Ann Thorac Surg 2006;82:1998-2002
© 2006 The Society of Thoracic Surgeons
Original Articles: General Thoracic
Differential Pulmonary Vein Gases Predict Primary Graft Dysfunction
Phil Botha, MRCS*,
Dipesh Trivedi, FRCS,
Cait P. Searl, FRCA,
Paul A. Corris, FRCP,
Stephan V.B. Schueler, FRCS,
John H. Dark, FETCS
Department of Cardiopulmonary Transplantation, Freeman Hospital, High Heaton, Newcastle upon Tyne, United Kingdom
Accepted for publication July 13, 2006.
* Address correspondence to Dr Botha, Department of Cardiopulmonary Transplantation, Freeman Hospital, Newcastle upon Tyne, NE7 7DN, United Kingdom (Email: p.botha{at}ncl.ac.uk).
Presented at the Poster Session of the Forty-second Annual Meeting of The Society of Thoracic Surgeons, Chicago, IL, Jan 30–Feb 1, 2006.
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Abstract
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BACKGROUND: Donor arterial blood gas measurements correlate poorly with lung allograft function in the recipient. We assessed the utility of reduced pulmonary vein gas (PVG) partial pressure of oxygen (PO
2) in predicting the incidence of primary graft dysfunction.
METHODS: While the donor was ventilated with 100% oxygen, superior and inferior pulmonary veins were directly aspirated bilaterally and pulmonary venous PO
2 measured. A PO
2 of less than 300 mm Hg was considered subnormal. These values were assessed for predictive value in terms of primary graft dysfunction in univariate and multivariate analysis.
RESULTS: In 112 of the 201 lung and heart-lung transplants performed during the period January 2000 to December 2004, full PVGs were available for analysis. The number of pulmonary veins with sub-normal PVG correlated significantly with the incidence of severe primary graft dysfunction posttransplant in univariate (p = 0.01) and multivariate analysis (hazard ratio 2.35, p = 0.016). When analyzed separately, this correlation remained significant for recipients of single or bilateral transplants alone. No correlation existed between arterial PO
2 at donor referral and incidence of primary graft dysfunction. Median duration of ventilation, intensive care unit stay, and 30-day and 90-day mortality were not significantly different for those with any subnormal PVG compared with those with all values in the normal range.
CONCLUSIONS: Differential PVGs are a useful tool in the assessment of donor lung function before procurement. It is a helpful indicator of whether preischemic dysfunction is localized or diffuse, and can be used to predict the extent to which ischemia and reperfusion will exacerbate any existing abnormality.
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Introduction
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he shortage of suitable donor organs continues to limit the benefit derived from lung transplantation. This shortage has resulted in an ever-expanding waiting list, and as a consequence, increasing waiting list mortality [1]. Attempts at increasing organ donation rates have been largely unsuccessful and, as a result, only the improved use of the available donor pool promises to relieve shortages to some extent in the near future. Conservative donor acceptance criteria were developed in the early era of lung transplantation based on good sense principles and the drive to improve outcomes. Many units have, however, out of necessity gradually relaxed these criteria and demonstrated that this can be done without an adverse effect on outcome [2]. More recently, however, it has been demonstrated that if the limits of donor acceptability are extended too far results will suffer [3, 4]. An objective measure of donor lung function at the time of retrieval is therefore needed to facilitate the relaxation of donor acceptability criteria within safe limits.
Only one of the original "standard" donor criteria [5], arterial partial pressure of oxygen (PO
2) on 100% inspired oxygen fraction and a positive end-expiratory pressure of 5 cm H2O, attempts to provide an objective measure of lung function at the time of organ procurement. Evidence for a predictive value in terms of graft function and outcome has, however, been conflicting, with many series failing to show any adverse effect from the use of donor lungs with an arterial PO
2 less than 300 [6, 7]. Donor management has also been shown to impact arterial PO
2, with a significant proportion of donors’ blood gases being brought into the acceptable range by donor optimization maneuvers [8]. Results from subsequent transplantation of these lungs have been similar to those with PO
2 within the acceptable range at the time of referral. The separate measurement of pulmonary vein PO
2 at the superior-inferior vein or confluence has been suggested to correlate better with graft function and allow expansion of the donor pool [9]. We sought to validate this practice by retrospective analysis of outcomes in a cohort with pulmonary vein gas (PVG) partial pressure of oxygen to fraction of inspired oxygen (PO
2/FIO
2) ratio less than 300 mm Hg after donor optimization, correlating this to the incidence primary graft dysfunction and other measures of outcome.
