require supplemental oxygen. In all but one (operated on 6 weeks ago) the chest x-ray changes have almost completely resolved. Bronchiolitis obliterans. One patient has had a clinical course suggestive of the development of obliterative bronchiolitis. Transbronchial biopsies have failed to give histologic confirmation ofthis and the patient has not had an open lung biopsy. The deterioration in her lung function tests was arrested with an intravenous course over 2 weeks of equine antilymphoblast globulin. CMV infection. Eighteen patients (51 %) have had 21 biopsy-proved episodes of CMV disease (17 episodes of pneumonitis with three recurrences and one case of hepatitis). The mean time to the first CMV-positive transbronchial lung biopsy was 70 days (median time 56 days, range 38 to 192 days, with all but one before i l? days). For the three patients with a second CMV illness, the average time from transplantation to the first episode was 58 days (range 55 to 63) and the second episode 128 days (range 108 to 168). Patients with bronchoalveolar lavage fluid and buffy coats that tested positive for CMV, by conventional culture or shell vial assay, but had negative biopsy results were not included in these numbers. No patient required reintubation. No CMV-related deaths occurred, but in the patient who died of a fatal airway hemorrhage, CMV pneumonitis was an incidental autopsy finding (included in aforegiven numbers). CMV infection was managed with ganciclovir 5 mg/kg every 12 hours given intravenously for 2 to 3 weeks. In recipients who were CMV positive, the CMV status of the donor had no effect on the prevalence of biopsyproved CMV disease (Table VI). For CMV-negative recipients the prevalence of CMV disease with a positive donor was the same as for CMV-positive recipients. No CMV-negative recipient has had a CMV infection when the donor was seronegative for CMV. Four patients have had a self-limited CMV-type syndrome. These patients have had fever, constitutional symptoms, and arthralgias associated with shedding of CMV into the blood, bronchial washings, or in the bron-

335

Table VI. CMV status of the 35 recipients and their donors and prevalence of CMV-proved infections in each category Biopsies +ve for CMV R/D CMV status R -l-ve/D +ve

=7

R +ve/D -ve = II R -velD +ve = 9 R -velD -ve = 8

No.

%

4

57 64 67

7 6

o

o

One patient (CMV negative before transplantation) required retransplantation and on both occasions the donor was CMV positive. He has been included only once in the table.

choalveolar lavage fluid. One of these patients is presumed to have had CMV pneumonitis, although studies of biopsy tissue yielded negative results.

Pulmonary infection BACTERIAL. Eleven patients (31.4%) received antibiotic treatment for microbiologically proved pulmonary infections. Most episodes occurred within the first 10 days (range 1 to 37). Treatment was started in the majority of patients (8/11) in response to culture results from bronchial washings that were obtained at the time of routine bronchoscopic studies. Three patients had clinical and radiologic signs consistent with pneumonia, and it was these findings that prompted specimen collection and subsequent treatment. Five infections were due to organisms that had also been present in the donor bronchial washings. FUNGAL INFECTIONS. Three patients had fungal infections. Aspergillus fumigatus was grown from washings, and the organism was demonstrated in biopsy specimens of bronchial ulcerations in one patient 3 months after transplantation. Torulopsis glabrata was isolated from both sputum and blood of a second patient. Both of these patients received amphotericin treatment with resolution of the infections. A third patient, who required retransplantation for bronchiolitis obliterans, had Torulopsis glabrata present in the sputum, bronchial washings, and urine before the second transplantation; this persisted postoperatively but was not treated, and there have been no subsequent problems with this organism. Urinary tract infection. Only one patient had a postoperative urinary tract infection. The causative organism was Candida albicans. This patient was treated successfully by removal of the indwelling bladder catheter. Herpes simplex infection. One patient had a herpes throat infection despite receiving acyclovir. This resolved without further complication. Clostridium difficile. Clostridium difficile was cultured and the associated toxin detected in the stool of sev-

336

Haydock et al.

