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Although social anxiety disorder (SAD) is strongly associated with the subsequent development of a depressive disorder (major depressive disorder or dysthymia), no underlying biological risk factors are known. We aimed to identify biomarkers which predict depressive episodes in SAD patients over a 2-year follow-up period. One hundred sixty-five multiplexed immunoassay analytes were investigated in blood serum of 143 SAD patients without co-morbid depressive disorders, recruited within the Netherlands Study of Depression and Anxiety (NESDA). Predictive performance of identified biomarkers, clinical variables and self-report inventories was assessed using receiver operating characteristics curves (ROC) and represented by the area under the ROC curve (AUC). Stepwise logistic regression resulted in the selection of four serum analytes (AXL receptor tyrosine kinase, vascular cell adhesion molecule 1, vitronectin, collagen IV) and four additional variables (Inventory of Depressive Symptomatology, Beck Anxiety Inventory somatic subscale, depressive disorder lifetime diagnosis, BMI) as optimal set of patient parameters. When combined, an AUC of 0.86 was achieved for the identification of SAD individuals who later developed a depressive disorder. Throughout our analyses, biomarkers yielded superior discriminative performance compared to clinical variables and self-report inventories alone. We report the discovery of a serum marker panel with good predictive performance to identify SAD individuals prone to develop subsequent depressive episodes in a naturalistic cohort design. Furthermore, we emphasise the importance to combine biological markers, clinical variables and self-report inventories for disease course predictions in psychiatry. Following replication in independent cohorts, validated biomarkers could help to identify SAD patients at risk of developing a depressive disorder, thus facilitating early intervention., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Airway bypass is a bronchoscopic lung-volume reduction procedure for emphysema whereby transbronchial passages into the lung are created to release trapped air, supported with paclitaxel-coated stents to ease the mechanics of breathing. The aim of the EASE (Exhale airway stents for emphysema) trial was to evaluate safety and efficacy of airway bypass in people with severe homogeneous emphysema., Methods: We undertook a randomised, double-blind, sham-controlled study in 38 specialist respiratory centres worldwide. We recruited 315 patients who had severe hyperinflation (ratio of residual volume [RV] to total lung capacity of ≥0·65). By computer using a random number generator, we randomly allocated participants (in a 2:1 ratio) to either airway bypass (n=208) or sham control (107). We divided investigators into team A (masked), who completed pre-procedure and post-procedure assessments, and team B (unmasked), who only did bronchoscopies without further interaction with patients. Participants were followed up for 12 months. The 6-month co-primary efficacy endpoint required 12% or greater improvement in forced vital capacity (FVC) and 1 point or greater decrease in the modified Medical Research Council dyspnoea score from baseline. The composite primary safety endpoint incorporated five severe adverse events. We did Bayesian analysis to show the posterior probability that airway bypass was superior to sham control (success threshold, 0·965). Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00391612., Findings: All recruited patients were included in the analysis. At 6 months, no difference between treatment arms was noted with respect to the co-primary efficacy endpoint (30 of 208 for airway bypass vs 12 of 107 for sham control; posterior probability 0·749, below the Bayesian success threshold of 0·965). The 6-month composite primary safety endpoint was 14·4% (30 of 208) for airway bypass versus 11·2% (12 of 107) for sham control (judged non-inferior, with a posterior probability of 1·00 [Bayesian success threshold >0·95])., Interpretation: Although our findings showed safety and transient improvements, no sustainable benefit was recorded with airway bypass in patients with severe homogeneous emphysema., Funding: Broncus Technologies., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: Lung transplantation for patients on ventilators is a controversial use of scarce donor lungs. We have performed 500 lung transplants in 12 years and 21 of these have been in ventilator-dependent patients., Methods: A retrospective review of patient records and computerized database was performed. Living patients were contacted to confirm their health and functional status., Results: Patients included 13 men and 8 women with a mean age of 43 years. Sixteen patients were considered stable awaiting lung transplant, whereas 5 patients were unstable with acute graft failure after prior lung transplantation. Stable patients had been ventilated for a mean of 57 +/- 46 days whereas unstable patients had been supported for 10 +/- 9 days. Half of the patients required cardiopulmonary bypass support during the transplant, and there was no statistical difference in the frequency of CPB in stable and unstable patients (p = 0.61). Three hospital deaths included 0 of 16 of the stable patients and 3 of 5 of the unstable patients (p = 0.01). Long-term actuarial survival was significantly better in stable versus unstable patients (p = 0.02), with 5-year survival 40% for stable patients and 0% for unstable patients., Conclusions: Lung transplantation can be successfully conducted in stable patients who have become ventilator dependent after listing for transplantation. Acute retransplantation for early lung dysfunction is high risk and has produced poor long-term results.

Objectives: We used whole-lung quantitative CT analysis (QCT)-an objective method of evaluating emphysema severity and distribution based on measurement of lung density-to determine whether subjective selection criteria for lung volume reduction surgery are applied consistently and to model the patient selection process, and assessed the relationship of the model to postoperative outcome., Design: Logistic regression analysis using QCT indexes of emphysema and preoperative physiologic test results as the independent variables, and the decision to operate as the dependent variable., Setting: University hospital., Patients: Seventy patients selected for bilateral lung volume reduction surgery and 32 otherwise operable patients excluded from surgery based on subjective assessment of emphysema morphology on chest radiography, CT, and perfusion scintigraphy., Intervention: Bilateral lung volume reduction surgery in the selected group., Measurements and Results: Emphysema in patients selected for surgery was more severe overall and in the upper lungs by multiple QCT indexes (p < 0.01, unpaired two-tailed t test). Physiologic abnormalities were slightly more severe in selected patients (p < 0.05, unpaired two-tailed t test). The range of many QCT and physiologic values overlapped considerably between the selected and excluded groups. The percent severe emphysema (<- 960 Hounsfield units [HU]), upper/lower lung emphysema ratio (- 900 HU threshold), and residual volume were the key variables in the model predicting selection decisions (model r(2) = 0.48; p < 0.0001). The model correctly predicted selection decisions in 87% of all cases, 91% of the selected group, and 78% of the excluded group. Surgical patients with a higher model-derived probability of selection had greater postoperative improvement in FEV(1) and 6-min walk distance., Conclusions: Radiologic selection criteria are applied consistently to the majority of patients. QCT features are strongly associated with selection decisions, are related to outcome, and may help improve consistency and confidence in patient selection.

Background: Sleeve lobectomy and bronchoplasty are established alternatives to pneumonectomy for bronchial malignancies involving a main bronchus. However, potential bronchial anastomotic complications have deterred the general application of these types of resection. Some reports have contained a mixture of non-small cell lung cancer (NSCLC) and tumors of low-grade malignancy, making it difficult to assess the long-term results of these procedures as an alternative to pneumonectomy for lung cancer., Methods: We retrospectively reviewed our experience with sleeve lobectomy and bronchoplasty for bronchial malignancies from January 1988 to September 1998 separating NSCLC (n = 58) from tumors of low-grade malignancy (n = 19). We compared the overall results between sleeve lobectomy and pneumonectomy (n = 142) performed for NSCLC over the same time interval., Results: For NSCLC, after sleeve lobectomy, the operative mortality was 5.2% (3 of 58 patients) and the overall 5-year actuarial survival was 37.5%. After pneumonectomy, the operative mortality was 4.9% (7 of 142 patients) and the overall 5-year actuarial survival was 35.8%. For tumors with low-grade malignancy, there was no operative mortality after sleeve lobectomy or bronchoplasty and the 5-year actuarial survival was 100%. Major bronchial anastomotic complications occurred in 3 patients among the 77 patients who underwent sleeve resection., Conclusions: Sleeve resection can be performed with a low risk of bronchial anastomotic complication. The long-term survival after sleeve resection for NSCLC is similar to pneumonectomy. Excellent results are obtained after sleeve resection for low-grade malignancies.

