Practical approach to patients presenting with multiple synchronous suspect lung lesions: a reflection on the current TNM classification based on 54 cases with complete follow-up.

OBJECTIVES: To examine the survival after surgical treatment of patients presenting with two synchronous suspect lung lesions, and to reflect on the recent TNM classification, which has upgraded patients with two malignant lung lesions of the same histology into the T4 (both lesions in the same ipsilateral lobe) or M1 (different lobes or lungs) category. METHODS: Retrieval of all consecutive patients with a diagnosis of two synchronous suspect lung lesions in the prospective database of the Leuven Lung Cancer Group in the interval between 1990 and 1994. Analysis of characteristics and survival of all patients, who underwent surgical resection with intention to cure for both lesions. RESULTS: Forty-eight of 54 patients had surgical resection with curative intent. Thirty-five of these proved to have two malignant lesions, in 13 the second lesion was benign. The 5-year survival rate in the patients with two malignant lesions was 33% (95% CI: 17-49). The median survival time was 28 months. Although the number of patients in the subgroups was small, there were no obvious differences between patients with two lesions in the same or in different lobes, if a complete resection could be achieved. CONCLUSIONS: An aggressive surgical approach in carefully selected patients presenting with two suspect pulmonary lesions can be rewarding. Although some degree of upstaging is appropriate in patients with two malignant lung tumours of the same histology, their current stage IIIB or IV classification probably underestimates their prospects for long-term survival after radical resection.

The impact of (18)F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) lymph node staging on the radiation treatment volumes in patients with non-small cell lung cancer.

PURPOSE: (18)F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) combined with computer tomography (PET-CT) is superior to CT alone in mediastinal lymph node (LN) staging in non-small cell lung cancer (NSCLC). We studied the potential impact of this non-invasive LN staging procedure on the radiation treatment plan of patients with NSCLC. PATIENTS AND METHODS: The imaging and surgical pathology data from 105 patients included in two previously published prospective LN staging protocols form the basis for the present analysis. For 73 of these patients, with positive LN's on CT and/or on PET, a theoretical study was performed in which for each patient the gross tumour volume (GTV) was defined based on CT and on PET-CT data. For each GTV, the completeness of tumour coverage was assessed, using the available surgical pathology data as gold standard. A more detailed analysis was done for the first ten consecutive patients in whom the PET-CT-GTV was smaller than the CT-GTV. Theoretical radiation treatment plans were constructed based on both CT-GTV and PET-CT-GTV. Dose-volume histograms for the planning target volume (PTV), for the total lung volume and the lung volume receiving more than 20 Gy (V(lung(20))), were calculated. RESULTS: Data from 988 assessed LN stations were available. In the subgroup of 73 patients with CT or PET positive LN's, tumour coverage improved from 75% when the CT-GTV was used to 89% with the PET-CT-GTV (P=0.005). In 45 patients (62%) the information obtained from PET would have led to a change of the treatment volumes. For the ten patients in the dosimetry study, the use of PET-CT to define the GTV, resulted in an average reduction of the PTV by 29+/-18% (+/-1 SD) (P=0.002) and of the V(lung(20)) of 27+/-18% (+/-1 SD) (P=0.001). CONCLUSION: In patients with NSCLC considered for curative radiation treatment, assessment of locoregional LN tumour extension by PET will improve tumour coverage, and in selected patients, will reduce the volume of normal tissues irradiated, and thus toxicity. This subgroup of patients could then become candidates for treatment intensification.

Prognostic importance of the standardized uptake value on (18)F-fluoro-2-deoxy-glucose-positron emission tomography scan in non-small-cell lung cancer: An analysis of 125 cases. Leuven Lung Cancer Group.

