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J Thorac Cardiovasc Surg 2006;131:73-80
© 2006 The American Association for Thoracic Surgery
General Thoracic Surgery |
University of Minnesota, Department of Surgery, Division of Cardiovascular and Thoracic Surgery, Minneapolis, Minn.
Read at the Eighty-fifth Annual Meeting of The American Association for Thoracic Surgery, San Francisco, Calif, April 10-13, 2005.
Received for publication June 14, 2005; revisions received October 12, 2005; accepted for publication October 25, 2005. * Address for reprints: Peter S. Dahlberg, MD, PhD, University of Minnesota, MMC 207, 420 Delaware St SE, Minneapolis, MN 55455. (Email: dahlb002{at}umn.edu).
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Abstract |
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METHODS: We reviewed donor and recipient medical records of 402 consecutive lung transplantations performed between 1992 and 2004. We calculated a worst International Society for Heart and Lung Transplantation primary graft dysfunction grade in the first 48 hours postoperatively. Severe primary graft dysfunction (International Society for Heart and Lung Transplantation grade 3) was defined by a ratio of arterial oxygen to fraction of inspired oxygen of less than 200. Associations of potential risk factors with grade 3 primary graft dysfunction in the first 48 hours postoperatively were examined through bivariate and multivariate analysis.
RESULTS: The 90-day mortality rate associated with the development of International Society for Heart and Lung Transplantation grade 3 primary graft dysfunction in the first 48 hours postoperatively was 17% versus 9% in the group without grade 3 primary graft dysfunction. Significant bivariate risk factors associated with this end point were increasing donor age, donor smoking history of more than 10 pack-years, early transplantation era (1992-1998), increasing preoperative recipient pulmonary artery pressure, and recipient diagnosis. In the multivariate analysis only recipient pulmonary artery pressure, donor age, and transplantation era were associated with grade 3 primary graft dysfunction in the first 48 hours postoperatively at a P value of less than .05.
CONCLUSIONS: Our analysis of donor and recipient risk factors for severe primary graft dysfunction identified patient groups at high risk for poor outcomes after lung transplantation that might benefit from treatments aimed at reducing reperfusion injury.
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Introduction |
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Reported 30-day mortality rates of patients with severe PGD are nearly 8 times as high as those for patients without severe PGD.
2
A classification system for PGD based on the measured partial pressure of arterial oxygen to fraction of inspired oxygen ratio (P/F ratio) has recently been proposed by an International Society for Heart and Lung Transplantation (ISHLT) working group.
3
It has many features in common with the American European Consensus Conference definition of acute respiratory distress syndrome.
4
Patients with the most severe PGD grade (ISHLT grade 3) have decreased perioperative survival, an increased rate of perioperative complications, and an increased length of hospital stay.
1-3
Other measures of PGD, such as oxygenation index or lung compliance, might have added prognostic utility, but these have not been validated in reports of large series of patients.
5-11
The purpose of this study was to identify donor and recipient characteristics that were associated with the development of ISHLT grade 3 PGD in the first 48 hours after lung transplantation.
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Methods |
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Transplant Criteria and Immunosuppression
The lung transplantation protocol at our institution, including details of organ retrieval, operative technique, and postoperative immunosuppression, has been previously reported.
12-14
The majority of patients received cyclosporine {INN: ciclosporin], prednisone, and azathioprine; however, the substitution of newer immunosuppressants, such as mycophenolate mofetil and tacrolimus, to the regimen of some recipients took place during the time period under review. Induction therapy was not used in our program during the study period.
At our institution, we have only offered transplantations to patients younger than 65 years of age at the time of their first evaluation. Other relative contraindications include significant concurrent medical illnesses (ie, hepatic disease with portal hypertension or coronary artery disease) that would limit survival, rehabilitation, or both; chronic high-dose steroid use (>20 mg of prednisone per day); and a diagnosis of a rheumatologic disease.
Assignment of ISHLT PGD Grades
Patients were assigned to PGD grades 1 through 3 on the basis of guidelines issued by a 2004 ISHLT working group conference on the subject (Figure 1). We made 2 changes to the ISHLT grading system for the purposes of our analysis (Table 1). First, the original grading system proposed including a fifth time point for grading PGD severity 72 hours after transplantation (T72). Second, any patient with a P/F ratio of greater than 300 was classified as having grade 1 PGD. We did not analyze their chest radiographs for the presence or absence of infiltrates. Time points chosen for analysis were at intensive care unit arrival (T0) and 12 hours (T12), 24 hours (T24), and 48 hours after transplantation (T48). The worst grade at T(0-48) reflected the most severe grade recorded during the 48-hour period.
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As a result of this finding, patients were stratified into 2 primary outcome groups for study: those who did and those who did not have modified ISHLT grade 3 PGD within the first 48 hours after the transplantation. To be placed in the favorable group on the basis of extubation (one of the definition's criteria), the patient had to remain extubated for 48 hours. Patients requiring extracorporeal membrane oxygenation support (23/402 [6%] of patients) were automatically classified as having grade 3 PGD.