Background: Heat shock has been associated with the acquisition of tolerance to a wide variety of stressful conditions, including ischemia. This is partly mediated by the production of various heat shock proteins (HSP), including HSP70. One novel approach to the reduction of ischemia-reperfusion injury after lung transplantation is the induction of HSP70 by heat pretreatment of the donor. The purpose of this study was to investigate the feasibility of this approach in an animal model of lung transplantation., Methods: Animals were divided into six main groups, with groups I to III representing transplanted animals: In groups I and II, donor animals were anesthetized and then underwent heat stress 6 and 12 hours before organ harvest, respectively. Control animals underwent general anesthesia but no heat stress. After harvest, left lungs from groups I to III were preserved for 18 hours at 40 degrees C and then implanted into isogeneic recipients, which were killed 24 hours after reperfusion to assess graft function. Group IV and V animals underwent heat stress followed by a recovery period of 6 and 12 hours, respectively. Lungs were collected both at the time of harvest (right lungs) and after 18 hours of cold preservation (left lungs). Group VI served as nontransplanted controls. Groups IV to VI did not undergo lung transplantation., Results: At the time of harvest but before implantation, HSP70 was significantly increased in heat-shocked nontransplanted donor lungs (groups IV and V) compared with group VI controls. After 18 hours of cold preservation, HSP70 levels were higher in group IV compared with group V and group VI controls. At 24 hours after reperfusion, mean arterial oxygenation was significantly higher in group I compared with group II and group III controls (290.25+/-24.5 vs 154.5+/-23.9 and 119.6+/-11.3 mm Hg, respectively; P < .001). Myeloperoxidase activity was improved in group I compared with group III controls (0.048+/-0.018 vs 0.137+/-0.036 deltaOD/mg/min, respectively; P < .05). The wet/dry weight ratio was also improved in group I compared with group III controls (6.2+/-0.3 vs. 7.8+/-0.4, respectively; P < .05)., Conclusions: Heat pretreatment of the donor 6 hours before harvest results in increased synthesis of HSP70, which offers a dramatic protective effect against subsequent ischemia-reperfusion injury in the lung isograft.

Background: Gene therapy is a promising strategy for the treatment of inoperable pulmonary tumors and rejection after lung transplantation. However, unlike ex vivo administration, intravenous in vivo transfection lacks organ specificity and has a limited duration of expression. The objectives of this study were to limit transfection to a single lung and to increase the duration of gene expression in vivo., Methods: Sixteen male Fisher rats were anesthetized and divided into two groups. Animals in group I (n = 7) received an intrajugular administration of 1,320 microg of chloramphenicol acetyl transferase (CAT) complementary DNA complexed with cationic liposomes. Animals in group II (n = 9) received 660 microg of CAT complementary DNA complexed with cationic liposomes into the pulmonary artery of an isolated left lung over 10 minutes. After 40 minutes of incubation, the lung was flushed with 10 mL of normal saline solution, and the perfusate was suctioned through a left pulmonary venotomy. The circulation to the left lung was then restored. After 48 hours, the animals were divided into subgroups (a and b) and CAT activity was assessed in the lungs, hearts, livers, and kidneys of groups Ia (n = 3) and IIa (n = 5). After 21 days, CAT activity was assessed in the left lungs of groups Ib (n = 4) and IIb (n = 4)., Results: After 48 hours, animals that had received intravenous administration of CAT cDNA showed strong expression in the lungs and hearts and negligible expression in the livers and kidneys. In contrast, animals in group IIa, which had received isolated left lung perfusion of CAT cDNA showed expression only in the left lung. After 21 days, the left lungs of animals in group Ib, which had received intravenous administration of CAT complementary DNA, showed no CAT expression, but the left lungs of animals in group IIb, which had received isolated left lung perfusion of CAT complementary DNA, exhibited strong CAT expression., Conclusions: Compared with intravenous administration, isolated lung liposome-mediated gene transfer provides prolonged organ-specific gene expression. This provides a useful model to study the effects of gene therapy on pulmonary tumors, which may have further application when gene therapy is used in clinical practice.

Background: Recombinant Kunitz protease inhibitor (rKPI-BG022) is more homologous to human Kunitz protease inhibitor than is aprotinin. Because aprotinin has been reported to inhibit free radicals, we hypothesized that rKPI would ameliorate reperfusion injury caused by free radicals. We examined its effect and the timing of administration in an in vivo rat lung transplantation model., Methods: All lungs were flushed with low-potassium dextran-1% glucose solution and stored for 24 hours at 4 degrees C, then orthotopic left lung transplantations were performed. Rats were divided into 4 groups (n=6) as follows: group 1 served as control; in Group 2, rKPI was added to the flush solution (10 micromol/L); in group 3, rKPI (5 mg/kg) was administered intravenously to the recipient just after reperfusion; and in group 4, rKPI was added to the flush solution (10 micromol/L) and rKPI (5 mg/kg) was administered intravenously to the recipient just after reperfusion. Twenty-four hours after transplantation, the right main pulmonary artery and right main bronchus were ligated, and the rats were ventilated with 100% O2 for 5 minutes. Peak airway pressure, blood gas analysis, serum lipid peroxide level, tissue myeloperoxidase activity, and wet-dry weight ratio were measured., Results: The partial oxygen tension values of group 2 were higher than those of groups 1 and 4 (groups 1, 2, and 4: 104.8+/-15.8, 245.1+/-49.0, 101.4+/-4.5 mm Hg, respectively; p < 0.01). The partial carbon dioxide tension values of groups 3 and 4 were lower than those of group 1 (groups 1, 3, and 4: 74.5+/-5.7, 42.0+/-11.0, 46.0+/-8.4 mm Hg, respectively; p < 0.05). Peak airway pressures were lower in groups 2 and 3 than in groups 1 and 4 (groups 1, 2, 3, and 4: 22.5+/-0.5, 18.2+/-0.5, 19.2+/-0.8, 22.5+/-1.1 mm Hg; p < 0.01). Serum lipid peroxide levels in groups 2 and 3 were lower than those of groups 1 and 4 (groups 1, 2, 3, and 4: 0.793+/-0.037, 0.577+/-0.069, 0.560+/-0.029, and 0.785+/-0.053 nmol/mL, respectively; groups 2 and 3 vs group 1, and group 3 vs group 4: p < 0.01; group 2 vs group 4: p < 0.05). There were no differences in wet-dry weight ratio and tissue myeloperoxidase activity between the groups., Conclusion: Recombinant Kunitz protease inhibitor ameliorates reperfusion injury caused by free radicals in an in vivo rat lung transplantation model. Administration of rKPI through the flush solution and intravenous injection after reperfusion were effective separately, but the combination of the two administrations was not effective.

Background: Lung volume reduction operation shows promise in relieving symptoms and improving function in highly selected patients with emphysema. Withdrawal of Medicare funding for patients selected for operation by standard criteria created a matched control group with which to compare lung volume reduction recipients., Methods: A retrospective study was done comparing 22 volume reduction candidates denied operation with 65 contemporaneous and comparable volume reduction recipients. Baseline physiologic characteristics were compared and longitudinal measures of pulmonary function were followed up for 24 months., Results: Patients denied operation were similar to volume reduction recipients in all baseline measurements. Patients denied operation experienced a progressive worsening of their function, whereas volume reduction patients experienced sustained improvements. Absolute survival to date is 82% for the surgical group and 64% for the medical group., Conclusions: The improvement seen in volume reduction patients cannot be attributed to the effects of patient selection or preoperative and postoperative rehabilitation.

Background: NPC18915, a member of new antiinflammatory agent called nactins (neutrophil activation inhibitors), has been shown to reduce reperfusion injury in rat lung transplantation at high dosage. In vitro studies have demonstrated effectiveness of this compound even at low dosage. We hypothesized that this compound ameliorates lung ischemia reperfusion injury even at low dosage levels if administration is optimally timed. The aim of this study was to determine the efficacy and the best timing for administration of low-dose NPC18915., Methods: Forty syngeneic rat left lung transplantations were performed. All isografts were flushed with low-potassium dextran-1% glucose solution 20 ml and preserved for 18 hours at 4 degrees C. Animals were divided into four groups. Group I animals (n = 10) served as control subjects. In groups II (n = 10), III (n = 10), and IV (n = 10), NPC18915 (0.04 mg) was added to the flush solution and was administered intravenously (0.4 mg/kg) immediately before reperfusion (group II) and 60 minutes (group III) and 120 minutes (group IV) after reperfusion. Pulmonary function was assessed 24 hours after reperfusion., Results: In group III, oxygenation improved in comparison to group I (247.2 +/- 59.8 versus 76.6 +/- 16.0 mm Hg, p < 0.002). Wet-to-dry weight ratio and graft myeloperoxidase activity were significantly improved (group III versus group I, 6.02 +/- 0.21 versus 7.19 +/- 0.41, p = 0.013) (group III versus group I, 0.093 +/- 0.019 versus 0.207 +/- 0.023 delta optical density/min/mg, p < 0.002). There were no significant differences in CD11b expression., Conclusion: These data suggest that delayed administration of NPC18915, 60 minutes after reperfusion, dramatically improves pulmonary graft function.