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Material and Methods
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A retrospective review of donor datasheets, case notes, and intensive care data of all lung transplants performed between January 2000 and December 2004 was undertaken. The Newcastle Hospitals ethics committee waived the need for individual patient consent and formal ethical review. Donor organ procurement in the United Kingdom is performed by the regional transplant center and therefore practices vary. Our assessment of donor acceptability has taken into account age, smoking history, chest X-ray findings, arterial PO
2 at referral, and findings at bronchoscopy. It has additionally been our practice to measure, routinely, pulmonary venous gases in all potential donors after donor optimization. This included hemodynamic optimization, flexible bronchoscopy with bronchial toilet, and optimization of ventilation strategy. Immediately before lung procurement at the time of organ inspection, careful manual ventilation was performed to expand areas of atelectasis. The donor was then returned to mechanical ventilation with a FIO
2 of 100% and positive end-expiratory pressure (PEEP) of 5 cm H2O, and superior and inferior pulmonary veins directly sampled by 21 gauge needle bilaterally. Pulmonary vein gases were analyzed using an i-Stat hand-held analyzer (Abbott Laboratories, Abbott, IL). Lungs with any PVG less than 300 mm Hg ("low PVG" group) were considered marginal, but used for transplantation if acceptable in other respects. For single lung transplants, only the PVGs of the transplanted lung were correlated with outcome. Pulmonary preservation by an antegrade flush of 60 mL/kg Perfadex (Vitrolife, Kungsbacka, Sweden) was followed by a retrograde flush with the same solution were performed by our retrieval team. Preservation techniques employed by other centers included Perfadex, Euro-Collins, and Papworth solutions as well as core cooling. Cardiopulmonary bypass was used routinely for heart-lung and bilateral lung transplantation, and for single lung transplantation only when necessitated by gas exchange. Primary graft dysfunction was scored by review of chest X-rays and arterial blood gases in line with the International Society for Heart and Lung Transplantation working group on primary graft dysfunction guidelines [10]. Severe primary graft dysfunction was defined as a PO
2/FIO
2 ratio less than 200 mm Hg with diffuse radiographic infiltrates consistent with pulmonary edema at arrival on the intensive care unit (ICU) or 24, 48, or 72 hours posttransplant. Additionally, those requiring mechanical ventilation with an FIO
2 greater than 0.5 or inhaled nitric oxide beyond 48 hours were also included in the severe (grade 3) primary graft dysfunction group. Additional outcome measures analyzed were duration of ventilation, ICU stay, and 30-day and 90-day mortality.
Statistical Analysis
Categoric data are presented as number followed by percentage in brackets and analyzed by the 
2 test. Continuous data are presented as mean ± standard deviation and analyzed by an unpaired t test if normally distributed. Nonparametric data are presented as median ± 95% confidence interval (CI) and analyzed by the Mann-Whitney U test. Multivariate models were constructed by forward stepwise inclusion of all variables with a p value less than 0.09 or of particular clinical relevance. Validity was assessed by backward stepwise exclusion with assessment of contribution to the model. All analyses were performed using SPSS version12.0 (SPSS Inc, Chicago, IL).
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Results
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A total of 1,501 lung offers were received during the study period. Of these, 285 were assessed by our own retrieval team and 88 by retrieval teams from other centers. Two hundred and one lung and heart-lung transplants were performed at our center and 63 organs exported to other transplant units (17.6% procurement rate). Full PVG and outcome data were available for 112 of the 201 transplantations performed at our center. This group included 37 single lung, 65 bilateral lung, and 10 heart-lung transplants (187 lungs). One hundred and thirty-three (71%) of these transplanted organs had been procured by our own retrieval team. A total of 374 PVG measurements were therefore made in lungs used for transplantation. Of these, 41 (11%) were below the threshold of 300 mm Hg. The PVG in transplanted lungs ranged from 68 to 713 mm Hg. The lowest PVG in each transplanted lung ranged from 68 to 615 mm Hg (mean, 367.17 ± 110.99). Thirty (27%) recipients received lungs from a donor with at least one PVG less than 300 mm Hg. Twenty-one (19%) donors had one subnormal PVG, 7 (6%) had two, and 2 (2%) had three PVG below the 300 mm Hg limit. Further donor demographics are listed in Table 1.