PURPOSE: The amount of radio-labeled (18)F-fluoro-2-deoxy-glucose (FDG) uptake, a measurement of the increased glucose metabolism of non-small-cell lung cancer (NSCLC) cells, has recently been correlated with proliferation capacity. The Standardized Uptake Value (SUV), a semi-quantitative measurement of FDG uptake on positron emission tomography (PET) scan, could thus be of prognostic significance. PATIENTS AND METHODS: We analyzed the follow-up of 125 potentially operable NSCLC patients, previously included in three of our prospective PET protocols. Performance status, maximal tumor diameter, tumor-cell type, SUV, and final staging were analyzed for their possible association with survival. RESULTS: Sixty-five patients had stage I or II NSCLC, 37 had stage IIIA, and 23 had stage IIIB. Treatment was complete resection in 91 cases. In a univariate analysis, performance status (P =.002), stage (P =.001), tumor diameter (P =.06), tumor-cell type (P =.03), and SUV greater than 7 (P =.001) were correlated with survival. For SUV, group dichotomy with a cut-off SUV of 7 had the best discriminative value for prognosis, both in the total and surgical cohort. A multivariate Cox analysis identified performance status (P =.02), stage (P =.01), and SUV (P =.007) as important for the prognosis. In the surgical group, patients with a resected tumor less than 3 cm had an expected 2-year survival of 86%, if the SUV was below 7, and 60%, if above 7. Nearly all resected tumors larger than 3 cm had SUV's greater than 7 and an expected 2-year survival of 43%. CONCLUSION: We conclude that the FDG uptake in primary NSCLC on PET has an important prognostic value and could be complementary to other well-known factors in the decision on adjuvant treatment protocols.

Potential use of FDG-PET scan after induction chemotherapy in surgically staged IIIa-N2 non-small-cell lung cancer: a prospective pilot study. The Leuven Lung Cancer Group.

BACKGROUND: Clearance of viable tumour cells in mediastinal lymph nodes (MLN) by induction chemotherapy (IC)--so-called MLN downstaging--is an important aspect of combined-modality treatment of N2-NSCLC. Reassessment of MLN after IC by CT is far from accurate, while re-mediastinoscopy is often technically difficult. Based on our previous results with FDG-PET in the initial staging of N2 disease, we investigated whether PET after IC could be helpful in predicting MLN downstaging and therapeutic outcome. PATIENTS AND METHODS: Patients underwent a first PET before IC. After three cycles of platinum-based IC, a second PET was performed before locoregional therapy, either surgery or radiotherapy. PET results were correlated with pathology of the MLN when available, and with survival. RESULTS: Fifteen surgically staged N2-NSCLC patients were prospectively included. Locoregional therapy after IC consisted of surgery in nine and radiotherapy in six. Correlation with pathology of the nine resection specimens revealed that the accuracy of PET in predicting MLN downstaging was 100% (six true negatives; three true positives), whereas for CT it was only 67% (two false pos; one false neg). Reassessment with PET after IC was correlated with the outcome after the entire combined modality treatment. Survival was significantly better in patients with mediastinal clearance (P = 0.01) or with a greater than 50% decrease in the Standardised Uptake Value (SUV) of the primary tumour (P = 0.03) after IC. CONCLUSIONS: Mediastinal PET after IC accurately assesses pathologic MLN downstaging in N2-NSCLC. The data suggest a possible correlation of early survival with mediastinal clearance and an important decrease of SUV in the primary tumour. Confirmation of these preliminary findings would establish PET as a useful non-invasive tool to select patients for intensive locoregional treatment after IC.

Warm ischemic tolerance in collapsed pulmonary grafts is limited to 1 hour.

