Chronic thromboembolic pulmonary hypertension.

Pulmonary arterial hypertension is a severe disease that has been ignored for a long time. However, over the past 20 yrs chest physicians, cardiologists and thoracic surgeons have shown increasing interest in this disease because of the development of new therapies, that have improved both the outcome and quality of life of patients, including pulmonary transplantation and prostacyclin therapy. Chronic thromboembolic pulmonary arterial hypertension (CTEPH) can be cured surgically through a complex surgical procedure: the pulmonary thromboendarterectomy. Pulmonary thromboendarterectomy is performed under hypothermia and total circulatory arrest. Due to clinically evident acute-pulmonary embolism episodes being absent in > 50% of patients, the diagnosis of CTEPH can be difficult. Lung scintiscan showing segmental mismatched perfusion defects is the best diagnostic tool to detect CTEPH. Pulmonary angiography confirms the diagnosis and determines the feasibility of endarterectomy according to the location of the disease, proximal versus distal. The technique of angiography must be perfect with the whole arterial tree captured on the same picture for each lung. The lesions must start at the level of the pulmonary artery trunk, or at the level of the lobar arteries, in order to find a plan for the endarterectomy. When the haemodynamic gravity corresponds to the degree of obliteration, pulmonary thromboendarterectomy can be performed with minimal perioperative mortality, providing definitive, excellent functional results in almost all cases.

Clamshell or sternotomy for double lung or heart-lung transplantation?

OBJECTIVE: To evaluate the influence of either incision on the lungs and chest wall. METHODS: Ninety-two double lung (DLT) or heart-lung (HLT) transplantations were done since January 1990. There were 22 (24%) hospital deaths, leaving 70 patients with complete data for evaluation. We did 38 DLT and 32 HLT for end-stage chronic respiratory failure (n = 22) and primary (n = 34) or secondary (n = 14) pulmonary hypertension, using 37 fourth or fifth interspace clamshell incisions and 33 median sternotomies. RESULTS: The clamshell group included a higher percentage of DLTs (73 vs. 33%, P = 0.001) but recipient age, gender, preoperative diagnosis, bronchial anastomotic complications, number of cytomegalovirus infection, episode of acute rejection per patient-months and incidence of bronchiolitis obliterans were not statistically different between the two groups. At a follow-up time of 3.7 +/- 2 years, the overall 5-year survival of 57% was not influenced by the type of incision. The clamshell incision caused sternal over-riding in 12 (32%) patients, and eight surgical clamshell revision were necessary as compared with one median sternotomy (P = 0.02). The clamshell incision was associated with a significantly higher incidence of postoperative chronic pain (27 vs. 6%, P = 0.02). Postoperative mechanical properties of the chest wall were significantly (P < 0.0001) worse in the clamshell-group patients while the intrinsic properties of the airways were not different. CONCLUSIONS: The clamshell incision results in more postoperative deformity, chronic pain, and impaired function as compared with median sternotomy. A bilateral anterolateral thoracotomy without division of the sternum is proposed for the sequential bilateral lung transplantation technique.

Respiratory sensation related to resistive loads in lung transplant recipients.

In order to assess the contribution of pulmonary afferent nerves to the processing of respiratory sensation, we compared sensation related to inspiratory resistive loaded breathing in 14 lung transplant recipients with normal lung function with that in 14 matched healthy control subjects. Respiratory sensation was characterized for each subject by the correlation coefficient and slope of the linear relationship between the intensity of sensation (expressed as Borg scores [BSc]) and peak inspiratory mouth pressure (peak Pm), which was considered the main physical stimulus of the sensation. Individual correlation coefficients were very high and did not differ between lung transplant recipients and controls. In contrast, individual slopes of BSc as a function of peak Pm (BSc/peak Pm slopes) were significantly lower in lung transplant recipients than in controls (0.63 versus 1.26; p < 0.01). Furthermore, ventilatory responses to external loads differed significantly between lung transplant recipients and controls in terms of higher values and ranges of generated peak Pm and peak inspiratory flow in lung transplant recipients than in controls (all p < 0.05). These results suggest that pulmonary afferent nerves may contribute to ventilatory and sensory responses to external loads. However, as suggested by the inverse relation between BSc/peak Pm slopes and peak Pm ranges, higher stimulus ranges in lung transplant recipients may also have contributed to intergroup differences in respiratory sensation related to loaded breathing.