en patients (20%). Diarrhea was the event that prompted stool culture. All patients responded to antibiotic therapy (metronidazole), but one patient had a second episode. No complications occurred as a result of this infection. Cardiac complications. Three patients had a cardiac arrest in the postoperative period. Two of the three had undergone single lung transplantation for pulmonary hypertension (one primary and one secondary to an atrial septal defect). The first ofthese had a cardiac arrest on postoperative day 3. It was preceded by a short period of arterial hypoxemia during chest physiotherapy. Cardiac massage, initially external followed by internal (through the abdominal wound), was maintained for almost I hour before a life-sustaining rhythm was obtained. Diffuse transplant lung injury developed and necessitated tracheostomy and prolonged ventilation (I month). The patient subsequently made a complete recovery and is now doing well 6 months after this event. Her exercise tolerance is excellent and she plans to return to work. The second patient (single lung transplantation for atrial septal defect with Eisenmenger's syndrome) was extubated on day 2 and was in stable condition in the intensive care unit on the third postoperative day when the cardiac arrest occurred. She had a few beats of unheralded ventricular tachycardia followed by ventricular fibrillation. Her rhythm reverted immediately with defibrillation and no further episodes of cardiac arrhythmias occurred. The third cardiac arrest was associated with massive intraabdominal hemorrhage occurring on the eighth posttransplantation day. Details are presented in the Abdominal complications section. One patient had an intraoperative myocardial infarction during a single lung transplantation. Postoperatively, both inotropic and intraaortic balloon pump support were needed to maintain hemodynamic stability. He ultimately survived with a well-maintained left ventricular ejection fraction according to radionuclide ventriculography. His preoperative coronary angiograms had not demonstrated any hemodynamically significant coronary lesion, but extensive calcification was seen in the coronary arteries on computed tomographic scan. The other patient having a myocardial infarction has been discussed in the Mortality section. Nine other patients (25.7%) had either atrial flutter or atrial fibrillation. Most commonly the arrhythmia occurred around postoperative day 4. Only one patient required electrical cardioversion. The remainder underwent either spontaneous or medical cardioversion. Five of these nine patients had had bilateral single lung trans-

The Journal.of Thoracic and Cardiovascular Surgery

plantation and three of the remaining four had a single lung transplantation for pulmonary hypertension, Abdominal complications. Cholecystitis developed 60 days after hospital discharge in one patient and necessitated a percutaneous laparoscopic cholecystectomy, performed without complication. Two patients had delayed episodes of intraabdominal bleeding from a branch of the superior mesenteric artery (postoperative days 8 and 29). In the first patient there was free rupture from the small bowel mesentery into the peritoneal cavity associated with a hypovolemic cardiac arrest. Resuscitation was possible only after the abdomen was opened and the abdominal aorta was hand clamped. The second patient had been discharged home and returned on postoperative day 29 with abdominal pain. A computed tomographic scan demonstrated blood in the peritoneal cavity, and at operation large amounts of blood clot Werediscovered in the root of the small bowel mesentery and extending into the retroperitoneum toward the right colic flexure. The vessel involved could not be identified because of the distortion of the anatomy, and a right colectomy was performed with a defunctioning colostomy (cecum). This patient has subsequently had one episode of gastrointestinal bleeding from a duodenal ulcer observed by endoscopic examination and also another episode of abdominal bleeding. On this occasion a repeat arteriogram demonstrated several mesenteric arterial malformations that had not been present on the angiograms taken at the time of the initial hemorrhage. These were successfully embolized. The cause of this'spontaneous mesenteric bleeding is not known. One patient had lethal pancreatitis in the late postoperative phase (see Mortality). Neurologic complications Seizures. Two patients had grand mal convulsions. One episode was during the resuscitation period after a cardiac arrest. The other was associated with imipenem therapy in a patient with no history of convulsions. A computed tomographic scan of the head showed no abnormalities. Neither patient had permanent neurologic damage. Headache. One patient had a spinal headache after epidural placement of a catheter. The patient refused a blood patch until postoperative day 8, when it was successfully performed with resolution of the headache. Organicbrain syndrome. Hallucinations and disorientation occurred in two patients. These symptoms finally responded to high-dose haloperidol therapy and have not recurred. Nerve injury. Two cases of phrenic nervepalsy have occurred. One abnormally located (left) nerve was inad-

Volume 103 Number 2

Lung transplantation

February 1992

vertently divided and subsequently repaired

with

microvascular techniques during a transplant procedure on a patient with pulmonary hypertension. This patient