OBJECTIVE: To determine the length of warm ischemic tolerance in pulmonary grafts from non-heart-beating donors. SUMMARY BACKGROUND DATA: If lungs could be retrieved for transplant after circulatory arrest, the shortage of donors might be significantly alleviated. Great concern, however, exists about the length of tolerable warm ischemia before cold preservation of pulmonary grafts retrieved from such non-heart-beating donors. METHODS: The authors compared the influence of an increasing postmortem interval on graft function in an isolated, room air-ventilated rabbit lung model during blood reperfusion up to 4 hours. Four groups of cadavers (four animals per group) were studied. In group 1, lungs were immediately reperfused. In the other groups, cadavers with lungs deflated were left at room temperature for 1 hour (group 2), 2 hours (group 3), or 4 hours (group 4). RESULTS: Pulmonary vascular resistance was enhanced in all ischemic groups compared with the control group. An increase was noted with longer postmortem intervals in peak airway pressure and in weight gain. A concomitant decline was observed in the venoarterial oxygen pressure gradient caused by progressive edema formation, as reflected by the wet-to-dry weight ratio at the end of reperfusion. CONCLUSIONS: Warm ischemia resulted in increased pulmonary vascular resistance. Graft function in lungs retrieved 1 hour after death was not significantly worse than in nonischemic lungs. Therefore, 60 minutes of warm ischemia with the lung collapsed may be tolerated before cold storage. Further studies are necessary to investigate whether lungs retrieved from non-heart-beating donors will become a realistic alternative for transplant.

FDG-PET scan in potentially operable non-small cell lung cancer: do anatometabolic PET-CT fusion images improve the localisation of regional lymph node metastases? The Leuven Lung Cancer Group.

Exact localisation of thoracic lymph nodes (LNs) on fluorine-18 fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) can be hampered by the paucity of anatomical landmarks. In non-small cell lung cancer (NSCLC) patients referred for locoregional LN staging, we prospectively examined to what extent localisation of LNs at PET reading could be improved by visual correlation with computed tomography (CT), or by anatometabolic PET+CT fusion images. Fifty-six patients with potentially operable NSCLC underwent CT, PET and surgical staging. Prospective reading was performed for CT, PET without CT, PET+CT visual correlation and PET+CT fusion. Reading was blinded to surgical pathology data and noted on a standard LN map. Surgical staging was available for 493 LN stations. In the evaluation per individual LN station, CT was accurate in 87%, PET in 91% and visual correlation and fusion in 93%. In the identification of the nodal stage, CT was correct in 28/56 patients (50%), PET in 37/56 (66%), visual correlation in 40/56 (71%), and fusion in 41/56 (73%). It is concluded that in the exact localisation of metastatic thoracic LNs, the accuracy of reading of PET is increased if the PET images can be visually correlated with CT images. PET+CT anatometabolic fusion images add only a marginal benefit compared with visual correlation.

Alveolar expansion itself but not continuous oxygen supply enhances postmortem preservation of pulmonary grafts.

OBJECTIVE: If lungs could be retrieved for transplant after circulatory arrest, the shortage of donors might be significantly alleviated. Great controversy still exists concerning the optimal mode of preservation of pulmonary grafts in these non-heart-beating donors. METHODS: Graft function was measured in an isolated room air-ventilated rabbit lung model during reperfusion with homologous, diluted (Hb +/- 8.0 g/dl) and deoxygenated (PaO2 +/- 40 mmHg) blood up to 4 h. Five groups of cadavers (n = 4 in each group) were studied: In the control group, lungs were immediately reperfused. In the other groups, cadavers were left at room temperature for 4 h after death with lungs either deflated (group 1), inflated with room air (group 2), or ventilated with room air (group 3) or 100% nitrogen (group 4). RESULTS: After 1 h of reperfusion, significant differences were noted between group 1 and groups 2, 3, and 4 in peak airway pressure (27 +/- 5 cm H2O vs. 15 +/- 1 cm H2O, 17 +/- 2 cm H2O, and 16 +/- 1 cm H2O, respectively; P < 0.05), in weight gain (137 +/- 24 vs. 31 +/- 7, 30 +/- 3, and 30 +/- 2%, respectively; P < 0.05), and in veno-arterial oxygen pressure gradient (9 +/- 5 vs. 95 +/- 13, 96 +/- 7 and 96 +/- 4 mmHg, respectively; P < 0.05). Also, wet-to-dry weight ratio at end of reperfusion was significantly different (10.2 +/- 1.0 vs. 6.0 +/- 0.3. 5.2 +/- 0.3 and 5.4 +/- 0.5, respectively; P < 0.05). No significant differences in any of these parameters were observed between groups 2, 3, and 4. CONCLUSIONS: These data suggest that: (1) pulmonary edema will develop in atelectatic lungs if reperfusion is delayed for 4 h after death; (2) postmortem room air-inflation is as good as ventilation in prolonging warm ischemic tolerance; (3) ventilation with room air is no different from that with nitrogen; (4) therefore, prevention of alveolar collapse appears to be the critical factor in protecting the warm ischemic lung from reperfusion injury independent of continuous oxygen supply.