Modulation of ICAM-1 expression in human alveolar macrophages in vitro.

Modulation of intercellular adhesion molecule-1 (ICAM-1) expression may be a basic mechanism by which alveolar macrophages (AMs) regulate the inflammatory process in the lung in response to local stimuli. As a model for studying the anti-inflammatory activity of drugs on human AMs, we investigated the effects of fusafungine, an antibiotic for local use by aerosol with anti-inflammatory properties, and that of the glucocorticoid dexamethasone, on ICAM-1 expression induced in vitro by recombinant interferon-gamma (rIFN-gamma). ICAM-1 protein expression was studied on AMs by means of flow cytometry with an anti-CD54 monoclonal antibody; messenger ribonucleic acid (mRNA) levels were determined by reverse transcriptase-polymerase chain reaction (RT-PCR). ICAM-1 was expressed before culture on 21% of bronchoalveolar lavage (BAL) cells, with low intensity. Culture for 24 h with rIFN-gamma resulted in a significant increase in ICAM-1 protein expression (82% of cells were strongly positive). Fusafungine significantly inhibited rIFN-gamma-induced ICAM-1-protein expression on AMs in a concentration-dependent fashion. The mechanism of ICAM-1 downregulation was mainly post-transcriptional, but also partly transcriptional. By contrast, dexamethasone did not influence rIFN-gamma-induced ICAM-1 expression. This in vitro model using human AMs should prove useful for investigating the cellular and molecular targets of anti-inflammatory drugs.

Particular phenotypic profile of blood lymphocytes during obliterative bronchiolitis syndrome following lung transplantation.

Bronchiolitis obliterans syndrome (OBS) remains the major complication in long-term survivors with heart-lung transplants, occurring in up to 50% of patients who survived the first year postsurgery. Until now, a significant decrease in small airway flow parameters has represented the most sensitive index for the detection of early OBS. Using immunocytofluorometric analysis, in a prospective study we have analysed the phenotype of peripheral blood lymphocyte effector and regulatory subsets in seven patients with inactive well-established OBS as compared with lung transplant recipients without any complication. We found a particular phenotypic profile during well-established OBS characterized by: (1) the disappearance of the CD19+ B cell population despite normal or increased immunoglobulin blood levels; (2) a marked decrease in the CD4+/CD8+ ratio; (3) a dramatic increase in phenotypic cytotoxic effector T cells CD8+S6F1+high and CD3+CD4-CD8-; (4) a dramatic increase in the CD4+CD29+/CD4+CD45RA+ ratio associated with the loss of the phenotypic suppressor/inducer CD4+CD45RA+T cells. The results of this preliminary study suggest that, using this selected combination of lymphocyte membrane markers, sequential phenotyping could be useful in the noninvasive follow-up of lung transplant recipients. The predictive value of this phenotypic profile for the early diagnosis of OBS is under investigation.

Double lung transplantation in situs inversus with Kartagener's syndrome. Paris-Sud University Lung Transplant Group.

En bloc double lung transplantation with bilateral bronchial anastomoses was successfully performed in three patients with complete situs inversus and end-stage Kartagener's syndrome. Dextrocardia was not a technical problem for institution of cardiopulmonary bypass, but a large azygos vein draining the systemic venous return was systematically preserved. The major technical difficulty was restoration of airway continuity, because patients with situs inversus have an inverse direction and length of the main stem bronchi. The right and left main bronchi of the recipients were approached in the aortocaval sinus and transected approximately at 1.5 cm from the carina. The donor right main stem bronchus was divided at its origin and the donor left main stem bronchus was divided proximal to the upper lobe takeoff. The different bronchial angulation was not an obstacle, and airway continuity was reestablished twice with an end-to-end anastomosis and once with a telescopic technique. Because of the midline position of the left atrium and pulmonary artery, the anastomoses with the respective recipient's structures were made as in patients with situs solitus. One patient required a right lower lobectomy because the position of the right side of the heart interfered with lobar expansion. One patient died of obliterative bronchiolitis 36 months after the operation. The remaining two are alive and doing well after 48 and 6 months, respectively.

Angiogenesis: an indicator of metastasis in non-small cell lung cancer invading the thoracic inlet.

