| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
a Pulmonary Institute, Rabin Medical Center, Beilinson Campus, Petah Tiqwa, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
b Department of Cardiothoracic Surgery, Rabin Medical Center, Beilinson Campus, Petah Tiqwa, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
Received 7 May 2008; received in revised form 9 September 2008; accepted 17 September 2008.
* Corresponding author. Address: Pulmonary Institute, Rabin Medical Center, Beilinson Campus, Petah Tiqwa 49100, Israel. Tel.: +972 3 9377221; fax: +972 3 9242091. (Email: kramerm{at}netvision.net.il).
 |
Abstract |
|---|
 Top Abstract 1. Introduction2. Methods3. Results4. DiscussionReferences |
|---|
Key Words: Surfactant • Lung transplantation • Primary graft dysfunction
|
1. Introduction |
|---|
|
TopAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
|---|
Pulmonary surfactant is a complex and highly surface-active material composed of lipids and proteins that are found in the fluid lining the alveolar surface of the lungs. Surfactant lowers surface tension to near 0 mN/m, hence it prevents alveolar collapse at low lung volume, preserves bronchiolar patency during normal and forced respiration, and prevents lung edema formation by balancing hydrostatic filtration forces (biophysical functions). In addition, it is involved in the protection of the lungs from injuries and infections caused by inhaled particles and micro-organisms (immunological, non-biophysical functions) [4,5].
In bronchoalveolar lavage (BAL) studies two subfractions of alveolar surfactant are distinguished: large aggregates (LA) largely corresponding to freshly secreted surface-active tubular myelin and small aggregates (SA) largely corresponding to degraded and inactive small unilamellar vesicles. The ratio of poorly functioning SA to superiorly functioning LA is thought to represent a marker of surfactant inactivation [6]. Impaired surfactant function leads to a disturbed fluid balance homeostasis resulting in pulmonary edema, decreased lung compliance and impaired gas exchange. Edema fluid may contain proteins that further reduce surfactant function [4].
Lung transplantation apparently causes impairment in intraalveolar surfactant activity. It leads to an elevated surface tension and an increase in the small (less functioning)/large (better functioning) surfactant aggregate ratio in the lavage fluid [6]. These disturbances may, in turn, result in a vicious cycle of intraalveolar edema formation and progressive surfactant impairment [7]. Exogenous surfactant improved deficits related to biophysical functions when given to lung transplant donors; it decreased surface tension and reduced BAL protein content indicating less leakage through the alveolocapillary membrane [8].
The aim of the present report is to discuss the effect of surfactant treatment for severe, life threatening PGD.
|
2. Methods |
|---|
|
TopAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
|---|
The study group included 5 patients (3 men, 2 women) with severe (grade 3) refractory life threatening PGD. Four received single-lung transplants for emphysema (n = 3) or pulmonary fibrosis (n = 1), and one received a double-lung transplant for cystic fibrosis.
Donor lungs were preserved by hypothermic antegrade perfusion with a modified Euro-Collins solution.
Initial treatment for PGD consisted of full ventilation in a controlled mode with high-flow oxygen and hemodynamic support with vasopressors and nitric oxide (NO–20 ppm). All patients were treated with all the conventional measures according to the decision of the ICU staff. Permissive hypercapnia and reverse I/E ratios were used according to their decision. Prone position was not used. ECMO was available, but we had a bad experience with that modality, so although ECMO is an optional treatment for PGD it was not considered a conventional one and it was not used in these cases. After all conventional measures failed, exogenous surfactant was instilled intratracheally via bronchoscopic instillation as salvage therapy, at 3 (n = 1) or 7 days (n = 4) after transplantation. Mammalian surfactant was used in all cases: porcine (Curosurf®, Chiesi, Farmaceutici, Parma, Italy) in 2 patients and bovine (calfactant; Infasurf®, ONY, Inc. Amherst, NY) in 3 patients. The surfactant was instilled up to the point of flooding, it was distributed first to the upper lobes and then to the other lobes.