Lymph node staging in non-small-cell lung cancer with FDG-PET scan: a prospective study on 690 lymph node stations from 68 patients.

PURPOSE: To compare the accuracy of computed tomography-(CT) scan and the radiolabeled glucose analog 18F-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) visually correlated with CT (PET + CT) in the locoregional lymph node (LN) staging of non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Sixty-eight patients with potentially operable NSCLC underwent thoracic CT, PET, and invasive surgical staging (ISS). Imaging studies were read prospectively and blinded to the surgical and pathologic data. A five-point visual scale was used for the interpretation of LNs on PET. Afterwards, with knowledge of the pathology, the relationship between standardized uptake values (SUVs) and the presence of metastasis in LNs was explored in a receiver operating characteristic (ROC) analysis, and the likelihood ratios (LRs) for SUVs of LNs were determined. RESULTS: ISS was available for 690 LN stations. CT correctly identified the nodal stage in 40 of 68 patients (59%), with understaging in 12 patients and overstaging in 16 patients. PET + CT was accurate in 59 patients (87%), with understaging in five patients and overstaging in four patients. In the detection of locally advanced disease (N2/N3), the sensitivity, specificity, and accuracy of CT were 75%, 63%, and 68%, respectively. For PET + CT, this was 93%, 95%, and 94% (P = .0004). In the ROC curve, the best SUV threshold to distinguish benign from malignant LNs was 4.40. The analysis with this SUV threshold was not superior to the use of a five-point visual scale. The LR of a SUV less than 3.5 in an LN was 0.152; for a SUV between 3.5 and 4.5, it was 3.157; and for a SUV greater than 4.5, it was 253.096. CONCLUSION: PET + CT is significantly more accurate than CT alone in LN staging of NSCLC. A five-point visual scale is as accurate as the use of an SUV threshold for LNs in the distinction between benign and malignant nodes. The very high negative predictive value of mediastinal PET could reduce the need for mediastinal ISS in NSCLC substantially.

Vindesine-ifosfamide-platinum (VIP) induction chemotherapy in surgically staged IIIA-N2 non-small-cell lung cancer: a prospective study. Leuven Lung Cancer Group.

PURPOSE: In the pioneer data from the Memorial-Sloan-Kettering group, preoperative mitomycin-C-vindesine-platinum (MVP) induction chemotherapy in N2-NSCLC was accompanied with substantial pulmonary toxicity. In this study, the efficacy and toxicity of three-drug VIP induction chemotherapy, the pathologic response in resection specimens, the early survival and relapse patterns are examined. PATIENTS AND METHODS: Between June 1995 and March 1997, 39 consecutive patients with pathology proven N2-NSCLC were treated with three cycles of VIP induction, followed by definitive locoregional treatment (resection and mediastinal dissection or radical radiotherapy). Several patients had unfavorable prognostic characteristics with respect to clinical and biological findings, tumor location and bulk of disease. RESULTS: The response rate to chemotherapy was 59% (95% Confidence Interval 34-75). Twenty-three responding patients had radical locoregional treatment: radical radiotherapy in four, resection in 19. Downstaging was present in nine of the 19 resection specimens, with two pathologic complete responses. The median survival time (MST) of all patients is 19 months, with a projected two-year survival of 49%. In patients responsive to chemotherapy who received definitive local treatment, the MST is not yet reached, and the projected two-year survival is 57%. Relapses were mainly distant, with isolated brain relapse as a disturbing finding. The main toxicity's were leukopenia and vomiting, but they were manageable. In contrast with MVP, no severe pulmonary toxicity occurred. CONCLUSIONS: VIP is a suitable induction regimen for N2-NSCLC, demonstrating a good activity and very acceptable toxicity.