Background: Vasoactive intestinal peptide (VIP) has been reported to have some properties that provide protection from lung injury. Furthermore, its protective effect in cold storage of donor lungs has been confirmed. We examined its effect and the timing of administration in an in vivo rat lung transplantation model., Methods: All lungs were flushed with low-potassium dextran-1% glucose solution, and orthotopic left lung transplantations were performed. Rats were divided into four groups (n = 6). Group I received no preservation or storage. Groups II, III, and IV grafts were stored for 18 hours at 4 degrees C. Group II received no VIP. Group III received VIP (0.1 g/ml) via the flush solution. Group IV recipients received VIP (3 microg/kg) intravenously just after reperfusion. Twenty-four hours after transplantation, the right main pulmonary artery and right main bronchus were ligated, and the rats were ventilated with 100% O2 for 5 minutes. Mean pulmonary arterial pressure, peak airway pressure, blood gas analysis, serum lipid peroxide level, tissue myeloperoxidase activity, and wet-dry weight ratio were measured., Results: The partial O2 tension values of groups III and IV were better than group II (groups II, III, and IV: 147.4 +/- 71.4, 402.1 +/- 64.8, 373.4 +/- 81.0 mm Hg; p < 0.05). Peak airway pressure was lower in groups III and IV than in group II (groups II, III, and IV: 19.7 +/- 0.8, 16.7 +/- 0.9. and 16.3 +/- 1.0 mm Hg; p < 0.05). Mean pulmonary arterial pressure in group III was lower than group II (groups II and III: 36.3 +/- 3.0 and 22.1 +/- 2.2 mm Hg; p < 0.01). Wet-dry weight ratio in group III was lower than in groups II and IV (group II, III, and IV: 5.2 +/- 0.2, 4.4 +/- 0.2, and 5.2 +/- 0.3; II vs III; p < 0.05, III vs IV; p < 0.01). Serum lipid peroxide levels in groups III and IV were significantly lower (groups II, III, and IV: 2.643 +/- 0.913, 0.455 +/- 0.147, and 0.325 +/- 0.124 nmol/ml; p < 0.01)., Conclusion: VIP ameliorates reperfusion injury in an in vivo rat lung transplantation model. Either administration of VIP via the flush solution or systemically just after reperfusion was associated with improved pulmonary function.

Background: We reviewed the long-term clinical outcome after transcervical thymectomy for generalized myasthenia gravis without thymoma in 52 patients who had this procedure at The Toronto Hospital between 1977 and 1986, and compared the results with those reported after more radical surgical approaches., Methods: Preoperative and postoperative patient evaluations were based on a modified Osserman classification. We defined complete remission as asymptomatic with normal strength and without medications for myasthenia gravis. The complete remission rate was selected as the best measure for comparison between different surgical approaches., Results: The 52 patients were followed up for a mean of 8.4 years (+/-6.1 years [standard deviation]). The preoperative mean Osserman grade was 2.7 compared with 0.4 at final follow-up. Complete remission occurred in 44.2% of patients. Similar results are reported after transsternal thymectomy., Conclusions: Comparable results after transcervical and transsternal thymectomy favor the use of the less radical approach.

Background: Heat shock proteins are expressed during several forms of stress and inflammation. This study was done to determine whether the expression of heat shock protein HDJ-2 (heat shock protein 40), heat shock protein 60, and heat shock protein 70 are increased during rejection in human pulmonary allografts., Methods: Thirty-five transbronchial biopsy specimens were obtained from adult lung transplant recipients. Histologic analysis and assessment of heat shock protein HDJ-2, heat shock protein 60, and heat shock protein 70 mRNA expression was performed. Total RNA was extracted, reverse transcribed, and amplified by polymerase chain reaction with oligonucleotide primers specific for the heat shock proteins. The identity of the amplified message was verified by Southern blot and slot blot analysis., Results: The expression of heat shock protein HDJ-2 was significantly higher in samples from lung transplant recipients undergoing rejection when compared with recipients without rejection or infection. Heat shock protein 70 expression was also increased in rejection. Expression of heat shock protein 60 did not show any increase in recipients with no evidence of rejection and infection or transplant recipients with rejection or infection. Serial analysis of heat shock protein HDJ-2 and heat shock protein 70 obtained in biopsy specimens during and after rejection showed a decrease of heat shock protein HDJ-2 and heat shock protein 70 expression after resolution of lung rejection., Conclusion: Our data demonstrate that the expression of heat shock protein HDJ-2 and heat shock protein 70 increases during lung rejection. However, only heat shock protein HDJ-2 was able to differentiate between rejection and infection. Measurement of heat shock protein HDJ-2 in transbronchial biopsy specimens may assist in the differential diagnosis between rejection and infection in lung transplant recipients.

The use of the system, automated sequential trace enrichment of dialysates (ASTED), to prepare plasma samples for the estimation of lamotrigine, its glucuronide and methylated metabolites in plasma prior to gradient high-performance liquid chromatography (HPLC) is described. Using this technique the procedure was observed to be specific for all three compounds and linear over the range 0.04 to 10 microg/ml for lamotrigine and the glucuronide metabolite and 2 to 500 ng/ml for the methylated metabolite. The within-run precision (C.V.) at four different supplemented plasma lamotrigine concentrations of 0.04, 0.10, 2.5 and 10.0 microg/ml was 6.21, 5.17, 1.29 and 0.73%, respectively, and the between-run precision (C.V.) estimated to be 13.49, 6.08, 1.95 and 1.78%, respectively. The overall accuracy (% bias) of the procedure was estimated to be 12.50, 0.00, 2.80 and 1.80%, respectively. The glucuronide and methylated metabolites in plasma showed similar assay performance.

The development of the ASTED (automated sequential trace enrichment of dialysates) system to prepare plasma samples prior to high-performance liquid chromatography (HPLC) of sildenafil and its demethylated metabolite (UK-103,320) is described. Investigations to elucidate potential pitfalls of the ASTED on-line sample preparation system prior to separation of the analytes by HPLC are presented. The procedure is shown to be selective for sildenafil and UK-103,320, and linear over the range 1.00-250 ng/ml. The intra-batch imprecision (C.V.) of the method at plasma analyte concentrations of 1.00, 5.00, 50.0 and 200 ng/ml was 11.2, 3.10, 1.50, and 1.30%, respectively, and the corresponding inter-batch imprecision was estimated to be 13.5, 7.09, 3.69, and 5.43%. At these plasma analyte concentrations the overall inaccuracy (% bias) of the procedure ranged from 3.6 to 8.4%. The method showed similar assay performance for the estimation of the metabolite, UK-103,320. The application of the assay to a pharmacokinetic investigation during a clinical study is presented.