2.2 Immunosuppression and prophylaxis
The following immunosuppression protocol has been used at our center for all lung transplant recipients: intravenous (IV) methylprednisolone, followed by standard prednisone oral taper, mycophenolate mofetil and tacrolimus. Every patient also received trimethoprim-sulfamethoxazole prophylaxis. If the recipients or donors had positive serology for cytomegalovirus (CMV), IV ganciclovir was added for 5 days, followed by valganciclovir for 3 months, in addition to itraconazole prophylaxis against Aspergillus infection, for 6 months.
2.3 Analysis
The impact of surfactant on lung graft function was assessed by the difference in the ratio of partial arterial oxygen tension (PaO2) to fractional concentration of oxygen in inspired gas (FIO2) before and after treatment using paired t-test, and also by clinical functional assessment and X-ray films. Patients were followed for 6 months or more (range 6–26 months).
We used the mean values for analysis.
|
3. Results |
|---|
|
TopAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
|---|
dropped from 66 mmHg (pH 7.11) to 43 mmHg (pH 7.33). Hemodynamic adrenergic support was withdrawn. Chest X-ray findings improved at a slower rate. Rehabilitation was started after 2 months. At the 2-year follow-up after transplantation, FEV1 measured 44%, with good lung function and no need for supplemental oxygen. The patient died 26 months after transplantation of bronchiolitis obliterans syndrome.
3.1.2 Patient 2
A 21-year-old man underwent bilateral lung transplantation due to cystic fibrosis. Before transplantation, he had been hospitalized in the intensive care unit because of respiratory failure and was mechanically ventilated through a tracheostomy. A bilateral sequential single-lung technique was used for transplantation. Ischemic time was 2.5 h for the first lung and 4.75 h for the second. PGD developed immediately after surgery, leading to severe oxygenation difficulties. Chest X-ray films demonstrated diffuse opacities, first in the left lung and later, bilaterally. He was ventilated in a controlled mode SIMV with pressure support of 22 cm H2O at first and PCV afterwards, with PEEP of 10 cm H2O FIO2 of 0.7–0.9 and NO. On day 7 after transplantation, the PaO2/FIO2 was 103 mmHg. The patient also had low blood pressure, which was treated with vasopressors. Bronchial instillation of porcine surfactant, 20 cc (22 mg phospholipids/kg weight), led to a gradual improvement in oxygenation. PaO2/FIO2 rose to 168 mmHg after 8 h, 206 mmHg after 24 h, and >500 mmHg after 30 h. The vasopressors were tapered down and stopped 30 h after surfactant instillation. Two days after surfactant treatment, chest X-ray findings improved, showing opacities only in the lower third of both lungs. At that point, Staphylococcus aureus and Acinetobacter spp. infection developed. The patient's oxygenation status worsened over 48 h and then improved with appropriate antibiotic treatment. Rehabilitation was started at about 1 month after transplantation. At the 2-year follow-up, FEV1 measured 56%, and the patient is fully active.
3.1.3 Patient 3
A 58-year-old man, past smoker, underwent right-lung transplantation due to emphysema. His past history also included mitral valve replacement for mitral stenosis 5 years before transplantation and chronic atrial fibrillation. On arrival to the intensive care unit after transplantation, the patient was hypotensive. Revision surgery was performed to correct intercostal arterial bleeding. The patient seemed to be improving and was extubated. However, 24 h later, PaO2/FIO2 measured 75 mmHg, and chest X-ray films demonstrated diffuse opacities in the transplanted lung. Treatment consisted of reintubation for ventilation in SIMV mode with pressure support of 30 cm H2O at first and then with PCV, PEEP of 10–11 cm H2O FIO2 of 0.65–0.9 and NO, and vasopressor support to maintain blood pressure. Nevertheless, his condition continued to deteriorate. On day 7 after transplantation, he was treated with bronchoscopic instillation of bovine surfactant, 90 cc (45 mg phospholipids/kg weight). PaO2/FIO2 increased from 89 mmHg before surfactant instillation to 160 mmHg after 12 h and 267 mmHg after 19 h. Chest X-ray findings improved dramatically, and at 24 h after surfactant treatment, only a small infiltrate remained. Vasopressors were stopped after 24 h. Two days later, pneumonia due to Acinetobacter spp. and Escherichia coli infection developed, and the hypoxia recurred, though not as severely as before surfactant treatment. The patient recovered with appropriate treatment, and rehabilitation was started one month after transplantation. At the follow-up visit 16 months after transplantation, FEV1 measured 45%, and the patient was well.