Pulmonary cell death in warm ischemic rabbit lung is related to the alveolar oxygen reserve.

BACKGROUND: If lungs could be retrieved for transplantation from non-heart-beating cadavers, the shortage of donors might be significantly alleviated. METHODS: We studied the effect of different postmortem lung conditions on pulmonary cell death. Lungs from 208 New Zealand white rabbits were flushed with trypan blue vital dye solution at intervals after circulatory arrest, fixed, and mounted for histologic examination. Pulmonary cells were judged to be viable on the basis of their ability to exclude trypan blue dye. In the control group, lungs were excised immediately after death and immersed in cold (4 degrees C) saline solution. In the other groups, cadavers were left at room temperature with lungs deflated, ventilated with room air or 100% oxygen or 100% nitrogen, or inflated with room air or 100% oxygen. RESULTS: There was a gradual increase in percentage (mean +/- SEM) of nonviable cells in the control group from 2.5%+/-0.9% (preischemic value) to 18.1%+/-2.8% at 24 hours after death (p < 0.001). In cadavers with lungs deflated, 79.7%+/-2.1% of cells were nonviable at 24 hours after circulatory arrest (p < 0.001 versus control group). In contrast, room air-ventilated cadavers showed only 21.4%+/-2.7% nonviable cells at this interval (p < 0.001 versus deflated group; not significant versus control group). Values in oxygen-ventilated animals were similar. Nitrogen-ventilated cadavers, however, had significantly more nonviable lung cells (73.8%+/-3.2%; p < 0.001 vs room air and oxygen-ventilated group, not significant vs deflated group). Oxygen-inflated lungs showed a parallel decrease in cell viability up to 4 hours after death when compared with room air-inflated cadaveric lungs, but thereafter more cells became nonviable in the latter group (11.1%+/-0.7% vs 19.6%+/-3.2% at 6 hours and 48.7%+/-7.2% vs 75.5%+/-4.6% at 24 hours, respectively; p < 0.01). CONCLUSIONS: Postmortem room air ventilation is as good as oxygen ventilation in delaying pulmonary cell death, and its effect is comparable to cold storage; nitrogen ventilation, however, is ineffective and not different from deflation; oxygen inflation will preserve ischemic cells for longer intervals as opposed to room air inflation. Therefore the alveolar oxygen reserve seems to be the critical factor to protect-the lung parenchyma from warm ischemic damage.

Clinical prognostic factors in surgically treated stage IIIA-N2 non-small cell lung cancer: analysis of the literature.

There remains controversy on the prognostic value of several common clinical factors in NSCLC patients with resected N2-disease. The aim of this paper is to give a comprehensive overview of the available data on this issue. Literature data on surgically treated N2-NSCLC-patients from 1980-1995, peer reviewed and listed in Index Medicus, were analysed. Reported and calculated or estimated survival data were indexed. Eighteen series were selected: in 12 of them, direct comparisons between survival curves of subgroups are reported; six contained sufficient data to make comparisons of survivors at 5 years; three of them also made a multivariate Cox model. The analysis of prognostic factors in a single study was often hampered by the limited number of patients. Nonetheless, it could be concluded that patients with a clinical N0- or N1-status (so-called unforeseen N2) do better. There was no clear difference between patients undergoing lobectomy or pneumonectomy. There was strong evidence that N2-patients with a less advanced primary tumour (T-stage) have a better prognosis, and this is the case for all operable T-stages (T1 versus T2, T1 versus T3, T2 versus T3). Squamous cell type was a favourable prognostic factor, as was the presence of only one metastatic mediastinal lymph node station or absence of metastases to the subcarinal nodes. There was some evidence that the presence of extracapsular spread in metastatic MLN is an unfavourable finding. Stratification for these prognostic factors could help in the planning of future trials on combined modality treatment in N2-NSCLC.