Background: Neutrophil adhesion is initiated by the interaction of rapidly expressed endothelial selectins with oligosaccharide structures (sialyl Lewis(x) on polymorphonuclear neutrophils (PMN). The carbohydrate sialyl Lewis X analogue CY-1503 blocks selectin receptors, thereby inhibiting PMN rolling and subsequent firm adhesion and migration., Methods: We evaluated the inhibitory effect of CY-1503 on PMN migration and reperfusion injury in canine left lung allografts. Donor lungs were flushed with modified Euro-Collins solution (1500 ml, 4 degrees C) and preserved for 21 hours at 1 degree C. Left lung allotransplantation was subsequently performed in 14 mongrel dogs. Immediately after transplantation and allograft reperfusion, the recipient contralateral right pulmonary artery and bronchus were ligated to permit assessment of isolated allograft function during a 6-hour postreperfusion period (FIO2 = 1.0). Allograft gas exchange (q 15 minutes) and hemodynamics (q 60 minutes) were assessed. After sacrifice, allograft bronchoalveolar lavage fluid (BALF) PMN count and allograft tissue myeloperoxidase (MPO) activity were measured. Two groups were studied: In group I (n = 7) CY-1503 was added to the donor lung flush (20 mg/L) and given to the recipient (35 mg/kg intravenous bolus) before reperfusion, followed by a continuous infusion (5.25 mg/kg/h intravenously) during the 6-hour assessment period. Group II animals (n = 7) received no CY-1503., Results: Gas exchange in group I was superior throughout the assessment period (p < 0.01 at 6 hours after reperfusion). BALF PMN count in group I was reduced to 0.57 +/- 0.3 x 10(6) PMN/ml compared with 3.9 +/- 1.3 x 10(6) PMN/ml in group II (p < 0.05). Group I allograft MPO activity was 0.21 +/- 0.06 compared with 0.40 +/- 0.02 delta OD/mg/ min in controls (p < 0.02). Two animals in each group died early after reperfusion as a result of graft failure and were excluded from analysis., Conclusions: Our observations indicate that selectin inhibition effectively reduces PMN adhesion, migration, and subsequent reperfusion injury in preserved canine lung allografts.

Background: Morbidity as a result of early allograft dysfunction remains a significant problem in clinical lung transplantation. We previously demonstrated that nitroprusside (NP), a potent nitric oxide donor, administered before storage and again during reperfusion, reduced lung reperfusion injury. The purpose of the present study was to determine whether these observations were storage effects, reperfusion effects, or both., Materials and Methods: Fifteen dogs underwent left lung allotransplant. Donor lungs were flushed with modified Euro-Collins solution and stored for 21 hours at 1 degree C. Immediately after transplantation, the contralateral right main pulmonary artery and bronchus were ligated to assess isolated allograft function. Hemodynamics and arterial blood gas analysis (FIO2 1.0) were assessed for 6 hours before sacrifice. Allograft myeloperoxidase (MPO) activity and wet to dry weight (W/D) ratio were assessed. Animals were divided into three groups for timing of NP administration. Group I (n = 5) animals received no NP. In group II (n = 5), donor lungs received NP (10 mg/L) in the flush solution only. In group III (n = 5), recipient animals received NP (0.2 mg/kg) just before reperfusion, as well as a continuous infusion (0.1 mg/kg/hr) during the assessment period., Results: Significant improvement in gas exchange was apparent in groups II and III compared with group I, but there was no significant difference between groups II and III. After 6-hour reperfusion, mean PaO2 values were 85.46 +/- 13.32 mm Hg in group I, 298.74 +/- 61.25 mm Hg in group II (p < 0.05), and 311.12 +/- 43.39 mm Hg in group III (p < 0.05). Systemic vascular resistance was significantly lower in group III than in group I (p < 0.05). MPO activities decreased in groups II (p < 0.05) and III (p < 0.05), indicating reduced neutrophil sequestration. W/D ratio was significantly lower in groups II and III., Conclusion: Both methods of NP administration are effective, but NP administration in the recipient is accompanied by a decrease in systemic vascular resistance. From a clinical point of view, NP administration in the flush solution is a sufficiently effective and practical method to reduce lung allograft reperfusion injury.

Background: Positron emission tomography with the glucose analogue 2-[18F]fluoro-2-deoxy-D-glucose (FDG) has been used to detect and stage a variety of malignancies. We hypothesized that FDG-positron emission tomography would improve staging of patients with esophageal cancer and thereby facilitate selection of candidates for resection., Methods: Fifty-eight patients (42 men and 16 women) with biopsy-proven esophageal cancer were evaluated with both FDG-positron emission tomography and computed tomography., Results: In all but 2 patients, increased FDG uptake was identified at the site of the primary tumor. Six patients were not operative candidates. Seventeen patients were not candidates for resection because of metastatic disease. Positron emission tomography identified the metastatic disease in all 17 (12 of whom underwent confirmatory biopsy), whereas computed tomography was positive for metastases in only 5. The remaining 35 patients underwent surgical exploration, were judged to have resectable disease and had esophagectomy. Pathologic examination of resected specimens identified lymph node metastases in 21 patients. These nodes were detected by positron emission tomography in 11 patients and by computed tomography in 6., Conclusions: Positron emission tomography improved staging and facilitated selection of patients for operation by detecting distant disease not identified by computed tomography alone.

The use of the system automated sequential trace enrichment of dialysates (ASTED), to prepare plasma samples for the estimation of L-NG-monomethylarginine (546C88) by pre-column o-phthalaldehyde-2-mercaptoethanol derivatisation and HPLC is described. Calibration is achieved using purified albumin as a substitute matrix for plasma. Using this technique the procedure was observed to be specific for 546C88 and linear over the range 0.10 to 50.0 mumol/l. The within-run imprecision (C.V.) at four different spiked plasma 546C88 concentrations of 0.10, 1.0, 8.0 and 40.0 mumol/l was 6.48, 2.55, 2.79 and 3.37%, respectively, and the between-run imprecision (C.V.) estimated to be 8.50, 1.80, 2.10 and 3.30%, respectively, for the same spiked 546C88 concentrations. The overall accuracy (% bias) of the procedure using an albumin matrix for calibration was estimated to be -2.50, -5.25, -3.56, -3.53%, respectively, and the recovery of 546C88 from six different spiked plasma samples estimated to be 99.1 +/- 1.4%.

Background: During the last 4 years, we have increasingly used lungs retrieved by other procurement teams. We therefore investigated whether the use of those lungs affected the outcome of lung transplantation., Methods: We analyzed the results of 159 consecutive lung transplantations performed at our institution between July 1, 1992, and December 31, 1995. The transplants were divided into three groups: distant donor lungs retrieved by our team (DB group, n = 68); distant donor lungs retrieved by other teams (DX group, n = 46); and local donor lungs retrieved by our team (LB group, n = 44). One transplantation with a local donor lung retrieved by another team was excluded from the analysis., Results: No significant differences were noted between the three groups in alveolar-arterial oxygen gradient immediately after transplantation (DB group, 359 +/- 18 mm Hg; DX group, 329 +/- 23 mm Hg; LB group, 327 +/- 20 mm Hg) and at 24 hours; days on ventilator; days in the intensive care unit; length of hospital stay; 30-day mortality; and actuarial 1-year survival (DB group, 81%; DX group, 87%; LB group, 89%)., Conclusions: The use of donor lungs retrieved by other teams achieves an equivalently satisfactory outcome after lung transplantation as lungs retrieved by our team.

A 67-year-old man underwent coronary artery bypass grafting 31/2 months after a bilateral lung volume reduction operation for end-stage pulmonary emphysema. The principles of anesthetic management we have developed for use during volume reduction operations were applied with success in this individual and are described in detail. With the increasing application of this intervention as an alternative to lung transplantation, we anticipate further experience in the operative management of associated conditions after lung volume reduction operations.

Background: Although whole-organ gene transfer has been reported in heart and liver transplant models, it has not been well characterized in lung grafts. The aim of this study was to determine the feasibility of ex vivo gene transfer to rat lung isografts during cold preservation using an adenoviral vector., Methods: F344 rats, divided into four groups, underwent orthotopic left lung transplantation. In group I, lung grafts were flushed with adenovirus carrying the beta-galactosidase gene. After storage at 10 degrees C, grafts were implanted in recipient animals. Group II underwent the same procedure but graft storage was at 4 degrees C. Groups III (10 degrees C) and IV (4 degrees C) served as controls. On postoperative day 5, recipients were sacrificed, and native and transplanted lungs were examined., Results: In group I, all animals showed successful, albeit patchy, gene expression. This occurred in 2 of 4 animals in group II, the other 2 showing no expression. Transduced cells were consistent morphologically with endothelial cells and pneumocytes. A minimal mononuclear inflammatory infiltrate was present. Control groups showed no transduction., Conclusions: It is feasible to perform ex vivo adenoviral-mediated gene transfer to rat lung isografts during cold preservation.