3.1.4 Patient 4
A 66-year-old woman, past smoker, underwent left-lung transplantation due to emphysema. At first she appeared to be doing well, and the endotracheal tube was removed 14 h post-transplantation. However, acute lung injury developed at 34 h, with hypoxemic respiratory failure and a PaO2/FIO2 of 78 mmHg (pH 7.32, PaCO2 39 mmHg, bicarbonate 19.8 mmol/L), Chest X-ray films demonstrated diffuse opacities in the transplanted lung. The patient refused reintubation, so she was treated with high-flow oxygen (nasal and reservoir mask – estimated FIO2 of 0.7) and NO. Vasopressors were used for hemodynamic support. Amiodarone and then digitalis were added because of atrial fibrillation. When she failed to improve by day 7, she was treated with bronchoscopic instillation of bovine surfactant, 30 cc (21 mg phospholipids/kg weight). PaO2/FIO2 rose from 115 mmHg before treatment to 208 mmHg after 8 h, and to 400 mmHg after 14 h. At that point, vasopressor support was stopped. Two days later, no supplemental oxygen was needed. Chest X-ray findings improved gradually, with clearing of the opacities 4 days after surfactant instillation. Two weeks later, the patient was discharged home. At follow-up, 14 months after transplantation, FEV1 measured 67% of predicted value.
3.1.5 Patient 5
A 53-year-old woman, past smoker, underwent right-lung transplantation due to emphysema. Her past history included peptic ulcer disease and lung volume reduction surgery 2 years before transplantation. After transplantation, severe PGD developed, with both hypoxemia and ventilatory difficulties. Chest X-ray films demonstrated diffuse opacities in the transplanted lung. Treatment consisted of mechanical ventilation in the SIMV mode with pressure support of 22 cm H2O and PCV afterwards with PEEP of 8–10 cm H2O. However, 48 h after transplantation, the patient's condition deteriorated, and severe, symptomatic bradycardia was noted. Cardiopulmonary resuscitation was performed with adrenaline and, later, noradrenaline. Because of suspected pneumothorax in the native lung, a chest tube was placed; NO was added as well. Following initial partial improvement, the patient's condition deteriorated again on the sixth day, with both oxygenation and ventilatory difficulties. On the seventh day with FIO2 of 1 her PaO2 was 94, she was given intrabronchial bovine surfactant, 30 cc (20 mg phospholipids/kg weight). PaO2/FIO2 improved from 94 mmHg before surfactant treatment to 275 mmHg 3 h later (Fig. 1
). Chest X-ray findings improved at 24 h (Fig. 2
), and extubation was performed. The patient was discharged home 15 days later. At the last follow-up, 16 months after transplantation, FEV1 was 67%.
|
|
|
4. Discussion |
|---|
|
TopAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
|---|
Several groups have reported abnormalities in intraalveolar surfactant activity following lung transplantation. These disturbances could lead to an increased permeability of the blood–air barrier, resulting in a vicious cycle of intraalveolar edema formation and progressing surfactant impairment [7]. In animal models, the appearance of surfactant alterations after reperfusion was associated with a prolonged ischemic time, poor graft preservation, and the effect of gas exchange [9].
The use of surfactant in lung transplantation has been investigated so far mainly in animal models. Novick et al. [10] administered bovine lung lipid extract directly into the left main bronchus of 8 dogs after 38 h of lung graft preservation. Findings were compared with 5 controls. All the non-treated dogs showed severe ischemia-reperfusion injury during reperfusion, whereas 3 of the 8 treated dogs had near-normal lung function after 6 h of reperfusion. The factors affecting the differential response to surfactant therapy were not determined [10]. However, the extremely long storage period and the use of lipid extract surfactant, which does not contain proteins and is considered to have lower biophysical activity, could have affected the results.