Mediastinal lymph node staging with FDG-PET scan in patients with potentially operable non-small cell lung cancer: a prospective analysis of 50 cases. Leuven Lung Cancer Group.

STUDY OBJECTIVE: To compare the performance of CT, radio-labeled 18F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) blinded to CT, and FDG-PET visually correlated with CT, in the detection of N2 metastatic mediastinal lymph nodes (MLN) in patients with non-small cell lung cancer (NSCLC) and to hypothesize how PET could influence our actual mediastinal staging procedures. SETTING: Tertiary university hospital. PATIENTS AND METHODS: In 50 patients with potentially operable NSCLC, thoracic CT, PET, and invasive surgical staging were performed. Blinded prospective interpretation was performed for each test and compared with surgical pathology results. Abnormalities on each of these staging examinations were recorded on a standard MLN map. RESULTS: The sensitivity, specificity, and accuracy in detecting N2 disease of CT was 67%, 59%, and 64%, respectively. Results of PET blinded to CT were significantly better (p=0.004): 67%, 97%, and 88%, respectively. For PET visually correlated with CT, this was 93%, 97%, and 96%, respectively. In 22 patients, both CT and PET were normal, and this was correct in all cases. CONCLUSIONS: PET was significantly more accurate than CT in the MLN staging in NSCLC. Both examinations were complementary, since visual correlation with the anatomic information on CT improved the reader's ability to discriminate between hilar vs subaortic MLN FDG uptake, and between paramediastinal tumor vs tracheobronchial MLN FDG uptake. If the results can be confirmed in larger numbers of patients, PET could reduce the need for invasive surgical staging remarkably.

Extended preservation of ischemic pulmonary graft by postmortem alveolar expansion.

BACKGROUND: If lungs could be retrieved for transplantation from non-heart-beating cadavers, the shortage of donors might be significantly alleviated. METHODS: Peak airway pressure, mean pulmonary artery pressure, pulmonary vascular resistance, and wet to dry weight ratio were measured during delayed hypothermic crystalloid flush in rabbit lungs (n = 6) at successive intervals after death comparing cadavers with lungs left deflated (group 1), inflated with room air (group 2) or 100% oxygen (group 4), or ventilated with room air (group 3), or 100% nitrogen (group 5), or 100% oxygen (group 6). RESULTS: There was a gradual increase in mean pulmonary artery pressure and pulmonary vascular resistance with longer postmortem intervals in all study groups (p = not significant, group 1 versus group 2 versus group 3). There was also a gradual increase in peak airway pressure and wet-to-dry weight ratio over time in all groups, which reflected edema formation during flush (airway pressure, from 14.5 +/- 1.0 cm H2O to 53.7 +/- 12.2 cm H2O, and wet-to-dry weight ratio, from 3.6 +/- 0.1 to 11.5 +/- 1.2, in group 1 at 0 and 6 hours postmortem, respectively; p < 0.05). Compared with group 1, however, the increase in groups 2 and 3 was much slower (airway pressure, 20.9 +/- 0.5 cm H2O and 18.8 +/- 1.2 cm H2O, and wet-to-dry weight ratio, 5.2 +/- 0.3 and 4.6 +/- 0.4 at 6 hours postmortem, respectively; p < 0.05 versus group 1 and p = not significant, group 2 versus group 3). Airway pressure and wet-to-dry weight ratio did not differ between groups 2 and 4 or between groups 3, 5, and 6. CONCLUSIONS: These data suggest that (1) pulmonary edema will develop in atelectatic lungs if hypothermic flush is delayed for 2 hours after death, (2) postmortem inflation is as good as ventilation in prolonging warm ischemic tolerance, (3) inflation with oxygen or ventilation with nitrogen or oxygen is no different from that with room air, and (4) therefore, prevention of alveolar collapse appears to be the critical factor in protecting the lung from warm ischemic damage independent of continued oxygen delivery.