Background: Inhalation of nitric oxide (NO) has been shown to have beneficial effects on a variety of acute lung injuries, including lung allograft reperfusion injury. The purpose of the present study was to investigate the effects of inhaled NO at the time of harvest on function of canine left lung allografts after transplantation., Methods: Ten dogs underwent left lung allotransplantation. Donor lungs were flushed with modified Euro-Collins solution and stored for 21 hours at 1 degree C. Immediately after transplantation, the contralateral main pulmonary artery and bronchus were ligated to assess isolated allograft function. Hemodynamics and arterial blood gases (inspired oxygen fraction, 1.0) were assessed intermittently for 6 hours prior to sacrifice. Allograft myeloperoxidase activity and wet to dry weight ratio were assessed. Donor animals were divided into two groups. Group I animals (n = 5) received no NO. In group II (n = 5), donors received inhaled NO (60 ppm) at the time of harvest., Results: Pulmonary vascular resistance decreased to 79.6% of baseline because of inhalation of 60 ppm NO in group II donor animals. Thiobarbituric acid-reactive materials were reduced during the storage period in group II, a finding suggesting less oxidant injury during storage in donor lungs treated with NO. Throughout the 6-hour assessment, oxygenation in group II was superior to that in group I (p < 0.05). At 360 minutes of assessment, mean arterial oxygen tension in groups I and II was 88.9 +/- 11.4 mm Hg and 169.1 +/- 33.0 mm Hg, respectively. Myeloperoxidase activity was significantly decreased in group II (p < 0.05), data indicating reduced neutrophil sequestration. Wet to dry weight ratio was significantly lower in group II., Conclusions: These data suggest that inhaled NO at the time of harvest improves early function of preserved lung allografts by attenuating oxidant injury during storage and subsequent neutrophil sequestration.

The use of selective protein precipitation to enhance the recovery of vitamin E from plasma, by minimising binding with very-low-density lipoproteins, is reported. The procedure employed treatment of plasma with magnesium chloride and tungstate, followed by methanol protein precipitation. Separation of vitamin E was performed using reversed-phase high-performance liquid chromatography of the methanol extracts with subsequent UV detection of the compound. Using this technique the procedure was observed to be specific for vitamin E and linear over the range 1.0 to 40.0 micrograms/ml. The within-run imprecision (C.V.) at three different supplemented plasma vitamin E concentrations of 5.0, 10.0 and 20.0 micrograms/ml was 4.51, 3.33 and 2.58%, respectively, and the between-run imprecision (C.V.) estimated to be 5.19, 3.69 and 3.67%, respectively. With the same supplemented plasma vitamin E concentrations, the overall accuracy (bias) of the procedure, using an albumin matrix for calibration, was estimated to be 6.0, -5.0 and -3.5%, respectively, and the recovery of vitamin E from six different spiked plasma samples estimated to be 98.2 +/- 2.6%.

Study Objective: This study was designed to examine the extent of smoking cessation prior to thoracotomy for resection of a pulmonary malignancy and the recidivism rate., Design: Prospective, longitudinal study., Patients: All patients presenting to the General Thoracic Clinic., Results: The study included 362 patients, with an average age of 64.7 years; 95% with a smoking history were followed up for an average of 17.5 months. Five surgeons in the same practice group performed the procedures: pneumonectomy, 45; lobectomy, 288; and lesser resections, 29. Forty-two percent of patients had quit prior to 1 year; 6% quit 3 months to 1 year; 15% quit between 2 weeks to 3 months; 12% quit at 2 weeks; and 19% continued to smoke up to surgery. Postoperatively, 86% of previously smoking patients were nonsmoking; 13% of patients started smoking again. Of the restarted smoking patients, 61% had never quit preoperatively. Only 59% of smoking patients admitted that a physician had ever told them to stop smoking; however, 89% of patients who were smoking postoperatively acknowledged physician advice to stop smoking., Conclusions: Long-term smoking cessation occurs in a large proportion of patients after resection of lung cancer. The longer the patient is nonsmoking preoperatively, the more likely he or she is to remain nonsmoking postoperatively. Conversely, patients who do not quit preoperatively are at significant risk of continuing to smoke postoperatively.

Background: Nitric oxide is believed to play a critical role in the maintenance of vascular integrity through its interaction with neutrophils, platelets, and cellular components of the vessel wall. It has been reported that endogenous nitric oxide level was depressed after ischemia, reperfusion, or both. Furthermore, exogenous as well as endogenous nitric oxide decreases reperfusion-induced vascular dysfunction. We hypothesized that nitroprusside, a potent nitric oxide donor, might enhance lung preservation and reduce posttransplantation lung allograft dysfunction., Methods: Ten dogs underwent left lung allotransplantation. Donor lungs were flushed with modified Euro-Collins solution and stored for 21 hours at 1 degree C. Immediately after transplantation, the contralateral right main pulmonary artery and bronchus were ligated to assess isolated allograft function. Hemodynamics and arterial blood gas analysis (inspired oxygen fraction, 1.0) were assessed for 6 hours before sacrifice. Allograft myeloperoxidase activity and wet-to-dry weight ratio were assessed. Group 1 (n = 5) animals received no nitroprusside. In group 2 (n = 5), the donor lung received nitroprusside in the flush solution (10 mg/L) and recipient animals received 0.2 mg/kg just before reperfusion as well as a continuous infusion (0.11 +/- 0.01 mg.kg-1. h-1) during the assessment period., Results: Superior gas exchange and hemodynamics were noted in lungs receiving nitroprusside. Although allograft myeloperoxidase activity and the total amount of fluid suctioned from the allograft were significantly reduced in group 2, protein levels in bronchoalveolar lavage fluid were not statistically different., Conclusions: Nitroprusside administration in the flush solution and during reperfusion improves lung allograft function and blood flow, and reduces pulmonary vascular resistance and myeloperoxidase activity in the transplanted lung. Nitroprusside reduces lung allograft reperfusion injury.

Background: Postischemic ischemia reperfusion injury is a frequent and unpredictable problem in clinical lung transplantation. Pentoxifylline (PTX) has a number of effects that could decrease reperfusion injury: reduced neutrophil adhesion to endothelium, decreased production of tumor necrosis factor, decreased platelet aggregation, and increased production of vasodilatory prostaglandins by vascular endothelium. We have demonstrated previously that PTX administered before storage and again during reperfusion reduced lung reperfusion injury. The purpose of the present study was to determine whether these observations were storage or reperfusion effects., Methods: Fourteen canine left lung allotransplantations were performed. Donor lungs were flushed with modified Euro-Collins solution and stored for 24 hours at 1 degree C. Immediately after transplantation, the contralateral right main pulmonary artery and bronchus were ligated to assess isolated allograft function. Hemodynamic indices and arterial blood gas analysis (inspired oxygen fraction 1.0) were assessed for 6 hours before sacrifice. Allograft myeloperoxidase activity was assessed. Bronchoalveolar lavage fluid was obtained from the allograft middle lobe for neutrophil counts. The animals were divided into three groups based on the timing of PTX administration. Group 1 (n = 5) animals received no PTX. Group 2 (n = 4) animals received PTX (20 mg/kg) just before reperfusion as well as continuous infusion (0.1 mg x kg-1 x min-1) during the assessment period. In group 3 (n = 5), donor lungs received PTX (200mg/L) in the flush solution only., Results: Superior gas exchange was noted in the lungs receiving PTX only in the flush solution (group 3). Myeloperoxidase activity in group-3 allografts was significantly reduced. In addition, protein levels and neutrophil counts in the bronchoalveolar lavage fluid were significantly reduced in group-3 allografts., Conclusions: Pentoxifylline ameliorates lung allograft reperfusion injury when administered in the flush solution. Our data suggest that PTX will prevent graft endothelial dysfunction during 24-hour cold ischemic storage and consequently will prevent neutrophil activation and migration into lung tissue.