We have attempted to identify a biologic rationale for the local aggressiveness and late treatment failure of resected non-small cell lung cancer involving the thoracic inlet. Tumor specimens from 28 patients who underwent a new transcervical approach were analyzed for the expression of tumor proliferative activity, suppressor-gene p53, intratumoral and peritumoral blood vessel invasion by tumor cells, the presence and degree of angiogenesis (induction of new capillaries and venules), and other biologic variables. Eighty-nine percent of the neoplasms were moderately or poorly differentiated, 89% expressed either an intermediate or high proliferative activity, 39% showed p53 aberrations, 71% exhibited induction of angiogenesis, and 39% had tumors that were positive for blood vessel invasion. With a median follow-up time of 3.5 years (range, 8 to 145+ months), the overall projected 5-year survival was 29% and the median disease-free interval was 23 months. Results of univariate and multivariate analysis of survival and the disease-free interval identified the degree of angiogenesis (density less than 1 versus more than 1 and number of neovessels less than 6 versus more than 6) as the only independent and significant predictors of the disease-free interval. Patients whose tumor showed a density of angiogenesis of 1 or greater and a number of neovessels of 6 or greater faced a significantly (p = 0.0001) higher relative risk of suffering systemic recurrence of their primary tumor than did their low-risk counterparts. Results demonstrate that angiogenesis significantly correlates with late treatment failure (metastasis), and this is acquired at a critical density and number of vessels.

Extended operations after induction therapy for stage IIIb (T4) non-small cell lung cancer.

Twenty-three patients with stage IIIb (T4) non-small cell lung cancer received induction chemotherapy (median, 2 cycles) with (n = 12) or without (n = 11) radiation (median, 45 Gy) before operation. Nine tumors involved the carina (n = 8) or lateral tracheal wall (n = 1), 11 were located centrally and invaded the proximal pulmonary artery (n = 6), veins (n = 3), or both (n = 2), three were apical tumors involving T4 structures, and six were associated with histologically diseased mediastinal nodes. Five complete and 18 partial responses were observed after induction treatment. Resection of all residual tumor at the primary site and involved vestiges was possible in 21 patients (91%); in two apical tumors, tumor was left behind. Nine right tracheal sleeve and 11 intrapericardial pneumonectomies and three resections of apical tumors were performed; 11 patients (48%) had radical mediastinal lymph node dissection. Complete sterilization of the primary tumor was observed in 3 patients (13%). Mean operating time was 209.3 +/- 86.8 minutes, and mean blood loss was 896.9 +/- 1031 mL. Major postoperative complications occurred in 6 patients (26%), including hemothorax requiring drainage (n = 1) or reoperation (n = 1), acute distress syndrome (n = 2), and bronchopleural fistula (n = 2), and their incidence was significantly higher (p = 0.0003) among patients receiving induction chemoradiation than among those receiving chemotherapy alone (42 versus 9%). Early (< 1 month) postoperative mortality was 8.6% (n = 2). With a median follow-up of 25 months (range, 12 to more than 39 months), the projected 3-year overall survival was 54%.(ABSTRACT TRUNCATED AT 250 WORDS)

Frequency of mechanical ventilation and respiratory activity after double lung transplantation.

We investigated the contribution of pulmonary afferent nerve fibers to the control of inspiratory activity in awake humans. Eight double lung transplant outpatients and eight normal subjects were hyperventilated with a mechanical ventilator. Respiratory frequency was increased until no respiratory activity was detectable. Then, by either adding CO2 in the inspired gas or decreasing respiratory frequency, end-tidal PCO2 (PETCO2) was increased until inspiratory activity (i.e. change in inspiratory airway pressure peak and/or time profile) was detected. In normal subjects, PETCO2 threshold for inspiratory muscle recruitment was significantly lower when frequency was decreased than when CO2 was added (31.3 +/- 6.8 Torr vs. 38.2 +/- 8.1 Torr respectively, P < 0.005). This was not the case in the double lung transplant group (31.5 +/- 6.5 Torr vs. 32.9 +/- 5.8 Torr). These findings suggest that pulmonary afferent nerves have an inhibitory effect on inspiratory activity in humans.

Anterior transcervical-thoracic approach for radical resection of lung tumors invading the thoracic inlet.

