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1 Dept of Pneumonology, Army General Hospital of Athens, Athens, Greece, 2 Respiratory Endoscopy Unit, and 3 Respiratory Endoscopy Unit, Unidad Médico-Quirúrgica de Enfermedades Respiratorias, Hospital Universitario Virgen del Rocío, Sevilla, Spain.
CORRESPONDENCE: K. Psathakis, Dept of Pneumonology, Army General Hospital of Athens, Liakataion 15, 11474 Gyzi, Athens, Greece. Fax: 30 2107494095. E-mail: kpsazakis{at}hol.gr
Keywords: D-dimer, fibrinolysis, inflammation, neutrophil, pleurodesis, talc
Received: August 20, 2005
Accepted December 3, 2005
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ABSTRACT |
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The current authors investigated a total of 168 patients with malignant pleural effusion, who were treated with talc poudrage. According to the outcome the patients were categorised into one of two groups, either successful or failed pleurodesis. In all cases, pleural fluid neutrophils and DDS were determined on serial measurements at 0, 3, 24 and 48 h after the procedure. The time course of these parameters was assessed in both groups and the time point at which they could better predict the outcome was further explored.
Neutrophils rose rapidly after talc poudrage in both groups, reaching a plateau at 24 h, although in successful pleurodesis this response was significantly higher. DD dropped markedly at 24 h in the group with the successful outcome, but it did not show significant changes in the other group. A cut-off value of 61% for neutrophils and 61 mg·L–1 for the DD at 24 h yielded the best prognosis for successful pleurodesis.
The current authors conclude that serial measurements of neutrophil and D-dimer values into the pleural fluid after talc poudrage could be used as predictors of the outcome of pleurodesis.
Chemical pleurodesis intends to achieve a symphysis between visceral and parietal pleural layers, in order to prevent the accumulation of either fluid or air in the pleural space. The palliative treatment of malignant pleural effusions (MPEs) is one of the main indications for pleurodesis 1.
There is a long list of sclerosant agents that have been proposed for pleurodesis 2. Presently, talc is considered as the preferable agent as it is effective, cheap, widely available and associated with minimal side-effects in most studies 3, 4.
The pathophysiological mechanisms involved in pleurodesis are still unclear. They may be specific to the agent used, but they may all follow a common final pathway. It has been hypothesised that after the instillation of the sclerosant agent an activation of the normal mesothelial cells follows, which in turn is followed by the activation of a coagulation cascade and the inhibition of fibrinolysis into the pleural space. The accumulation of fibrin into the pleural cavity serves as a fibrin bridge between the visceral and parietal pleura, which is the first step for fibroblast recruitment and the formation of fibrous tissue 1. According to this hypothesis, it was found that increased levels of D-dimer (DD) in the pleural cavity after talc instillation, which reflected increased fibrinolytic activity, were associated with the failure to develop talc pleurodesis 5. Previous observations also demonstrated that after talc instillation a neutrophilic inflammation was elicited into the pleural cavity 6. Although the role of polymorphonucleates (PMN) in achieving pleurodesis is still unclear, it was found that the intensity of neutrophilic inflammation was higher in cases where pleurodesis was eventually successful, compared with the cases where pleurodesis attempts failed 5.
The current authors hypothesised that combined serial measurements of the PMN and DD values into the pleural space, after talc instillation, could be used to predict the outcome of pleurodesis.
The aim of this study was to monitor the intensity of the neutrophilic response (PMN levels) and the fibrinolytic activity (DD levels) into the pleural fluid, after talc insufflation, in patients with MPE. The current authors' main objective was to examine whether these parameters could be used as predictors for the outcome of pleurodesis. A secondary objective was to examine the relation between PMN and DD into the pleural cavity, during the response to talc, as well as the association of the pleurodesis outcome with the local disease extension.