Background: Depletion of neutrophils (PMNs) and inhibition of PMN endothelial adhesion ameliorate post-ischemic lung reperfusion injury. Lidocaine reduces PMN adhesion to endothelial surfaces in vivo, and inhibits upregulation of PMN-CD11b/CD18 (Mac-1) in vitro. We evaluated the effect of lidocaine on reperfusion injury, PMN adhesion, and PMN migration in preserved lung allografts., Methods: Donor lungs were flushed with modified Euro-Collins solution (4 degrees C) after prostaglandin E1 administration (250 micrograms), inflated with 550 mL (inspired oxygen fraction = 1.0), and stored for 24 hours at 1 degree C. Left lung allotransplantation was performed in 13 mongrel dogs. Immediately after reperfusion the recipient right pulmonary artery and bronchus were ligated to permit assessment of allograft function during a 6-hour postreperfusion period. Allograft gas exchange (every 15 minutes) and hemodynamics (every 60 minutes) were assessed. Peripheral blood PMN CD11b expression was determined by flow cytometry. After sacrifice allograft bronchoalveolar lavage fluid PMN count and allograft tissue myeloperoxidase activity were measured. Two groups were studied: In group I (n = 8) lidocaine hydrochloride was added to the donor flush (20 mg/L) solution. In addition lidocaine was given to the recipient at the time of thoracotomy (intravenous bolus of 4 mg/kg) followed by a continuous infusion of 4 mg/kg/h during implantation and the assessment period. Three dogs that did not reach effective lidocaine blood levels at the time of reperfusion (3 to 4 micrograms/mL) were excluded from analysis. Group II animals (n = 5) received no lidocaine., Results: Gas exchange in group I was superior throughout the assessment period (p < 0.05). Bronchoalveolar lavage fluid PMN count in group I was reduced (0.36 x 10(6)PMN/mL versus 6.2 x 10(6) PML/mL; p < 0.03). Group I allograft myeloperoxidase activity was 0.17 U/mg/min compared with 0.28 U/mg/min in group II (p < 0.01). In lidocaine-treated animals PMN CD11b expression was maintained at basal levels 2 hours after reperfusion, compared with group II, in which upregulation of CD11b was observed. Lower lobe wet/dry ratio was not different in the two groups., Conclusions: Our observations indicate that lidocaine reduces reperfusion injury and inhibits PMN adhesion and subsequent migration to the lung allograft.

Background: Bronchiolitis obliterans syndrome (BOS) is the main cause of late morbidity and mortality in lung transplantation. This study was designed to accurately determine the prevalence of this syndrome of chronic lung allograft dysfunction (which is presumed to be due to chronic rejection)., Methods: A retrospective analysis was done of 212 consecutive lung transplantations performed at Barnes Hospital between July 1988 and March 1994 to characterize the prevalence and course of BOS. One hundred eighty-seven transplant recipients survived at least 3 months after transplantation, putting them at risk for BOS. Recipients free of BOS (group I) were distinguished from those with BOS (group II) based on the presence of declining spirometry (forced expiratory volume in 1 second persistently less than 80% of previous baseline) or histologic obliterative bronchiolitis in group II., Results: There were 110 transplantations in group I (59%) and 77 in group II (41%). At follow-up, BOS was detected using the following criteria: declining forced expiratory volume in 1 second alone, 40 of 77 (52%); positive histologic results alone, 7 of 77 (9.1%); and both, 30 of 77 (38.9%). Declining spirometry was the most common initial sign of BOS onset (57 of 77, 74%). There were no differences between groups with respect to age, sex, indication for transplantation, or type of transplantation performed. The mortality rate was significantly higher with BOS (group II, 22 of 77 [28.6%] versus group I, 8 of 110 [7.3%]; p = 0.001) and was not related to either the type of transplantation performed or the indication for transplantation. Follow-up of group II (mean 35.1 months; range, 7.1 to 63.7 months) showed a delay until BOS onset (16.1 +/- 1.2 months); when BOS was fatal, death ensued within 11.5 +/- 2.4 months of its onset. Comparison of the first and last quartiles of recipients in this series (QTR1 versus QTR4, 53 patients in each) demonstrated a higher prevalence of BOS in QTR1 (24 with BOS of 43 at risk [55.8%] versus QTR4, 5 with BOS of 52 at risk [9.6%]; p < 0.001) and a worse BOS functional score in QTR1 (2.2 +/- 0.2 versus QTR4, 0.8 +/- 0.2; p = 0.007)., Conclusions: (1) Bronchiolitis obliterans syndrome is truly a clinical syndrome, not simply a pathologic entity; (2) BOS displays considerable latency in onset and progression; (3) lung transplant recipients must therefore be followed up for a sufficient interval to determine the actual prevalence and mortality rate of BOS; and (4) the prevalence and mortality rates of BOS are higher than previously appreciated, exceeding 50% and 40%, respectively.

Background: Early allograft dysfunction remains a frequently encountered problem in clinical lung transplantation. Lung ischemia-reperfusion injury is associated with increased vascular permeability, which may be due in part to oxygen (O2) free radicals. However, it is not clear whether O2 free radicals are produced during ischemia under storage conditions in clinical lung transplantation., Methods: Using an isolated ex vivo rabbit lung model, we studied the effects of preservation temperature on pulmonary capillary filtration coefficient (Kf) and lipid peroxidation in rabbit lungs inflated with 100% O2 after preservation with or without the O2 free radical scavenger dimethylthiourea. New Zealand white rabbits weighing 2.7 to 3.1 kg were intubated and ventilated with room air or 100% O2 (tidal volume = 25 mL). After heparinization and sternotomy, the pulmonary artery was flushed with low-potassium-dextran-1% glucose solution (200 mL). The heart-lung block was excised, submerged, and stored for 24 hours at 1 degree or 10 degrees C. After 24-hour preservation, the heart-lung block was suspended from a strain-gauge force transducer and ventilated with room air. The pulmonary artery cannula was connected to a reservoir of hetastarch solution. The lungs were flushed briefly with the hetastarch solution, and the reservoir was raised sequentially at 8-minute intervals to achieve 1.0 to 1.5 mm Hg increments in pulmonary artery pressure. Lung weight gain, airway pressure, pulmonary artery pressure, and left atrial pressure were measured continuously. The slope of steady-state lung weight gain was used to determine Kf (g.min-1.cm H2O-1 x 100 g-1 wet weight)., Results: Twenty-four-hour lung preservation at both 1 degree and 10 degrees C increased Kf. A similar increase in Kf was observed in lungs stored at 1 degree C while inflated with 100% O2. However, a significant increase in Kf was observed when lungs inflated with 100% O2 were stored at 10 degrees C. This increase in Kf was ameliorated by dimethylthiourea. Thiobarbituric acid-reactive substance levels were increased in lungs stored at 10 degrees C while inflated with 100% O2. This finding was eliminated by dimethylthiourea., Conclusions: These results indicate that free radical injury occurs during the ischemic phase when lungs are stored at moderate hypothermia while inflated with 100% O2.

Background: It has been suggested that the frequency and severity of allograft rejection may be related to the degree of allograft ischemia. The purpose of this study was to determine whether ischemic insult correlates with lung allograft rejection., Methods: Forty-eight left lung transplants were performed from Lewis donor rats into F344 recipient rats. Allografts were divided into two groups based on the degree of ischemic insult. Transplantation was performed immediately (group 1, minimum injury) or after 18 hours of cold (1 degree C) preservation (group 2, severe injury). Allografts were evaluated radiographically based on aeration scores (0 = opaque to 6 = normal). Animals were randomly sacrificed on days 7, 14, or 21 for histologic and immunohistochemical evaluation of rejection., Results: On postoperative day 3, significantly lower aeration score was demonstrated in group 2 (3.69 +/- 1.71) compared to group 1 (5.0 +/- 1.09) (p < 0.05) as a result of the difference in reperfusion injury. However, by day 7 and thereafter, there was no significant difference. Histologic rejection was present by day 7 and peaked at day 14 with no significant difference between groups. There was also no difference in CD4+, CD8+ infiltrating lymphocyte population or expression of class II major histocompatibility complex antigen on bronchial epithelium., Conclusions: We conclude that ischemic injury in rat lung allograft does not correlate with the onset or severity of rejection.