Three years later, the same group [11] reported the administration of bovine lipid extract surfactant to 5 donor dogs (5 controls) that underwent prolonged (8 h) mechanical ventilation. The grafts were stored for 17 h and then retransplanted and reperfused for 6 h. The lung grafts treated with surfactant showed much better oxygenation (mean PaO2/FIO2 307 ± 63 mmHg vs 73 ± 14 mmHg in untreated grafts) and a lower small/large surfactant aggregate ratio. These findings indicated that exogenous surfactant therapy may protect lung grafts from ventilation-induced injury [11]. Accordingly, Hausen et al. [12] in a double-lung transplant model with 16 h of ischemia, found that porcine surfactant replacement therapy in the donor before organ perfusion significantly enhanced graft function after extended ischemia. Improvement was noted in compliance, resistance, oxygenation, and pulmonary vascular resistance, even with a low dose of 20 mg/kg [12]. In other studies in rats, the effect of surfactant was more pronounced after 6 h of ischemia than after 20 h [13], and superior graft function was demonstrated even after 7 days [14]. Similar improvements in graft biochemical and biophysical properties were shown in treated minipigs [15] and dogs [9,16].
In humans, the only clear indications for surfactant therapy at present are a high risk of respiratory distress syndrome (RDS) (prophylactic) and presence of RDS (rescue treatment) in premature infants. Surfactant therapy has been found to decrease the incidence of RDS, the RDS-related mortality rate, and the rate of air leaks associated with RDS [17].
In RDS surfactant treatment prevents lung injury by equalization and facilitation of lung inflation [17]. As primary graft dysfunction is a form of acute lung injury, involving lung deflation and inflation damage, surfactant therapy may have beneficial effects resembling those reported in RDS.
Struber et al. gave surfactant to lung transplant donors as a preventive measure. They demonstrated improvement in surfactant function but they were unable to show significant differences in the postoperative course. This may be because of a small sample that did not include enough patients with severe PGD [8].
Previous experience in treating humans with severe PGD includes one case of a double-lung transplant recipient who responded to combined therapy with inhaled NO and intrabronchial surfactant instillation [18]. Others described 6 patients given nebulized phosphatidylcholine preparation, which led to a decrease in alveolar arterial oxygen gradient and improved compliance [19].
Although primary graft dysfunction is now well defined, this syndrome is considered to represent a spectrum of diseases and other known maladies could occur with PGD and are difficult to exclude [2].
We tried conventional treatment before using surfactant in these patients, with no improvement. We considered surfactant treatment only when we figured that the patient was deteriorating under conservative treatment and that there was a very serious life threat.
We believe that it is less likely that conservative treatment under which the patient deteriorated cured the patient and more likely that surfactant did help, especially in the above time frame. We also believe that patients who improved after surfactant instillation had also PGD being at least one of their major diagnoses.
Our results suggest that in patients with severe PGD surfactant treatment improves oxygenation and may be life-saving. The more protracted the PGD, the greater the susceptibility of the patient to secondary injuries from mechanical ventilation, and the longer the ICU stay. Further larger studies are needed to assess the early use of surfactant instillation, as soon as PGD develops, and its possible role as a preventive mode.
|
References |
|---|
|
TopAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
|---|
This article has been cited by other articles:
|
|
 |
|
  F. R. Adler, P. Aurora, D. H. Barker, M. L. Barr, L. S. Blackwell, O. H. Bosma, S. Brown, D. R. Cox, J. L. Jensen, G. Kurland, et al. Lung Transplantation for Cystic Fibrosis Proceedings of the ATS, December 15, 2009; 6(8): 619 - 633. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| ANN THORAC SURG | ASIAN CARDIOVASC THORAC ANN | EUR J CARDIOTHORAC SURG |
| J THORAC CARDIOVASC SURG | ICVTS | ALL CTSNet JOURNALS |
