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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Christian A. Bermudez Prasad S. Adusumilli Kenneth R. McCurry Yoshiya Toyoda Permission Requests Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Bermudez, C. A. Articles by Toyoda, Y. Search for Related Content PubMed Articles by Bermudez, C. A. Articles by Toyoda, Y. Related Collections Lung - transplantation

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Original Articles: General Thoracic

Extracorporeal Membrane Oxygenation for Primary Graft Dysfunction After Lung Transplantation: Long-Term Survival

Heart, Lung and Esophageal Surgery Institute, Division of Cardiothoracic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania

Accepted for publication November 17, 2008.

^_* Address correspondence to Dr Bermudez, UPMC-Presbyterian University Hospital, 200 Lothrop St, Suite C900, Pittsburgh, PA 15213 (Email: bermudezc{at}upmc.edu).

Presented at the Poster Session of the Forty-third Annual Meeting of The Society of Thoracic Surgeons, San Diego, CA, Jan 29–31, 2007.

Cardiothoracic anesthesiology: The Annals of Thoracic Surgery CME Program is located online at http://cme.ctsnetjournals.org. To take the CME activity related to this article, you must have either an STS member or an individual non-member subscription to the journal.

 

	Abstract

Top Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
Background: Primary graft dysfunction (PGD) after lung transplantation is a major cause of morbidity and mortality. Venovenous or venoarterial extracorporeal membrane oxygenation (ECMO) allows lung recovery; however, the optimal approach and impact on long-term survival are unknown. We analyzed outcomes after ECMO use for PGD after lung transplantation at a single center over a 15-year period and assessed long-term survival.

Methods: From March 1991 to March 2006, 763 lung or heart-lung transplants were performed at our center. Fifty-eight patients (7.6%) required early (0 to 7 days after transplant) ECMO support for PGD. Venovenous or venoarterial ECMO was implemented (32 and 26 cases) depending on the patient's hemodynamic stability, surgeon's preference, and the era of transplantation. Mean duration of support was 5.5 days (range, 1 to 20). Mean follow-up was 4.5 years.

Results: Thirty-day and 1- and 5-year survivals were 56%, 40%, and 25%, respectively, for the entire group. Thirty-nine patients were weaned from ECMO, 21 venovenous and 18 venoarterial (53.8% and 46.2%), with 1- and 5-year survivals of 59% and 33%, inferior to recipients not requiring ECMO (p = 0.05). Survival at 30 days and at 1 and 5 years was similar for the patients supported with venoarterial or venovenous ECMO (58% versus 55%, p = 0.7; 42% versus 39%, p = 0.8; 29% versus 22%, p = 0.6).

Conclusions: Extracorporeal membrane oxygenation can provide acceptable support for PGD irrespective of the method used. Long-term survival of patients with primary graft dysfunction requiring ECMO (overall and weaned) was inferior to that of patients who did not require ECMO.

Primary graft dysfunction (PGD) is the leading cause of early mortality after lung transplantation [1]. Despite refined surgical and preservation techniques, PGD of variable severity occurs commonly after lung transplantation and severe PGD occurs in 15% to 35% of patients. Ischemia-reperfusion injury is a major determinant of PGD but some data suggest that prolonged ischemic time, prolonged cardiopulmonary bypass use, and massive blood transfusion may exacerbate or lead to PGD [2]. The clinical course of severe PGD is characterized by progressive hypoxemia in association with decreased pulmonary compliance and may occur immediately after graft reperfusion or days later. In most cases, clinical improvement can be achieved with supportive therapy, although some patients with PGD will continue to deteriorate with an inability to sustain ventilation and oxygenation. If not treated adequately and promptly, this persistent hypoxemia can progress to hemodynamic instability and multiorgan dysfunction.