Background: The expression of intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and class II major histocompatibility complex antigens was studied in control lung tissue and preserved human donor lungs. The three controls were represented by wedge biopsy specimens taken from non-neoplastic lung surrounding bronchogenic carcinomas., Methods: Nine lungs were harvested from six brain-dead donors, flushed with Euro-Collins solution or low potassium-dextran-glucose solution, and stored at 1 degree C or 10 degrees C. Samples of the latter organs were taken at the time of surgical harvest (baseline) and after 2, 12, 24, and 48 hours of preservation time. Immunostains with monoclonal antibodies against intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and class II major histocompatibility complex molecules were performed on all samples, and the relative presence of these determinants was evaluated., Results: In both the controls and preserved lungs, intercellular adhesion molecule-1 expression was intense in the septal capillary endothelium and alveolar pneumocytes, but essentially absent in bronchial epithelium. Vascular cell adhesion molecule-1 was moderately to strongly labeled in the endothelia of large and small blood vessels of all types, and it was not seen in other cell types. Class II major histocompatibility complex antigens were variably observed in pulmonary epithelial cells, but they were not expressed by endothelia. There appeared to be no significant difference in the immunohistologic density of intercellular adhesion molecule-1 or vascular cell adhesion molecule-1 immunostaining in allografts at the specified time points of preservation; this conclusion was confirmed by Western blot analysis. Similar findings pertained to staining results for human leukocyte DR antigens. There was likewise no significant difference in the expression of the three analytes when donor lungs perfused with Euro-Collins solution versus low potassium-dextran-glucose solution were compared; this was also true of organs preserved at 1 degree C versus 10 degrees C., Conclusions: These results suggest that, in the immediate post-harvest period, modulations in the expression of intercellular adhesion molecule-1, vascular cell adhesion molecule-1, or class II major histocompatibility complex antigens in pulmonary allografts are not attributable to the influences of preservation conditions.

Background: Perioperative monitoring of pulmonary artery (PA) pressures in lung transplant recipients is critical. This report characterizes an intraoperative gradient across the PA anastomosis in a series of patients undergoing bilateral sequential lung transplantation., Methods: Hemodynamic measurements were obtained in a series of 10 patients before anesthetic induction, during one-lung ventilation/perfusion of the newly transplanted first lung with the PA catheter proximal and distal to the anastomosis and after arrival in the intensive care unit. The following measurements were recorded: central venous pressure, cardiac output, PA occlusion pressure, and systemic and pulmonary arterial pressures (systolic, diastolic, mean)., Results: Although a systolic pressure gradient of more than 10 mm Hg across the anastomosis was observed in all patients, there was a significant variation in systolic (13 to 59 mm Hg), diastolic (2 to 10 mm Hg), and mean (5 to 27 mm Hg) PA gradients. Mean proximal systolic PA pressure measurements (56.2 +/- 20.6 mm Hg) were greater when compared to measurements obtained distal to the anastomosis (28.6 +/- 10.1 mm Hg, p = 0.001) and to those obtained in the postoperative period (32.1 +/- 9.7 mm Hg, p = 0.004)., Conclusions: The present study demonstrates that during single-lung ventilation and perfusion, the PA pressure measured proximally may not reflect accurately the pressure distal to the vascular anastomosis.

Background: Cytokines participate in host responses to allografts, largely through recruiting and activating various regulatory and effector cells. We performed this study to determine the feasibility of using polymerase chain reaction methodology to define the expression of three important cytokines (tumor necrosis factor-alpha, interleukin-2, and interferon-gamma) in human pulmonary allografts., Methods: Twenty-six graft-derived samples (11 transbronchial biopsy and 8 macrophage and 7 lymphocyte cell pellets isolated from bronchoalveolar lavage) were obtained from 13 lung transplant recipients and treated as follows: extraction of RNA; reverse transcription of RNA to complementary DNA; polymerase chain reaction amplification of cDNA with oligonucleotide primers specific for the three cytokines; gel electrophoresis of the polymerase chain reaction products; and verification of correct cytokine message by Dot blot technique (with specific 32P-labeled oligonucleotide probes)., Results: Concomitant pathologic evaluation of biopsy specimens from these 13 recipients showed five diagnostic groups: "normal" (no rejection/infection), n = 2; acute rejection, n = 4; nonspecific inflammation, n = 3; infection, n = 3; and obliterative bronchiolitis, n = 1. Interleukin-2 was expressed predominantly in acute rejection and infection (seven of ten and five of six samples positive, respectively), whereas tumor necrosis factor-alpha was expressed mainly in nonspecific inflammation (four of five samples) and somewhat less in rejection (six of ten). Interferon-gamma was expressed less frequently (in two of six samples with infection, but in none of ten with rejection and none of five with nonspecific inflammation). Serial data from one patient (6 months apart) showed considerable increase in interleukin-2 and interferon-gamma expression as she progressed from normal histologic status to obliterative bronchiolitis., Conclusions: Cytokine gene transcripts can be determined from minute samples derived directly from pulmonary allografts. Although our data are insufficient to make definitive conclusions, the suggestion of trends of cytokine expression in different posttransplantation pathologic conditions may indicate a useful role for this approach in the clinical evaluation of the lung transplant recipient.

Recent reports have suggested that the retention of blood group antigen expression on tumor cells may be an important prognostic factor for survival. From 1986 to 1991, 136 patients underwent operative resection for their T1 N0 non-small cell lung carcinoma. One hundred twenty tissue blocks were available for antigen testing, and the histologic types were as follows: adenocarcinoma (73 patients), squamous cell (39 patients), large cell/undifferentiated (7 patients), and mucoepidermoid (1 patient). Follow-up is complete for all patients (mean, 41 months). This distribution of patients among the blood groups was as follows: A, 56 (47%); O, 53 (44%); B, 9 (7.5%), and AB, 2 (1.7%). Immunostaining was performed for A, B, and H blood group antigens. The 5-year actuarial survival in the blood group A patients (53%) did not differ significantly from that in the blood group O patients (59%). Similarly, when tumors were examined for their respective antigens, no significant differences were found in the 5-year survival of either blood group A or O patients between the tumors that retain and those that lose blood group antigen expression. Retention or loss of blood groups A or O antigen expression does not predict survival in patients with early-stage lung carcinomas.

A technique for internal fixation of a silicone elastomer tracheal stent is described. This technique allows the use of a short stent in situations where complex stent placement otherwise would be necessary. The procedure was used successfully to manage a postresection stricture in the subglottic trachea.

To evaluate the contribution of the respiratory pattern to the ventilatory response after lung transplantation, we studied the changes in minute ventilation, tidal volume, and respiratory rate during CO2 rebreathing in 14 patients with severe obstructive pulmonary disease, and compared them with 10 normal subjects. Seven patients underwent a bilateral lung transplantation and 7 patients had single-lung transplantation. Single-lung transplant recipients increased their respiratory rate by the last postoperative test compared with either preoperative or initial test periods (0.38 +/- 0.13 versus 0.027 +/- 0.24 or 0.12 +/- 0.08 breaths.min-1.mm Hg-1; p < 0.005). Bilateral lung transplant recipients showed a diminished ability to augment their respiratory rate by the last postoperative test compared with either preoperative or initial test periods (0.13 +/- 0.23 versus 0.54 +/- 0.25 or 0.25 +/- 0.29 breaths.min-1.mm Hg-1; p < 0.06). The restored ventilatory response by the fourth postoperative week was due to a statistically significant increase in tidal volume for both single and bilateral lung transplant recipients. This study demonstrates that when lung transplant recipients have an appropriate ventilatory response to CO2 rebreathing, single-lung transplant recipients have a respiratory pattern similar to normal; whereas the bilateral lung transplant recipients show the effects of total pulmonary denervation. We conclude that the preserved ventilatory response in lung transplant recipients is composed of a respiratory pattern that is influenced by the presence or absence of vagal inputs.