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Table 1. Donor Demographics in "Normal" Group With All Pulmonary Vein Gases (PVG) Greater than 300 mm Hg and "Low PVG" Group With One or More PVG Less Than 300 mm Hg
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The preservation method (Perfadex versus non-Perfadex) did not differ significantly between the "normal" and "low PVG" groups (80% vs 82%, respectively, p = 0.87). Ischemic times were also not significantly different between the "normal" and "low PVG" groups 315.5 (± 62.7 minutes) versus 329.7 (± 77.8 minutes), p = 0.35). Recipient demographics are listed in Table 2.
Twenty-two (27%) of patients in the "normal" group, and 16 (53%) of patients in the "low PVG" group suffered severe (grade 3) primary graft dysfunction (p = 0.009). The number of pulmonary veins with subnormal PVG (<300 mm Hg) correlated significantly with the incidence of severe PGD posttransplant (p = 0.01) (Fig 1). This correlation remained significant for recipients of single or bilateral transplants when analyzed separately (Fig 2). Mean arterial PO
2 at the time of referral was similar in groups suffering severe PGD or not (456.8 ± 88.9 mm Hg vs 466.5 ± 91.4 mm Hg, p = 0.6) and correlated poorly with the lowest PVG in transplanted lungs (Fig 3). The lowest PVG in transplanted lungs correlated significantly with the PO
2/FIO
2 ratio in the ipsilateral pulmonary vein. In univariate analysis, donor age (p = 0.005) and PVG less than 300 mm Hg (p = 0.007) showed significant predictive value for PGD. Multivariate regression analysis included these variables, and also arterial PO
2/FIO
2 at referral, smoking history, donor chest X-ray abnormality, preservation method, ischemic time, and use of cardiopulmonary bypass. In this analysis only donor age (p = 0.005), PVG less than 300 mm Hg (p = 0.016), and donor smoking greater than 20 cigarettes per day (p = 0.05) were significant predictors of PGD. Median duration of ventilation and ICU stay for those with at least one subnormal PVG was 37.5 hours and 4 days, respectively, compared with 28 hours and 2 days in those with all values in the normal range (not significant). There was no statistical difference in 30-day mortality (13.8% vs 6.3%, p = 0.34) and 90-day mortality (16.3% vs 12.5%, p = 0.77) in those with normal and subnormal PVG, respectively.
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Fig 1. General correlation between the number of pulmonary veins with partial pressure of oxygen (PO
2) less than 300 mm Hg in the donor and the incidence of primary graft dysfunction (PGD; p = 0.01). Only pulmonary vein gases of transplanted lungs were included in the analysis.
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Fig 3. Scatter plot demonstrating the poor correlation between arterial partial pressure of oxygen to fraction of inspired oxygen PO
2/FIO
2 ratio at referral and the lowest pulmonary vein gas (PVG) PO
2/FIO
2 ratio in each transplanted lung.
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Comment
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Harjula and colleagues [11] were the first to document death from lung failure after transplantation of lungs from a donor with a PO
2/FIO
2 ratio (P/F) of less than 250 mm Hg, prompting due caution. This level of gas exchange also falls below that of the consensus definition of acute lung injury and would therefore seem an appropriate prudence. The subsequent literature demonstrates a gradual progression of acceptance of donors with increasingly low arterial PO
2 but until recently, series have contained relatively small numbers with low oxygenation and it has often been unclear as to whether initial (referral) PO
2 or the preretrieval figures are quoted. Before 1995, Shumway and colleagues [12] documented successful outcomes with 25 marginal donors, including one with a P/F ratio of less than 350 and the series of Sundaresan and colleagues [6] included 6 patients with a P/F less than 300. Gabbay and colleagues [8] demonstrated that donor optimization can improve the oxygenation in a significant proportion of donors and also that the initial P/F before optimization did not predict poor outcome if donor management resulted in a ratio greater than 300. In 2005, Lardinois and colleagues [7] documented experience with 63 marginal donors including 15 with a PO
2 less than 300. Eight of these donors had a PO
2 of less than 250 and 30-day survival was 87.5% in this group; one patient dying from acute organ failure after severe reperfusion injury. Thabut and colleagues [13] reported on the French multicenter experience with 77 donors with a P/F ratio between 300 and 350 and 34 donors with a P/F below 300. These values were determined at organ offer in the ICU with no analysis of the impact of donor optimization. Theirs is the first series to demonstrate significantly poorer gas exchange within the first six hours posttransplant, prolonged mechanical ventilation, and decreased long-term survival when corrected for recipient age, recipient diagnosis, and ischemic time. Similarly, Pilcher and colleagues [14] demonstrated a correlation between low donor P/F and the lowest recipient P/F in the first 24 hours posttransplant by multivariate analysis of a cohort of 128. Luckraz and colleagues [15] analyzed 300 heart-lung and 62 double lung transplants in a single institution and found a higher 30-day but not higher overall mortality in the group of 52 with a donor P/F ratio between 225 and 300.