Survival and prognostic factors in resected N2 non-small cell lung cancer: a study of 140 cases. Leuven Lung Cancer Group.

BACKGROUND: The selection of stage IIIA N2 non-small cell lung cancer patients for primary surgical treatment remains controversial. METHODS: One hundred forty patients with resected non-small cell lung cancer who eventually proved to have pathologic N2 disease were studied with a univariate and multivariate analysis of prognostic factors. RESULTS: Nineteen patients had a positive mediastinoscopy; the others had a preoperative N0 or N1 stage. Complete resection rate was 80.7%. Five-year survival was 20.8% (95% confidence interval, 17.2% to 24.4%), 32.2% in mediastinoscopy-negative patients. In the univariate analysis, clinical N stage at mediastinoscopy, complete resection, performance status, T stage, number of metastatic levels in adenocarcinoma, and nodal capsule rupture were important factors. In a multivariate model, survival was worse in case of higher T stage (relative risk = 1.43), lower performance status (relative risk = 1.37), involvement of more than one node level (relative risk = 1.68), nonsquamous histology (relative risk = 1.29) and clinical N2 stage (relative risk = 1.43). Long-term survival was unlikely when lactic dehydrogenase or carcinoembryonic antigen levels were elevated. CONCLUSIONS: In clinical N0 or N1 cancer, complete resection resulted in reasonable survival prospects. In patients with N2 disease discovered at mediastinoscopy, surgical treatment was only worthwhile in case of minimal N2. Several unfavorable prognostic factors could be identified in the univariate analysis and confirmed in a multivariate Cox model.

External cooling of warm ischemic rabbit lungs after death.

BACKGROUND: If lungs could be retrieved for transplantation after circulatory arrest, the shortage of donors might be significantly alleviated. However, in such non-heart-beating donors, there is great concern that even a short period of warm ischemia will be deleterious for lung tissue, jeopardizing the transplant recipient. It was the purpose of this study to look for the efficacy of different methods of lung cooling inside a cadaver after circulatory arrest. METHODS: New Zealand white rabbits were sacrificed with an intravenous overdose of pentobarbital and left at room temperature. Subcutaneous, rectal, lung core, lung surface, and endobronchial temperatures were measured at intervals after death. Cooling of the lung during ischemia differed between groups (n = 6 in each group): lungs left deflated at room temperature (24 degrees C) (group 1 = control non-heart-beating donors), lungs ventilated with cooled (4 degrees C) room air (group 2), lungs left deflated plus topical cooling (1 degree C) of both the cadaver and its lungs (group 3), and lungs flushed in situ immediately after circulatory arrest with a cold (4 degrees C) crystalloid solution followed by ex vivo deflated storage in cold (1 degree C) saline solution (group 4 = control heart-beating donors). RESULTS: There was a slow decline in lung core, lung surface, and endobronchial temperatures toward room temperature in group 1 (1.5 degrees +/- 0.0 degree C/h, 1.8 degrees +/- 0.2 degree C/h, and 1.9 degrees +/- 0.1 degree C/h, respectively). In contrast, all three lung temperatures immediately ( < 5 minutes) dropped to less than 10 degrees C in group 4. Hypothermic ventilation (group 2) decreased endobronchial temperature (p < 0.05 at 30 minutes) but not lung surface, rectal, or subcutaneous temperature when compared with group 1. Cooling rate for lung surface and endobronchial temperatures during the first 4 hours after death was faster (p < 0.01) in group 3 (6.6 degrees +/- 0.3 degree C/h and 6.1 degrees +/- 0.2 degree C/h, respectively) when compared with group 2 (2.5 degrees +/- 0.3 degree C/h and 3.9 degrees +/- 0.1 degree C/h, respectively), but slower (p < 0.001) when compared with group 4 (9.2 degrees +/- 0.1 degree C/h and 8.7 degrees +/- 0.1 degree C/h, respectively). CONCLUSIONS: These data demonstrate that in the non-heart-beating donor, (1) in situ cold flush will result in immediate cooling of the lung, (2) ventilation with cooled air will only accelerate the decline in endobronchial temperature but has no effect on lung surface temperature, and (3) topical cooling of the cadaver is more efficacious in decreasing lung temperature than hypothermic ventilation.