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2 test for nominal and ordinal data or the independent sample t test for continuous variables. Analyses were performed with SAS for Windows, Version 9.1 (SAS Institute Inc, Cary, NC).
Donor and patient characteristics that were statistically significantly related to severe PGD (P < .100) were tested for inclusion in the final multivariate analysis. Multivariate logistic regression was used to adjust for potential confounding. Characteristics were introduced stepwise in the following order: demographic and personal characteristics, pulmonary arterial pressures/ISHLT grade, and donor characteristics. The final model included donor and patient characteristics that were independently and statistically associated (P < .05) with severe PGD. Final results were expressed as multivariate odds ratios and 95% confidence intervals. The odds ratios can be interpreted as the increased or decreased odds of grade 3 PGD, with those with the characteristic compared with the odds of the event in those without the characteristic (the reference category). The c-statistic was used to measure the discrimination of the final model. Values approaching 0.70 or greater were considered the minimum necessary for a sound model. The Hosmer-Lemeshow test for goodness of fit was used to measure the calibration of the final model. A statistically nonsignificant 2 test result is accepted for adequate agreement between the observed and expected events.
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Results |
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The occurrence of severe PGD (modified ISHLT grade 3) within the first 48 hours after transplantation was also associated with a decreased long-term survival (Figure 2). Increasing preoperative pulmonary artery pressure, an SLT procedure, and the need for cardiopulmonary bypass during the transplantation were other independent predictors of these end points in this group of patients.
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Donor Characteristics
Reliable donor data were available on sex, age, height and weight, year of transplantation, type of procedure, days on ventilator, CMV status, mechanism of death, arterial blood gases, smoking history, ischemic times, bronchoscopic findings, and Gram stain results. All of these characteristics were examined for their bivariate associations with the development of severe PGD (Table 3). Donor age, a history of smoking of greater than 10 pack-years, and a transplantation occurring in the earlier era of the study (1992-1998) were associated with the end point at a P value of less than .05.
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Multivariate Model
Donor and recipient characteristics associated with the development of severe PGD in the respective bivariate models were entered as potential risk factors in a multivariate logistic regression model. The performances of the transplantation in the earlier era of the study (1992-1998), increasing donor age, and increasing recipient preoperative pulmonary artery pressure were independently associated with the end point of severe PGD (Table 4). A graphic display of the multivariate adjusted odds of severe PGD according to donor age and preoperative pulmonary artery pressure is shown in Figure 3. There is an inflection of the donor age risk curve at approximately 30 years of age and in the pulmonary artery pressure curve at a mean pressure of 30 mm Hg.
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Discussion |
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The identification of risk factors associated with the development of severe PGD is important for several reasons. Their modification might be effective in reducing the rate of development of severe PGD. Donor-recipient matching might also be improved. Many centers have begun to use marginal or extended donors after several reports suggesting that the practice was not associated with excessive early mortality rates.
14,18-21
Pierre and colleagues,
21
however, have recommended that caution be exercised in the widespread application of these modified donor criteria, which include donor age greater than 55 years, smoking history of longer than 20 pack-years, bronchoscopic findings of purulent secretions, the presence of infiltrates on the chest radiograph, and a PO
2 of less than 300 mm Hg. In our series increasing donor age and smoking history were both associated with increased rates of PGD, although the 10 pack-year smoking history breakpoint did not achieve the level of statistical significance in the multivariate model. The rate of development of grade 3 PGD within the first 48 hours for the 26 patients in the series who received lungs from donors with a greater than 20 pack-year history was 52%.
The transplantation of lungs from donors older than 50 years does appear to be associated with very high risks of grade 3 PGD (Figure 3). In fact, the relationship between the odds of development of grade 3 PGD and donor age in our series is linear from about age 35 years upward, a trend very similar to that found in the analysis of other series and of ISHLT registry data with respect to longer-term mortality.
3
The most favorable recipient outcomes seem to be associated with donors between 20 and 30 years of age.
Our program has been conservative with respect to our acceptance of marginal donors by other criteria outlined by Pierre and colleagues.
21
Very few donors had arterial blood gas PO
2 values of less than 300 mm Hg, only 11% of donor lungs had an infiltrate on the chest radiograph, and only 6% had significant purulent bronchoscopic secretions. None of these characteristics were significantly associated with the development of grade 3 PGD in our series. A positive Gram stain result was reported in 143 (49%) of 289 donors for whom data were available. There was no difference in the rate of development of grade 3 PGD among recipients receiving lungs from a donor with a positive or a negative Gram stain result, although the vast majority of these patients had only 1+ gram-positive organisms identified on the test.