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MATERIAL AND METHODS |
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and 2. All the patients were referred to the Hospital Universitario Virgen del Rocío (Seville, Spain) Endoscopy Unit for a diagnostic thoracoscopy and/or palliative treatment with talc pleurodesis. The diagnosis was established either by thoracoscopic pleural biopsy, performed at the time of the study or it was already known from a previous pleural fluid cytology. Patients who were proven to have benign pleural effusions were not included in the study. Patients who lived <1 month after the procedure were also excluded. None of the patients had previously been treated for pleural disease or had undergone invasive diagnostic procedures for pleural disease, other than thoracocentesis. All patients gave informed consent and the study was approved by the Hospital Universitario Virgen del Rocío Ethics Committee.
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The outcome of pleurodesis in each case was evaluated 1 month after the procedure and at 3-month intervals thereafter until death, using previously published criteria 10. According to the outcome, the patients were then categorised into two groups, either successful (S) or failed (F) pleurodesis. Total leukocyte and neutrophil blood cell counts were normal in both patient groups at baseline (before thoracoscopy).
Pleural fluid sample collection and analysis
Pleural fluid samples were collected by thoracocentes is immediately before the induction of pneumothorax for thoracoscopy and again at 3, 24 and 48 h after the procedure, through the chest tube. The pleural fluid samples were immediately stored in plastic containers with sodium citrate (ratio of 5:1, respectively) and were processed within 30 min after collection. After the centrifugation of the samples, the cells were collected and direct smears, as well as cytospin slides, were prepared. Cell staining was performed with Quick Panoptic stain (Química Clínica Aplicada, Amposta, Spain). Cell differentiation was conducted by counting 400 cells per slide and PMN levels were expressed as the percentage of the total nucleated cells.
In the supernatant of each sample DD levels were measured by the sandwich ELISA technique (NycoCard kit; Axis-Shield, Oslo, Norway) and expressed as mg·L–1. The method had a detection limit of 0.1 mg·L–1.
Statistical analysis
Normal distribution of the various parameters was assessed by Shapiro–Wilks test. Homogeneity of variance was assessed by the Box's M-test. Patients' characteristics were expressed as mean±SD. PMN and DD values were given as means with 95% confidence intervals (CIs). The time course of PMN and DD was assessed with repeated measures of ANOVA with one-within factor (time with four levels) and one-between factor, with two levels (S and F patients). Post-hoc Bonferroni-adjusted tests were performed to pinpoint differences. Receiver-operating characteristic curves were constructed in order to assess at which time-point the two parameters (PMN, DD) contained better prognostic information for an outcome. Pearson's correlation coefficient was used to assess the extent of association between continuous parameters (PMN and DD). Unpaired t-test for independent samples was used to assess whether the score of lesions between the two groups (S and F) was different. A p-value <0.05 was considered significant.
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RESULTS |
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Repeated measures ANOVA showed that the mean PMN values in the S group of patients rose rapidly (p<0.001) during the first few hours, reaching a peak at 24 h (changing from 7 to 50% within 3 h and then to 79% at 24 h) where it remained practically constant for the next day. The mean PMN values in the F group of patients rose during the first 3 h at the same rate as in the S group, but the increase rate during the remaining 21 h was significantly less (p = 0.005) than those with a successful outcome. The mean PMN values in the F group of patients at 24 h were not significantly greater than those at 3 h (p = 0.73) or than those at 48 h (p = 0.85, table 3, fig. 1).
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The mean DD values in the S group of patients started to drop significantly 3 h post-talc application, falling from 86 to 35 mg·L–1 by the end of the day, where it remained for the next day (p<0.001). The DD changes did not reach statistical significance (p = 0.30) during the 48-h period in the F group. Unlike the S group of patients though, DD increased during the first 3 h (table 3, fig. 2).
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). PMN values at 24 h gave the best prognosis for successful pleurodesis. A cut-off value of 61% yielded 82% sensitivity and 75% specificity. DD at 24 h had a similar prognostic value. A cut-off DD value of 61 mg·L–1 yielded 85 and 80% sensitivity and specificity, respectively.