was extubated on the third postoperative day. Lower lobe collapse persisted for the first 3 weeks, but this has subsequently resolved. Despite his percent predicted FEV 1 (58% at 3 months) and 6-minute walk distance (1340 feet at 3 months) being the lowest of the six patients with pulmonary hypertension, he appears to have little functional impairment as a result of this injury. A second phrenic (right) nerve was damaged by an inadvertent forceps crush injury. This patient, a 51-year-old patient having single lung transplantation for chronic obstructive pulmonary disease, has a percent predicted FEV 1 at 6 months of 38% (15.3% before transplantation) and a 6-minute walk distance of 2300 feet while breathing room air. Two left recurrent laryngeal nerves have been damaged. One patient had Teflon injection to the affected vocal cord to assist with coughing. The other patient had no further treatment. One left brachial plexus injury occurred in a patient undergoing a right single lung replacement for emphysema, with subsequent recovery. A right sciatic nerve compression syndrome occurred in a patient undergoing a second transplantation for obliterative bronchiolitis. This patient was on the operating table for more than 16 hours. This complication has subsequently resolved.A branch of the femoral nerve that supplies the right quadriceps was apparently injured in a patient who required groin cannulation for ECMO after transplantation. This patient has residual weakness 3 months after transplantation but is steadily improving and is now able to walk freely without a brace. Hematologic complications Thrombocytopenia. Ten patients had a platelet level that was less than 100,OOOjmm3 for more than 3 days or less than 60,000jmm 3 at any stage of recovery. In eight patients this problem became apparent before postoperative day 10 (six had undergone cardiopulmonary bypass). Of the two patients in whom thrombocytopenia developedlater, one is mentioned in the Mortality section and the other has subsequently had a bone marrow biopsy that demonstrates hypoplasia. This patient was receiving cyclophosphamide (Cytoxan) preoperatively for pulmonary fibrosis. Leukopenia. Three patients had white cell counts below 2500jmm 3• It was not possible to determine whether the cause of this problem was CMV infection or azathioprine j trimethoprimjsulfamethoxazole administration, or both. All patients recovered with temporary

337

Table VII. Surgical procedures performed in addition to transplant operation (excluding bronchoscopies) Procedure Open lung biopsy Chest tube placement Reoperation for bleeding Tracheostomy Intraaortic balloon pump Pericardial patch to pulmonary vein Airway stent placement ECMO placement and removal Sternal debridement Retransplantation Laparoscopic cholecystectomy Sternal wire removal Vocal cord injection Middle lobectomy (transplant lung) WPW accessory pathway ablation

No. undertaken 3 3 3 2

2 2

2 1 1 1

1 I

1 1

1

WPW, Wolff-Parkinson-White.

cessation of the likely causative drugs and treatment of CMV infection. Hemolytic anemia. Four patients received lungs from donors of nonidentical blood groups (three group A recipients and one group B recipient received organs from group 0 donors). In three of these patients hemoglobin levels decreased in association with a positive direct Coombs test, low haptoglobin levels, and presence of ABO-directed antibodies in the blood between I and 3 weeks postoperatively. This immune-mediated phenomenon was presumed to be due to a production of ABO antibodies by the lymphocytes transplanted in the donor lung. Washed red cells were transfused from group 0 donors, and evidence of this problem disappeared after the third postoperative week. Further surgical procedures. Twelve patients underwent 25 surgical procedures in conjunction with or after their transplant operation (Table VII). All but the following two of the major procedures have been discussed in other sections. A middle lobectomy was performed in a patient undergoing a second bilateral lung replacement when it became apparent that the donor lungs were too large for the contracted and scarred pleural spaces. The middle lobe, which was large and mobile, was therefore excised and the stump was covered with a pleural flap. No complication ensued. In one patient, the Wolff-Parkinson-White syndrome was diagnosed during the pretransplantation evaluation, and an electrophysiologic study demonstrated the potentially life-threatening nature of the aberrant pathway.

The Journal .of

338

Thoracic and Cardiovascular Surgery

Haydock et at.

She underwent ablation of the pathway via an epicardial approach without cardiopulmonary bypass through a left thoracotomy incision, and the left lung was transplanted at the same time. Renal function. Two patients had transient early postoperative episodes of renal dysfunction with creatinine levels rising to more than 2.0 mg/dl. Renal function returned spontaneously in both patients, and no patient has required hemodialysis. For the group of 35 patients the mean creatinine level on postoperative days 3 (0.91 ± 0.19 mg/dl) and 14 (0.9 ± 0.11 mg/dl) did not change significantly when compared with the preoperative levels (0.88 ± 0.08 mg/dl). Wound complications. Two wound infections have occurred. One patient with cystic fibrosis has required incision and drainage of the sternal wound for Candida infection. The other patient had a minor wound infection in the groin after ECMO decannulation. An override of the lower part of the sternum on the upper part of the sternum after bilateral single lung transplantation is frequent (four patients). This is usually detected only radiologically or is associated with a mild cosmetic deformity. Stability has been attained in all patients. Deep vein thrombosis. Three patients have had deep vein thrombosis diagnosed by Doppler ultrasound. One was a below-knee thrombosis that was not treated. A second patient had a right axillary vein thrombosis with arm swelling. This patient was not given anticoagulants and has not had further symptoms since resolution of the swelling. The third deep vein thrombosis occurred in a patient who required ECMO support in the postoperative period. An iliofemoral vein thrombosis was detected. Because the patient had thrombocytopenia and had already undergone reexploration for bleeding, she was not given anticoagulants; instead, a percutaneous bird's nest filter was placed in the inferior vena cava. There have been no proved episodes of pulmonary embolism. Lymphoproliferative disorder. The patient who underwent retransplantation for obliterative bronchiolitis subsequently had several lesions in both lung fields consistent with a lymphoproliferative disorder. An open lung biopsy had not been performed, but results of a needle biopsy had shown atypical lymphocytes and were negative for organisms. This patient was receiving FK 506, prednisone, and azathioprine (Imuran) antirejection treatment when these lesionsdeveloped. After the dose of immunosuppressive agents was reduced, the various lesions either reduced in size or disappeared completely. However, the patient has subsequently died of fulminant