Our analysis has several limitations. First, we choose to analyze only one of many possible end points that reflect the development of severe PGD in a patient after a transplantation. Other choices incorporating the 72-hour time measurements or the associated chest radiographic findings might have additional discriminate validity with respect to early or longer-term patient outcomes. The optimal indicator of PGD will likely be identified once the working group definition is published and transplant centers have had the opportunity to validate the predictive power of its various components. Because severe PGD occurs with a greater frequency than death and is associated with a poor short- and long-term outcome, the analysis of this end point in clinical care and in clinical trials is warranted. We believe that because severe PGD is associated with a poor outcome, the analysis of risks of severe PGD, rather than mortality, would be more predictive.
In summary, the development of severe (modified ISHLT grade 3) PGD is associated with a high operative mortality and a poor long-term survival. The incidence of severe PGD in our program has decreased over time. In a multivariate analysis, additional risk factors for grade 3 PGD development within the first 48 hours after transplantation (one measure of PGD) are (1) an increased preoperative pulmonary artery pressure and (2) an increasing donor age. Identification of at-risk patients and selective management through altered strategies of ventilation to reduce airway pressure, as in ARDS, or with ß-blockade to limit perfusion, with pharmacologic agents to reduce ischemia-reperfusion injury, or with extracorporeal membrane oxygenation to allow the lungs a period of low-perfusion recovery might ultimately improve the outcomes of patients undergoing pulmonary transplantation.
9,12
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Discussion |
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The International Society for Heart and Lung Transplantation Pulmonary Council Working Group, under the direction of Dirk Van Raemdonck and Jason Christie, have developed and will soon publish in the Journal of Heart and Lung Transplantation a standardized definition of PGD, which was referred to here today. This report by the Minnesota group is an effort to use the new definition to identify risk factors for the development of PGD.
I have a couple of questions. I do not know that you referred to this specifically in your presentation, but in the article you eliminated donor radiograph or graft radiograph review. There is no comment in your article about radiographic infiltrates. Can you explain why that is?
Dr Whitson. Well, that is used in the ISHLT criteria. In our analysis, or at least when the data were initially collected, the chest radiographic reports were not initially looked at. We reviewed a small number of patients who had a P/F ratio that was greater than 300 and looked at their infiltrates, and looking at the outcomes for their long-term survival, whether it was by grade 0 or grade 1, it did not seem to have a difference, and therefore we lumped them together, partly because those data had not been collected, looking back at it. When we looked at the survival, both short-term and long-term survival, their stratification is on whether they did or did not have grade 3 PGD, and the chest radiograph was not included in the grade 3 definition. Therefore we did not go back and pull those.
Dr Patterson. You have demonstrated quite clearly that the incidence of reperfusion injury or PGD is decreasing over time. There is a clear difference in your own experience with respect to its incidence in the former era and the more recent era. Surely that has to be a surrogate marker for technical changes. Can you make any specific comments about your perfusion strategy or your flush strategy, your inflation strategy, and how that has changed in those 2 intervals of time?
Dr Whitson. Over those 13 years, we have essentially kept the technical aspects the same. We have used antegrade perfusion. In 2001, we switched from Euro-Collins to Perfadex for the perfusion solution.
Dr Patterson. Do you not use retrograde flush in your preservation strategy?
Dr Whitson. No.
Dr Patterson. The other question I have—and I am not a statistician—but you have examined many possible risk factors, both donor and recipient risk factors. Close to 30 separate risk factors were studied. It seems to me that by chance alone you are going to identify something that is significant and predictive. Specifically with regard to cardiopulmonary bypass, it seems to me that your use of cardiopulmonary bypass is really quite high, certainly higher than it is in our own institution, particularly because you use a single-lung transplantation as an operative strategy in quite a few, in almost half of your patients or perhaps more, and therefore it is not clear to me whether cardiopulmonary bypass is actually a risk factor or whether it is a result. In our program we use cardiopulmonary bypass most frequently when we have failure of the initial graft, and therefore we have already got graft dysfunction before bypass is used. Can you comment?
Dr Whitson. You are correct that the more risk factors that are analyzed the more likely it is that a type I error will be made. We only analyzed risk factors that made sense clinically, and reasonable arguments can be made for why each of those significant in the multivariate analysis could cause early graft dysfunction. Bypass was used in 12% of single lung procedures and in 60% of bilateral single transplants. The usual indications were significant adhesions or pulmonary hypertension and to some extent surgeon preference, especially in the bilateral transplants.
Dr R. Duane Davis, Jr (Durham, NC). I want to follow up a little bit on what Alec had asked you. Does your group have a strategy for the reperfusion of the recipient, or is it just kind of unclamp and go?
Dr Whitson. Thank you, Dr Davis. We avoid using 100% FIO 2 and high inspiratory tidal volumes when reinflating the lung. More recently, we have used beta blockade in selective circumstances to limit unnecessarily high cardiac outputs. If patients are on cardiopulmonary bypass, we let the heart fill slowly and cut back the flow rate over a 10-minute period. As for the clamps, they are released gradually over a 5- to 10-minute period.
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