Extracorporeal membrane oxygenation (ECMO) is considered a useful system to provide cardiorespiratory support in patients with severe lung dysfunction after transplantation and has been used in 2% to 9% of patients undergoing lung transplantation [2–5]. Support by ECMO may allow time for allograft recovery and treatment of the associated comorbidities and may be used as a bridge to retransplantation [6]. Reported mortality rates have been variable, between 30% and 60%, depending on the patient's characteristics, including time of ECMO implantation (early versus late), the presence of coexisting infection or rejection, and the type of ECMO support (venovenous versus venoarterial) [2, 4, 7–10]. In adult lung transplantation, only a few studies of ECMO for PGD have been reported, and the effects of ECMO use on long-term survival have not been clarified [11]. In this large single-center study, we analyzed our experience over a 15-year period with patients requiring ECMO for PGD early after lung transplantation (less than 7 days after transplant) to assess long-term survival, causes of early and late morbidity and mortality, and outcomes based on the type of support used.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
Study Protocol
We performed a retrospective analysis of patients who underwent lung transplantation and required early ECMO support for PGD from March 1991 to March 2006. Data were obtained from the UPMC transplant database and patient charts. This study was reviewed and approved by the Total Quality Council of the University of Pittsburgh Medical Center. The informed consent requirement was waived.

Donor Criteria
Standard procurement technique was used in all cases. Donors considered included those with adequate oxygenation (PaO₂ >300 mm Hg) and lung compliance and the absence of signs of active infection or aspiration on bronchoscopy. Mean PaO₂ before harvest was 449 mm Hg (range, 179 to 655 mm Hg). The preservation solution was University of Wisconsin Solution in the early phase of the program and Perfadex after 2001 (Vitrolife, Englewood, CO). Donors with extended criteria, including age more than 55 years and smoking history, were not excluded from this study.

Patient Selection
After lung transplantation, it has been our policy to use ECMO to support patients with progressive hypoxemia despite maximal ventilatory support. In recent years, nitric oxide (NO) has been initiated and ECMO has been reserved for those patients who do not respond to NO. Extracorporeal membrane oxygenation was implemented in 58 patients with early PGD (0 to 7 days after transplant) after support criteria were met. Patients were considered for ECMO support based on clinical and laboratory criteria when oxygenation and organ perfusion were unable to be maintained through conventional methods including ventilator support with elevated inspired oxygen fraction, NO, pharmacologic paralysis, high positive end-expiratory pressure, and vasopressors. We have observed a more rapid progression of respiratory deterioration in lung transplant patients as compared with patients with acute respiratory distress syndrome due to other causes. Thus, we would rarely tolerate persistent PaO₂ less than 60 mm Hg with an inspired oxygen fraction above 80%, especially if accompanied by poor end-organ perfusion during the early postoperative period due to the deleterious effect to the allograft. In most of these patients, ECMO was initiated without exhausting other methods of support. During the 15-year period analyzed in this study, 705 lung transplant recipients did not require ECMO support. These patients served as a control group.

ECMO Considerations
Both venoarterial (VA) and venovenous (VV) ECMO techniques were used (26 and 32 cases, respectively) depending on the patient's hemodynamic stability and the surgeon's preference. Five patients had conversion from VA to VV ECMO after a period of stabilization, and 1 patient from VV to VA ECMO due to severe hemodynamic instability. In these cases, we considered the initial method used as the primary technique of support.

In the initial phase of the program (1991 to 2000), VA ECMO was used frequently if hemodynamic compromise complicating respiratory failure was present, and central cannulation was preferred if deterioration was present while the patient was in the operating room. In the more recent period, VV ECMO has been favored using central cannulation or peripheral cannulation (preferred), because of its potential advantages over VA support [2]. Central cannulation was performed in 13 patients (12 VA ECMO), and peripheral cannulation was performed in 37 patients. For 8 patients, the cannulation site was not noted in the transplantation database and was, therefore, unavailable. Technical aspects of implantation in our institution have been previously published by Glassman and colleagues [4].