Puskas and colleagues [16] first described a technique of single lung ventilation and pulmonary artery clamping for the assessment of single lung function where one lung is clearly unsuitable due to aspiration or consolidation. It was demonstrated that if arterial PO2 improved with this maneuver, single lung transplantation could be undertaken using this lung with excellent results. El-Gamel and colleagues [17] were the first to describe the use of selective pulmonary vein sampling and gas analysis in donor assessment. They went on to demonstrate that the donor pool could be significantly extended with good results by using donors with a subnormal arterial PO
2 at referral, but all PVG within normal range [9]. More recently, McGiffin and colleagues [18] demonstrated the superiority of unilateral pulmonary vein confluence gases over arterial PO
2 in predicting outcome. They recommended this should form an integral part of lung donor assessment, especially where unilateral abnormality exists on chest X-ray.
This study documents a correlation between low PVG before procurement and posttransplant graft function. We have demonstrated a direct correlation between both the presence of any PVGs below 300 mm Hg and the number of subnormal PVGs with the incidence of PGD in univariate and multivariate analysis. Arterial PO
2/FIO
2 ratio at the time of referral correlated poorly with PVG and was not a significant predictor of PGD in multivariate analysis. We have chosen to perform individual inferior and superior PVGs to minimize the possibility of pulmonary venous admixture in the left atrium influencing the results. Our analysis of the correlation between the lowest PVG in transplanted lungs and the PVG in the ipsilateral pulmonary vein demonstrated a statistically significant correlation. Although statistically significant, the wide confidence interval of this correlation demonstrated in Figure 4
reflects the clinical reality of an occasional wide discrepancy between upper and lower PVG. Our analysis suggests that atelectasis, neurogenic edema, aspiration, or other causes of dysfunction in an isolated section of the lung may be revealed by individual vein gas measurements and predict the occurrence of PGD.
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Fig 4. Scatter plot demonstrating the correlation between the lowest pulmonary vein gas (PVG) PO
2/FIO
2 ratio and the PO
2/FIO
2 ratio in the ipsilateral pulmonary vein. Best-fit linear regression with 95% confidence interval. (y = 188.57 + 0.71x; PO
2/FIO
2 = partial pressure of oxygen to fraction of inspired oxygen.)
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Although the influence of subnormal PVG on duration of ventilation and ICU stay did not reach significance, a trend toward an increase in both was observed. Early mortality was not significantly different in the groups with all-normal or at least one subnormal PVG. The apparent higher early mortality in the group with normal PVG should not be interpreted as a trend toward the significant in a cohort of this size. The group included several patients who died from causes unrelated to early graft function, which may be misleading. The main limitations of our study are its small numbers and retrospective nature. Our overall rate of severe PGD has been higher than expected due to a highly sensitive PGD definition, which includes all patients meeting the criteria for grade 3 PGD at any of the analyzed time-points within 72 hours posttransplant. Some selection bias may also exist as only 112 of 201 patients during the study period had full PVG data available. It is conceivable the sampling of pulmonary veins may have been omitted in more patients with excellent gas exchange as reflected in arterial PO
2 and where no suggestion of unilateral dysfunction existed on X-ray. It has previously been demonstrated that PVG analysis is an effective way of increasing the use of the existing donor pool. It represents a simple method for assessing unilateral lung function and can increase the availability of single lungs from otherwise unpromising donors. Although the transplantation of lungs with PVG below 300 mm Hg resulted in an increased incidence of PGD, this may well be acceptable in the face of increasing waiting list mortality.
Conclusion
Differential PVGs are a useful tool in the assessment of donor lung function before procurement. It is a helpful indicator of whether preischemic dysfunction is localized or diffuse and can be used to predict the extent to which ischemia and reperfusion will exacerbate any existing abnormality.
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Acknowledgments
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The authors would like to express their gratitude to Dr Tom Chadwick of the Newcastle University Department of Mathematics and Statistics for his advice on the statistical analyses performed in this manuscript.
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References
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- Pierson RN, Barr ML, McCullough KP, et al. Thoracic organ transplantation Am J Transplant 2004;4:93-105.
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Abstract
Introduction
= single; 
= bilateral.)