Delay of adenosine triphosphate depletion and hypoxanthine formation in rabbit lung after death.

BACKGROUND: If lungs could be retrieved for transplantation from non-heart-beating cadavers, the shortage of donors might be significantly alleviated. METHODS: Adenosine triphosphate (ATP) and hypoxanthine levels were measured postmortem in rabbit lungs comparing deflation (group 1), ventilation with room air (group 2), inflation with room air (group 3), ventilation with oxygen (group 4), ventilation with cooled air (group 5), deflation plus cadaver cooling (group 6), and cooling by pulmonary arterial flush (group 7). RESULTS: The level of ATP dropped to 25.9% and HYP increased elevenfold at 30 minutes in group 1 but remained constant during 24 hours in group 7. The ATP catabolism beyond 2 hours postmortem appeared less in group 2 compared with group 3 (3.58 +/- 1.24 versus 0.39 +/- 0.08 mumol/g dry weight for ATP and 3.03 +/- 0.49 versus 7.64 +/- 0.94 mumol/g dry weight for hypoxanthine at 24 hours, respectively; p < 0.05). Cadaver cooling significantly slowed ATP catabolism. Changes in ATP level were similar in groups 2, 4, and 5. CONCLUSIONS: These data suggest that in the non-heart-beating cadaver (1) cooling, ventilation, and inflation can delay ATP catabolism; (2) postmortem ventilation but not inflation for more than 2 hours will inhibit further ATP breakdown; (3) ventilation with either oxygen or cooled air is not more beneficial than room air ventilation; and (4) cold flush more than cadaver cooling will prevent ATP depletion.

Effect of inflation on adenosine triphosphate catabolism and lactate production during normothermic lung ischemia.

Although few biochemical data comparing adenosine triphosphate (ATP) catabolism or lactate production in isolated deflated versus inflated lung tissue are available, most transplant centers preserve their donor lungs inflated. We measured ATP level (using high-performance liquid chromatography), energy charge, and lactate level during 2 hours of normothermic ischemia in deflated lung tissue (n = 6), in lung tissue inflated with room air (n = 6), and in lung tissue inflated with 100% oxygen (n = 6). To determine the onset of anaerobic metabolism in lung tissue inflated with 100% O2, ATP and lactate levels were measured in another group (n = 6) during 8 hours of normothermic ischemia. Rabbit lungs were flushed in situ with a modified Krebs-Henseleit solution (60 mL/kg). They were isolated and immersed in 0.9% NaCl at 37 degrees C. In deflated lung tissue, ATP level (control value, 9.4 +/- 0.58 mumol/g dry wt) decreased and lactate level (control value, 5.6 +/- 1.16 mumol/g dry wt) increased after 15 minutes of ischemia (ATP, 5.2 +/- 0.86 mumol/g dry wt; lactate, 13.3 +/- 1.58 mumol/g dry wt). When the lung was stored inflated with room air, ATP breakdown and increase of lactate concentration only occurred after 90 minutes of normothermic ischemia (at 60 minutes: ATP, 8.0 +/- 0.58 mumol/g dry wt; lactate, 6.3 +/- 1.1 mumol/g dry wt). In lungs stored inflated with 100% O2, ATP breakdown and lactate accumulation only occurred after 5 hours of normothermic ischemia (at 4 hours: ATP, 8.1 +/- 0.74 mumol/g dry wt; lactate, 5.9 +/- 1.28 mumol/g dry wt).(ABSTRACT TRUNCATED AT 250 WORDS)