A Carmeda heparin-bonded Maxima oxygenator (Medtronic, Anaheim, CA) was used early in the study period (36% of the patients). Since December 2001, a Medtronic Carmeda heparin-bonded Affinity oxygenator was used in the majority of the patients (46%). A small group (18% of the patients) had a combination of the Medtronic Maxima and Affinity oxygenators. A centrifugal pump (BP-80; Medtronic, Biomedicus, Eden Prairie, MN) was used in all cases. Heparin was administered in the absence of significant bleeding or after correction of coagulopathy and titrated to maintain an activated clotting time of 180 to 250 s. The VA ECMO flows were titrated to maintain adequate systemic perfusion and also pulsatile flow with right ventricular ejection to ensure lung perfusion. The rate and tidal volume on the mechanical ventilator were decreased to minimize ventilator-induced lung injury.

The decision to wean a patient from ECMO was based on the clinical stability of patient and improvement of lung function as indicated by lung compliance, roentgenogram, pulmonary artery pressure, and oxygenation. Based on these factors, a weaning trial was performed, evaluating the ability of the transplanted lungs to oxygenate and to decrease CO₂ (decreasing the sweep flow) while the patient was maintained on adequate support on the mechanical ventilator. Weaning from VV ECMO support was considered if radiographic clearing of infiltrates was noted and improvement in pulmonary compliance with plateau pressure less than 32 mm Hg on 6 cc/kg of tidal volume, a respiratory rate of 20 to 24 breaths per minute, and 10 cm H₂O positive end-expiratory pressure occurred. The ECMO oxygen source (sweep flow) was disconnected and ventilation maintained at 40% to 50% fraction of inspired oxygen (FiO₂). Arterial blood gases were checked frequently to assess oxygenation and CO₂ clearance. Weaning from VA ECMO was considered by the same pulmonary assessment and ventilation management but was limited to temporary flow reduction because of the risks of thromboembolic complications if maintained and the requirement of increased anticoagulation in the interim.

Data Analysis
Continuous variables are shown as mean ± SD. Actuarial survival estimates were calculated using Kaplan-Meier life table analysis. The log-rank statistic was used to determine whether the survival curves differed, with p less than 0.05 considered statistically significant. Statistical analysis was performed using STATA, version 8.2 (STATA Corp, College Station, TX).

	Results

Top Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
Of the 763 lung transplants performed, 58 (7.6%) required ECMO support postoperatively. The incidence PGD requiring ECMO support was variable during the study period and was necessary in 14 of 249 patients (5.6%) from 1991 to 1995, 19 of 188 patients (10.1%) from 1996 to 2000, and 25 of 326 patients (7.6%) from 2001 to 2006. Since 2001, inhaled NO was used in cases where impaired oxygenation or pulmonary hypertension were noted after allograft reperfusion. The use of an aggressive donor selection did not require us to increase the use of ECMO support. Patient demographics, underlying disease, sex, age, and type of transplant for the ECMO group are depicted in Table 1. The cause of death among lung donors for these patients was traumatic head injury in 27 donors, intracerebral hemorrhage in 18 donors, and ischemic cerebrovascular accident in 5 donors. For 2 patients, living-related lung transplantation was performed. Donor pO₂ before lung procurement averaged 459 mm Hg (range, 136 to 655 mm Hg). The posttransplant patients not requiring ECMO during the same time period included 705 patients. The median age at transplantation in the control group was 52 years (range, 17 to 72); 358 patients (51%) in the control group were female. The most frequent diagnoses in this control group included chronic obstructive pulmonary disease (40%), pulmonary fibrosis (16%), cystic fibrosis (15%), and primary pulmonary hypertension (4%). Double lung transplant was performed in 307 patients (44%), and the average ischemic time was 308 minutes (range, 35 to 587) for the entire group.