We describe an original anterior transcervical-thoracic approach required for a safe exposure and radical resection of non-small-cell lung cancer that has invaded the cervical structures of the thoracic inlet. Through a large L-shaped anterior cervical incision, after the removal of the internal half of the clavicle, the following steps may be performed: (1) dissection or resection of the subclavian vein; (2) section of the anterior scalenus muscle and resection of the cervical portion of the phrenic nerve, if invaded; (3) exposure of the subclavian and vertebral arteries; (4) dissection of the brachial plexus up to the spinal foramen; (5) section of invaded ribs; and (6) en bloc removal of chest wall and lung tumor, either directly or through an extension of the cervical incision into the deltopectoral groove. An additional posterior thoracotomy may be required for resection of the chest wall below the second rib. Between 1980 and 1991, 29 patients underwent radical en bloc resection of the inlet tumor, chest wall (ribs 1 and 2), and underlying lung, either through the anterior transcervical approach alone (n = 9) or with an additional posterior thoracotomy (n = 20). The inferior root of the brachial plexus, either alone (n = 11) or with the phrenic nerve (n = 4), was involved and resected in 15 patients (52%). Twelve patients (41%) had a vascular involvement that included the subclavian artery alone (n = 3); subclavian artery and subclavian vein (n = 3); subclavian artery, subclavian vein, and vertebral artery (n = 2); subclavian artery and vertebral artery (n = 1); subclavian vein alone (n = 1); vertebral artery alone (n = 1), or subclavian artery and vertebral artery (n = 1). The subclavian artery was revascularized either with a prosthetic replacement (n = 7) or an end-to-end anastomosis (n = 2), and the median graft patency was 18.5 months (range, 6 to more than 73 months); only 1 patient had postradiotherapy graft occlusion in the revascularized artery 6 months after operation. We performed 14 wedge resections, 14 lobectomies, and 1 pneumonectomy. There were no operative or hospital deaths. Postoperative radiotherapy (median, 56 Gy) was given to 25 (86%) patients, either alone (n = 14) or in combination with adjuvant systemic chemotherapy (n = 11). With a median follow-up time of 2.5 years, overall 2- and 5-year survivals were 50% and 31%, respectively. This transcervical-thoracic approach affords a safe exposure and radical resection of non-small-cell lung cancer involving the thoracic inlet and results in encouraging long-term survival.

Technique for resecting primary and metastatic nonbronchogenic tumors of the thoracic outlet.

Although primary or metastatic nonbronchogenic tumors infrequently arise in or involve the thoracic outlet, they represent a major surgical challenge because of their tendency to encapsulate outlet structures. Fourteen patients with a histologically proven primary (n = 8) or metastatic (n = 6) nonbronchogenic outlet tumor were treated by an anterior transcervical approach, including an L-shaped cervicotomy extended into the deltopectoral groove, resection of the internal half of the clavicle, and, in the case of tumor involvement, resection of the jugular and subclavian veins, phrenic nerve, subclavian artery, brachial plexus, and ribs. All patients underwent a radical resection. Tumors extended to bony (usually the first rib), muscular (usually the anterior scalenus muscle), and nerve (usually the phrenic nerve) outlet structures in 8, 10, and 7 patients, respectively. Ten patients had involvement of outlet vessels: 6 had simple ligature (n = 5) or wedge resection (n = 1) of the subclavian vein and related branches, 1 had revascularization of both the subclavian vein by an end-to-end anastomosis and the subclavian artery by a ringed polytetrafluoroethylene graft, 1 had revascularization of the subclavian artery alone, and 2 had revascularization between the left brachiocephalic vein and superior vena cava (ringed polytetrafluoroethylene graft). Follow-up venograms showed complete patency of the anastomoses. There was one postoperative death (7%) due to multiorgan system failure. Other complications were mild and short-lasting. With a median follow-up of 3.4 years, all patients but 1 (who had systemic progression) are alive and disease free 3 to 127 months postoperatively.(ABSTRACT TRUNCATED AT 250 WORDS)

Increased lung clearance of 99mTcDTPA in allograft lung rejection. The Paris-Sud Lung Transplant Group.