pancreatitis (see Mortality) and at autopsy the presence of a polymorphous B-celllymphoma was demonstrated. This tumor manifested itself as a mass in the upper lobe of the right lung. Miscellaneous. Insulin-dependent diabetes mellitus developed in two patients. It was temporary in one and permanent in the other. Two patients had sacral pressure areas both of which resolved without surgical intervention. One patient with a long history of steroid therapy and osteoporosis has had debilitating pain from vertebral compression fractures. Discussion

Although a l-year survival rate of 91.7% and a hospital survival rate of 97.2% are gratifying, these results have not been achieved without considerable postoperative morbidity. There is no surviving patient in the group whose pulmonary status is not better than it was before transplantation. No patient is oxygen dependent and only one patient has not returned to routine daily activities;this patient has severe osteoporosis and severe back pain from multiple compression fractures. The dramatic reduction in hospital mortality reported here in comparison with those in previous reports is due to several factors. First and foremost, the increased frequency of the procedure and the presence of an experienced and dedicated team of physicians, nurses, physiotherapists, and other skilled specialists has created a favorable environment for success.Second, the design and application of the bilateral single lung transplant operation to replace the original double lung procedure has significantly reduced the morbidity and mortality associated with the replacement of both lungs. The one hospital death in this series followedour last use of the original double lung procedure. Cardiac complications have occurred despite careful screening of the recipients (including cardiac catheterization). Atrial arrhythmias are not an unexpected complication of this type of operation, given the fact that atrial clamps are applied and some handling of the heart is inevitable, especially with bilateral single lung transplantation. The patients with pulmonary hypertension were highly represented in the group with cardiac complications, which occurred in four of the six patients (three with atrial arrhythmias, one having a cardiac arrest, and one having both problems). This is perhaps not surprising inasmuch as this group of patients all had severely depressed right ventricular function, tricuspid incompetence, and enlargement of right atrium and ventricle. Although dramatic resolution of the elevated right heart

Volume 103 Number 2 February 1992

pressures and improvement in right heart ejection fractions have been documented, there still appears to be a tendency to cardiac irritability in this group in the immediate postoperative period. Airway complications have appeared in 17.2% of the patients in this series. Half of these have been of clinical significance. The role of an omental wrap in reducing mortality and serious complications is not possible to determine, because we continue to use it for all cases. The airway complication rate per anastomosis performed is 12.2%with a mortality rate per patient being 2.9%. This rate of airway complications is comparable with that reported after sleeve resection for lung cancer," even though complete interruption ofthe bronchial circulation, the use of immunosuppressive drugs, and the routine use of postoperative ventilatory support would seem to prejudice the results against the transplant group. A significant proportion (20%) of this series of patients had persistent donor lung dysfunction. There are three patients in whom an explanation for the postoperative graft dysfunction is not evident. This seemed to occur despite all retrieval parameters being within the normal range and with the recipient procedure being technically smooth and uncomplicated. Whether better preservation techniques or improved maintenance of graft hypothermia during implantation will prevent this complication is yet to be determined. With six of seven of these patients avoiding retransplantation and 100% surviving, we advocate persistenceand patience in the handling patients with prolonged graft dysfunction. A separate report on the management of these patients is in preparation. Although biopsy-proved CMV infections appear to be prevalent, the overall outcome for the group has been satisfactory and without mortality. We have tried a number of approaches to reduce the prevalence of this infection, but so far the only effective method has been to give CMV-negative recipients lungs from CMV-negative donors. We use transbronchial biopsy liberally after the first 3 weeks and monitor the buffy coat for CMV at weekly intervals. With aggressive use of the appropriate antibiotics, we have found clinically important bacterial infections to be relatively uncommon, with the exception of Clostridium difficile. The prevalence of Clostridium difficile is almost certainly related to our antibiotic use. From the point of patient isolation, we have adopted a policy of masks and glovesfor the first 7 days, then handwashing precautions after that. At present we believethere is no need to change our approach. Functionally, each patient in the group is in dramatically better condition than before transplantation. Post-