Survival After ECMO
After stabilization of the patients and improved lung compliance, 39 patients were successfully weaned from ECMO, including 18 of 26 patients (69%) in the VA group and 21 of 32 patients (65%) in the VV group (p = 0.77; Table 1). Thirty-day survival of all patients supported by ECMO after lung transplantation was 56% (VA 58% and VV 55%). One-year survival for the entire group was 40% (VA 42% and VV 39%). Five-year survival for the entire group was 25% (VA 29% and VV 22%; p = 0.6; Fig 1). Among the patients who were weaned off ECMO (39 patients), 30-day, 1-year, and 5-year survivals were 80%, 59%, and 33%, respectively. The 1-year and 5-year survivals (59% at 1 year and 33% at 5 years after transplant) of patients who received ECMO after lung transplantation were inferior to those of lung transplant recipients who did not require ECMO during the same period (82% and 54% surviving at 1 and 5 years, respectively; Fig 2). However, the events dictating this difference primarily occurred before 1 year after transplant. After this initial recovery period, the Kaplan-Meier curves possessed similar slopes, suggesting similar survival in a subset of patients (Fig 2). Thirty-day, 1-year, and 5-year survivals for patients weaned from VA ECMO were 78%, 56%, and 38%, respectively; and 81%, 62%, and 28%, respectively, for patients weaned from VV ECMO (p = 0.81; Fig 3).

View larger version (9K): [in this window] [in a new window]   Fig 1. Kaplan-Meier 5-year survival after extracorporeal membrane oxygenation support for lung transplantation, both venoarterial (VA [solid line]) and venovenous (VV [dashed line]).

View larger version (10K): [in this window] [in a new window]   Fig 2. Kaplan-Meier 5-year survival in patients weaned off extracorporeal membrane oxygenation (Ecmo-weaned [dashed line]) compared with all lung transplant patients (solid line).

View larger version (9K): [in this window] [in a new window]   Fig 3. Kaplan-Meier 5-year survival weaned off venoarterial (VA) and venovenous (VV) extracorporeal membrane oxygenation.

	Comment

Top Abstract Introduction Patients and Methods Results Comment Acknowledgments References

Primary graft dysfunction is a common problem after lung transplantation. The programmatic philosophy of aggressive donor management and organ usage has not resulted in differences in survival [12]. However, recent improvements in postoperative care and donor selection and management have been associated with decreased requirement for ECMO after lung transplantation, despite significant increase in surgical volumes and the use of an extended donor population. The factors contributing to the recent, relatively lower incidence of ECMO after lung transplantation have included: (1) improved donor lung preservation strategies such as extracellular preservation solutions, intraoperative administration of blood-based pulmonoplegia with additives to prevent free radical formation and controlled reperfusion; (2) prospective T-cell and B-cell cross matching; (3) decreased use of cardiopulmonary bypass; and (4) mechanical ventilation techniques favoring low airway pressures and differential ventilation for unilateral graft failure. In our study population, the incidence of ECMO support after lung transplantation was 7.6%. A higher incidence of ECMO support was seen after double lung transplantation than after other transplant types; however, this is probably associated with the high proportion of double lung transplantation at our center (47% of the total transplants). Chronic obstructive pulmonary disease was the most frequent primary diagnosis among our patients requiring ECMO. This contrasts with previous publications in which primary pulmonary hypertension and retransplant were associated with higher risk of PGD and ECMO use [13].

In our study, survival and the ability to successfully remove patients from ECMO (weaning) was the same for both the VA and VV ECMO techniques. That may correlate with prognosis being mainly associated with the degree of initial lung damage and reperfusion injury. Thus, the success of ECMO support after lung transplantation may also be influenced primarily by the initial degree of allograft involvement and not by the type of support utilized. Initially, we favored the use of VA ECMO to improve oxygenation, obtain hemodynamic stability, and potentially limit the ischemic-reperfusion response from decreasing the pulmonary artery pressure and flow. Although our results were comparable to those obtained by other centers [5, 13], with close to 50% of the patients surviving the procedure, the need for higher anticoagulation levels and concerns of hemorrhagic and neurologic complications associated with VA ECMO led to an increasing use of VV ECMO.