To evaluate the respiratory responses after lung transplantation, we studied the hypercarbic ventilatory response in 20 patients with severe obstructive pulmonary disease and compared it with that of 10 normal subjects. Eleven patients underwent bilateral lung transplantation and 9 patients had single-lung transplantation. All patients had preoperative hypercapnia (51.3 +/- 9.7 mm Hg) and blunted slopes of CO2 rebreathing curves for minute ventilation (0.39 +/- 0.20 L.min-1.mm Hg-1) and inspiratory occlusion pressure (0.35 +/- 0.30 s-1). The hypercapnia and blunted ventilatory responses persisted at the initial postoperative test (5.8 +/- 2.0 days) despite improved pulmonary function (preoperative forced expiratory volume in 1 second [FEV1], 0.57 +/- 0.16 L; initial postoperative FEV1, 1.83 +/- 0.65 L; p < 0.001). By the 15th to 30th postoperative day (21.3 +/- 6.0 days), compared with preoperative and initial postoperative values, end-tidal CO2 had normalized (40.6 +/- 6.9 versus 51.3 +/- 9.7 and 49.6 +/- 10.3 mm Hg; p < 0.005) and was coupled with enhanced ventilatory responses for the rebreathing curve for minute ventilation (1.26 +/- 0.7 versus 0.39 +/- 0.20 and 0.32 +/- 0.32 L.min-1.mm Hg-1; p < 0.005) and the inspiratory occlusion pressure curve (0.98 +/- 7.4 versus 0.35 +/- 0.30 and 0.41 +/- 0.29 s-1; p < 0.005). These respiratory responses developed without a change in postoperative pulmonary function (initial postoperative FEV1, 1.83 +/- 0.65 L versus last postoperative FEV1, 1.96 +/- 0.66 L; p = not significant).(ABSTRACT TRUNCATED AT 250 WORDS)

Single-lung transplantation is an effective treatment for end-stage pulmonary failure caused by a variety of lung diseases. Although single-lung recipients may undergo a similar operative procedure, physiologic differences in the remaining native lung dictate differences in postoperative management and perhaps outcome. To examine these effects on the early results after single-lung transplantation, we retrospectively reviewed the course of 83 patients undergoing single-lung transplantation from September 1988 through July 1993. The cause of the lung disease was obstructive (OLD) in 43, idiopathic pulmonary fibrosis (IPF) in 16, and primary pulmonary hypertension (PPH) in 24 patients. The hospital mortality was 5% in OLD, 13% in IPF, and 8% in PPH. Gas exchange as demonstrated by alveolar-arterial oxygen gradients was worse after transplantation in patients with IPF (349 +/- 159 mm Hg) or PPH (270 +/- 171 mm Hg) compared with patients with OLD (174 +/- 105 mm Hg; p < 0.05). Mean pulmonary artery pressures were higher in patients with IPF (28 +/- 6 mm Hg) and PPH (26 +/- 7 mm Hg) compared with patients with OLD (22 +/- 5 mm Hg; p < 0.05). Peak airway pressures after transplantation were greater in patients with IPF (36 +/- 6 cm H2O) compared with patients with OLD (28 +/- 6 cm H2O; p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Early graft dysfunction continues to be a major clinical problem after lung transplantation. The objective of this experiment was to determine whether continuous administration of prostaglandin E1 (PGE1) after lung transplantation has a beneficial effect on early graft function. Left lung allotransplantation was performed in 10 size-matched mongrel dogs (weight, 24.4 to 31.4 kg). Lung preservation consisted of a bolus injection of PGE1 (250 micrograms) into the pulmonary artery, followed by a pulmonary artery flush with 50 mL/kg of 4 degrees C modified Euro-Collins solution. The lungs were then stored at 1 degree C for 12 hours. Left lung transplantation was performed using standard technique. The right pulmonary artery and right bronchus were ligated prior to chest closure. Animals were placed in the supine position and ventilated for 6 hours with 100% oxygen at a rate of 20 breaths/min, a tidal volume of 550 mL, and a positive end-expiratory pressure of 5 cm H2O. Animals were randomly allocated to one of two groups. Group I animals (n = 6) received continuous PGE1 infusion from the onset of implantation. The dose was gradually increased and fixed when mean systemic pressure showed a 10% decrease (mean PGE1 dose, 31.7 +/- 6.9 ng.kg-1.min-1). Group II animals (n = 4) received no PGE1. After the 6-hour assessment period, arterial oxygen tension and alveolar-arterial oxygen pressure difference were preserved in group I compared with group II (group I versus group II: arterial oxygen tension, 255.8 +/- 37.6 mm Hg versus 64.7 +/- 7.9 mm Hg [p < 0.05]; alveolar-arterial oxygen pressure difference, 411.1 +/- 70.5 mm Hg versus 597.5 +/- 1.3 mm Hg [p < 0.05]).(ABSTRACT TRUNCATED AT 250 WORDS)

Early graft dysfunction remains a significant problem in clinical lung transplantation. Pentoxifylline, a methylxanthine derivative, has been shown to have various beneficial effects on neutrophil-induced lung injury. We investigated effects of pentoxifylline on early posttransplantation lung function in a canine allograft model. Ten dogs underwent left lung allotransplantation. Donor lungs were flushed with modified Euro-Collins solution (50 mL/kg) and stored in an inflated state for 18 hours at 1 degrees C. In five experiments (group I), pentoxifylline was added to the flush and storage solutions (200 mg/L) at the time of harvest. The recipient animals received pentoxifylline (20 mg/kg intravenously) before reperfusion followed by pentoxifylline (0.1 mg.kg-1.min-1 intravenously) during the 6-hour posttransplantation assessment period. In group II, donors and recipients received no pentoxifylline. To evaluate only allograft function, the right main pulmonary artery and bronchus were ligated immediately after implantation. For 6 hours thereafter hemodynamics and gas exchange were assessed at 15-minute intervals while the animal was ventilated at an inspired oxygen fraction of 1.0. After 1 hour of assessment there was a significant difference in gas exchange between the groups, which persisted until the end of the study. By the end of the 6-hour assessment, the mean arterial oxygen tension was 236.7 mm Hg for group I versus 101.1 mm Hg for group II (p < 0.01), and the alveolar-arterial oxygen difference was 443.1 mm Hg versus 562.2 mm Hg (p < 0.015). Hemodynamics were not different between groups.(ABSTRACT TRUNCATED AT 250 WORDS)

The records for 162 lung transplantations performed in 158 patients were reviewed with regard to the predictors for, frequency of, and indications for using cardiopulmonary bypass during the procedure. There were a total of 8 en bloc double-lung transplantations, 83 single-lung transplantations, and 71 bilateral single-lung transplantations. Bypass was used electively for all double en bloc and three of the bilateral sequential lung transplantation procedures and for 26 unilateral lung replacement procedures in patients with pulmonary hypertension. Of the remaining patients, 1 single-lung transplant recipient required bypass for correction of a surgical mishap and 18 bilateral single-lung recipients required bypass during replacement of the second lung. No preoperative predictors for the need of bypass could be identified. Among the bilateral sequential lung recipients, the use of bypass did not seem to adversely affect outcome, as expressed in terms of the time until extubation, the time spent in the intensive care unit, and the time required to reach a room air oxygen tension greater than 60 mm Hg.

Wedge excision of emphysematous lung tissue by means of a stapling device is frequently associated with prolonged air leakage. We have used bovine pericardial strips to buttress the staple line, preventing air leakage, which otherwise can occur at the staple holes when the lung is reinflated.

The capillary filtration coefficient (Kf) is one of the most accurate measures of change in pulmonary vascular permeability and has been used in various models of acute lung injury. To evaluate the isolated effects of ischemia on Kf, we have developed an ex vivo rabbit lung model in which the influences of reperfusion are eliminated. The current study was designed to validate this model by determining the effect of cold flushing with low-potassium-dextran solution containing 1% glucose (LPDG), ischemic time, temperature, and inspired oxygen fraction on Kf. On completion of the ischemic period, the ventilated lungs, with the heart still attached, were suspended from a strain-gauge force transducer. After the lungs were flushed with 50 mL hetastarch solution (6% hetastarch solution with physiologic saline solution), the left atrial drainage cannula was occluded and the pulmonary artery pressure was incrementally increased by elevation of the reservoir. The Kf was calculated as the slope of the line relating the weight gain rate and pulmonary capillary pressure.(ABSTRACT TRUNCATED AT 250 WORDS)