To investigate whether lung 99mTc-DTPA clearance is altered during allograft lung rejection, a group of four double lung and 24 heart-lung transplant patients was studied using serial measurement of the clearance rate of aerosolized 99mTc-DTPA (DTPA-Cl), in association with pulmonary function tests, bronchoalveolar lavage, and transbronchial lung biopsies. Using histologic diagnosis as a standard, we compared 56 episodes with normal lung histology to 32 episodes with allograft lung rejection. A control group of 20 healthy nonsmokers was used to define normal DTPA-Cl. In patients with normal lung histology, DTPA-Cl was higher than in control subjects (2.62 +/- 0.25 versus 1.20 +/- 0.12 %/min; p less than 0.001). In the episodes of allograft lung rejection, DTPA-Cl increased to 3.65 +/- 0.41 %/min (p less than 0.02) as compared with episodes of normal lung histology. The change in DTPA-Cl during allograft lung rejection was correlated (r = 0.3, p less than 0.01) with the increased percentage of lymphocytes in bronchoalveolar lavage (27.8 +/- 3.5% in rejection versus 19.9 +/- 2.2% in normal histology; p less than 0.02). Sensitivity and specificity of DTPA-Cl measurement in detecting lung rejection were 69 and 82%, respectively, versus 45 and 85% for FEV1 measurement. These results suggest that DTPA-Cl monitoring could be used in conjunction with pulmonary function testing as a noninvasive approach for the detection of lung rejection.

[TNF-alpha synthesis by cells from bronchioloalveolar lavage and by circulating mononuclear cells in recipients of heart-lung transplantation]. / Synthèse de TNF-alpha par les cellules du lavage bronchiolo-alvéolaire et les cellules mononucléées circulantes chez les transplantés coeur-poumon.

In 10 patients who received a heart lung transplant, TNF-alpha generation by cells collected during bronchioloalveolar lavages (n = 30) and by circulating mononuclear cells was measured. Basal and recombinant IL-2-stimulated productions (50 U/ml) were measured. TNF-alpha concentration was determined by an immunoradiometric assay (IRMA). Circulating mononuclear cells produced at least 4 times less TNF-alpha than BAL cells. Rejection episodes or CMV diseases were not associated with significant changes in TNF-alpha generation. Recombinant IL-2 increased this production in both cell populations but the magnitude of this effect was smaller in BAL cells, suggesting an in vivo preactivation.

[Anesthesia and intensive care for heart-lung transplantation]. / Anesthésie et réanimation pour transplantation coeur-poumons.

Since Shumway carried out the first successful heart-lung transplant (HLT) in Stanford in 1981, HLT has become a new therapeutic means for patients with end-stage pulmonary disease or arterial hypertension. However, it is still rarely carried out because of a lack of donors and the complexity of the surgery and postoperative course. This review described the criteria for proper donor and recipient selection, as well as the anaesthetic and postoperative management of HLT patients at Marie Lannelongue Hospital. The lack of suitable organ grafts results, at least in part, from improper donor management. Pulmonary oedema by fluid overloading and excessive haemodilution should be carefully prevented. Low doses of catecholamines and vasopressin maintain circulatory stability and convenient organ function. The indications for HLT (primary pulmonary hypertension, Eisenmenger's complex, and end-stage bronchopulmonary disease) are all characterized by severe pulmonary hypertension, hypoxaemia and cardiac failure. Careful anaesthetic induction is required to avoid circulatory collapse. Cardiopulmonary bypass (CPB) should be started early, so that mediastinal dissection may be carried out in satisfactory haemodynamic conditions. After unclamping the aorta, circulatory support with fluid and catecholamine infusion is often required. High inspired oxygen fraction and end-expiratory positive pressure may be required because of reperfusion pulmonary oedema. Blood transfusion is often needed as there are major blood losses due to dissection of the posterior mediastinum during CPB. Postoperative catecholamine administration is prolonged over several days. Negative fluid balance is often necessary to reduce pulmonary oedema. Improvement in surgical technique, early extubation, and late prescription of steroids have reduced the incidence of tracheal complications. Acute renal failure often occurs as a result of prolonged CPB, hypovolaemia, drug nephrotoxicity and sepsis. Bacterial complications (pneumonia, mediastinitis) are the main causes of early death. After the 15th postoperative day, opportunistic infections and allograft rejection are the main complications. Since 1981, major advances in HLT recipient management resulted in improved survival rates (70-80% at 1 year, and 60-70% at 2 years for the best teams). Despite the complexity of management, and the longterm threat of obliterative bronchiolitis, HLT is, at present time, the only possibility for these young patients to recover a normal quality of life.