Since 1998, we have preferred VV ECMO to support PGD after lung transplantation unless there is severe, concomitant ventricular dysfunction or hemodynamic compromise despite adequate management. The potential benefits of this approach include the simplicity of peripheral cannulation (internal jugular and femoral veins), which is crucial if the procedure is performed at the bedside in the intensive care unit, and anticoagulation levels that are less strict than those required in VA ECMO and, therefore, lowering the risk of thoracic and vascular bleeding [13]. Additionally, the controlled flow of oxygenated blood through the lungs maintained by VV ECMO may facilitate recovery of the lung parenchyma, minimizing the hypoxic pulmonary vasocontrictive response and the risk of distal pulmonary vasculature thrombus formation. Because perfusion through the bronchial arteries is lacking after transplantation, limiting pulmonary arterial blood flow through the use of VA ECMO could worsen parenchymal ischemia. This concept has been debated, and some centers still prefer use of VA ECMO to minimize reperfusion injury. Clearly, multicenter prospective analyses should be considered.

When considering prolonged support (more than 5 to 7 days), VV ECMO may again be preferable to VA ECMO because of the additional thromboembolic and vascular complications accompanying prolonged support. We were able to maintain patients on VV ECMO for as long as 20 days with adequate oxygenation and the absence of evident vascular or thromboembolic complications. The longest supports on VA and VV ECMO were 11 and 20 days, respectively. The relevance of this is not clear, however, because the mean duration of support for patients able to be weaned from ECMO was comparable (4.5 days for the VA group and 6.1 days for the VV group). No patients on ECMO support for longer than 14 days were successfully weaned. Therefore, in light of these results, the futility of support longer than 14 days must be considered in patients with acute PGD unless retransplantation is considered. Thus, although VV ECMO presents no clear benefit in post-ECMO survival, its use simplifies the technical aspects of ECMO implementation and will likely decrease the number of thromboembolic and vascular complications, especially when prolonged support is considered.

The main causes of early mortality in our patients were severe and permanent graft failure and associated infection (bacterial and fungal), which corroborates the importance of the initial lung injury and the detrimental effect of prolonged extracorporeal circulation (ECMO) in severely immunosuppressed patients. Both bacterial and fungal infection (including invasive Aspergillus) were significant causes of mortality during the initial experience (before 2000). Fortunately, adequate prophylaxis with antifungal and broad-spectrum antibiotics has limited these deleterious effects.

Our data suggest that although 67% of patients can be weaned from ECMO support, a subset of these weaned patients will continue to have progressive lung dysfunction. However, the mortality of this group of patients may be most significant early after transplant affecting 20% of the weaned group in the first month, which suggests that after this initial period, the surviving patients are likely to continue on a course similar to that of patients not requiring ECMO support. Accordingly, lung function 1 and 2 years after the transplant did not differ in the patients who had received ECMO compared with rest of the lung transplants performed in our institution. This dichotomy is clearly an interesting area for further investigation.

Limitations of this study include the retrospective nature of the analysis, the inclusion of patients during different periods of the program with modifications in immunosuppression and surgical management, and the inclusion of patients in which a combination of initial VA ECMO with later conversion to VV ECMO was used (5 patients). A carefully designed, prospective, multicenter study would allow more definitive conclusions as to the short- and long-term results of the use of ECMO in PGD.

In conclusion, we have demonstrated that ECMO support used for early PGD is a useful resource with the potential to allow allograft recovery, and it is associated with acceptable survival and complication rates. Although the overall mortality of patients with severe PGD requiring ECMO support is higher than that of other lung transplant recipients, patients who survive and recover from the initial insult of PGD and ECMO are likely to have adequate long-term survival and comparable organ function.

	Acknowledgments

Top Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
We thank Julie Buchanan and Shannon Wyszomierski for support with the data collection and manuscript preparation.

	References

Top Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Christian A. Bermudez Prasad S. Adusumilli Kenneth R. McCurry Yoshiya Toyoda Permission Requests Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Bermudez, C. A. Articles by Toyoda, Y. Search for Related Content PubMed Articles by Bermudez, C. A. Articles by Toyoda, Y. Related Collections Lung - transplantation