Lung transplantation

339

operative pulmonary function after transplantation has been reviewed in more detail elsewhere." and because the follow-upis so short conclusions have to guarded. It would appear that those patients receiving two lungs for obstructive disease have a significantly greater improvement in FEV 1 and percent predicted FEV 1. This would be expected because of the presence of obstruction in the remaining emphysematous lung after single lung transplantation. In some patients receiving a single lung for obstructive lung disease there does appear to be some initial compression of the transplanted lung, but this trend tends to resolveover the first 3 months with the x-ray films showing the mediastinum to be more central. The group with restrictive disease is small, but they have tended to be the most oxygen-dependent, debilitated patients before transplantation. One patient required mechanical ventilation with paralysis, 100% oxygen, and 5 em of positive end-expiratory pressure to maintain arterial oxygen satura tions of 90% before transplantation. The results for this group, although short term, have been satisfactory, with restoration of a satisfactory total lung capacity and relief from oxygen dependency. The early results of the group with pulmonary hypertension have been encouraging in that their pulmonary artery pressures and right-sided heart function have returned to normal or near normal levels within weeks. We believe that the volume of transplantations being performed at our institution has helped make the procedure more routine with subsequent attainment of a 97.2% hospital survival rate and a l-year actuarial survival rate of 91.7%. These results are at least equivalent to those obtained with other thoracic organ transplants.f The complications seen with lung transplantation are numerous but usually manageable and not the source of longterm morbidity. Because of the satisfactory results achieved, indications for lung transplantation have been widened and criteria for recipient selection relaxed. It remains to be determined what long-term survival will result, but it seems reasonable to assume that results with lung transplantation will parallel those achieved with other more established vital organ transplants. REFERENCES 1. The Toronto Lung Transplant Group: Unilateral lung transplantation for Pulmonary Fibrosis. N Engl J Moo 1986;314:1140-1145.

2. Patterson GA,Cooper JD, DarkJH, et al:Experimental and clinical double lung transplantation. J Thorac Cardiovasc Surg 1988;95:70-74. 3. Egan TM, Kaiser LR, Cooper JD. Lung Transplantation: Current Problems in Surgery. Oct 1989;26(10):673-752.

The Journal, of

340

Haydock et al.

4. Pasque MK, Cooper JD, Kaiser LR, Haydock DA, Triantafillou A, Trulock EP. Improved technique for bilateral lung transplantation: rationale and initial clinical experience. Ann Thor Surg. 1990;49:785-91. 5. Schaefers H-J, Haydock DA, Cooper JD. The incidence and management of bronchial anastomotic complications in Lung Transplantation. (In press). 6. Maeda M, Nakamoto K, Ohta M, et al. Statistical survey of tracheobronchop1asty in Japan. J Thorac Cardiovasc Surg 1989;97:402-14. 7. Grossman RF, Frost A, Zamel N, et al. Results of singlelung transplantation for bilateral pulmonary fibrosis.N Engl J Med 1990;322(11):727-733. 8. Kriett JM, Kaye MP. The Registry of the International Society for Heart Transplantation: Seventh Official Report. J Heart Transplant 1990;9:323-330.

Thoracic and Cardiovascular Surgery

The Washington University Lung Transplant Group

Surgery: J. D. Cooper, MD, L. Kaiser, MD, M. Pasque, MD, C. Dressler, MD; Anesthesia: A. Triantifillou, MD; Pulmonology: E. P. Trulock, MD, and N. A. Ettinger, MD; Cardiology: E. Fry, MD; Radiology: D. Anderson, MD, and H. Royal, MD; Pathology: E. Brunt; Nurse Coordinators: Laura Ochoa and Kate Sander; Psychiatry and Psychology: T. Richardson, MD, S. Khojasteh, MD, and D. Schlitt, MD; Respiratory Therapy and Pulmonary Rehabilitation: D. Biggar, J. Malen, A. Weilitz, and B. Sutterer; Physical Therapy: T. Versluis; Social Work: C. Robertson; Nutrition and Dietetics: D. Reinhart.