In this group of patients, a cut-off value of 61% for the PMN at 24 h was calculated to have a positive predicted value (PPV) of 95% and a negative predictive value (NPV) of 21.4% for successful pleurodesis. A cut-off value of 61 mg·L–1 for the DD at 24 h was calculated to have a PPV of 97.4% and a NPV of 12.2% for successful pleurodesis.
PMN and DD were marginally correlated before pleurodesis (r = 0.193, p = 0.046). After the procedure, PMN showed a significant negative correlation with DD at 24 h (r = –0.3, p = 0.004) and at 48 h (r = –0.282, p = 0.014, table 4).
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DISCUSSION |
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TOPABSTRACTMATERIAL AND METHODSRESULTSDISCUSSIONREFERENCES |
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PMN levels, in the first 24 h after talc poudrage, were significantly increased when compared with the baseline values and after this time they reached a plateau. This profile was similar in both groups of patients (S and F), although after the first 3 h PMN reached significantly higher levels in the S than in the F group. This difference remained significant, at least, for the next 45 h after talc poudrage. These findings may imply that the more intense the neutrophilic response to talc, the more likely the pleurodesis is to be successful. The highest failure rate was found in mesotheliomas in the current series, and most of those cases showed a poor neutrophilic response to talc. The current authors thus speculate that the tumoural mesothelium was unable to react adequately to talc stimulation. Also, the DD profile in most of those failed cases showed an increased fibrinolytic activity, which is in relation with the well known pro-fibrinolytic expression of many tumours in advanced stages 11, 12.
DD values, in the S group, showed a marked drop in the first 24 h after talc poudrage and remained there for the next 24 h. In the F group the DD values remained practically unchanged, since they oscillated around the baseline levels without significant changes.
In successful pleurodesis, PMN and DD values showed their most dramatic changes during the first 24 h. At this time, a dissociation between the PMN and DD curves was observed (fig. 3), with the PMN reaching their highest levels and DDs reaching their lowest levels. Both values remained in a plateau for the next 24 h. It seems that the events taking place in the first 24–48 h, in the pleural cavity, may be critical for the outcome of pleurodesis. In order to achieve a successful pleurodesis, it is crucial for the lung to have been re-expanded at this period of time and the two pleural layers to have been opposed 1. This apposition facilitates a primary, loose connection of the two layers by a locally elaborated transitional fibrin neomatrix. Remodelling of the fibrin neomatrix by migration of inflammatory cells and fibroblast into the pleural cavity will eventually result in the formation of fibrotic tissue 13. It is evident that the early apposition of the parietal and visceral pleura and the formation of the fibrin neomatrix are both necessary for the achievement of pleurodesis 1, 8.
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The role of PMN in pleurodesis is unclear but it has been shown that proteolytic enzymes, released by PMN may cause mesothelial denudation, which has a key role for the development of pleural fibrosis 18, 19. Proteolytic enzymes may also degrade many coagulation proteins, thus modulating both the thrombotic and the fibrinolytic systems 20. PMN interact mostly with platelets to activate coagulation 21, but also enhance fibrin deposition through platelet-independent mechanisms 22. It has been shown that the migration of PMN into the pleural space facilitates the exudation of fibrinogen 23.
In the present study, it was observed that PMN and DD values were marginally correlated before talc poudrage, but they showed a strong negative correlation within 24 and 48 h. Although the nature of this interrelation is obscure, it seems that a successful pleurodesis with talc needs an intense neutrophilic reaction with concurrent suppression of fibrinolysis. This loss of fibrinolytic activity might be caused by PMN-mediated degradation of plasmin, as well as both urokinase and tissue-type plasminogen activators 24.
The current authors found that PMN values >61%, and DD values <61 mg·mL–1, 24 h after talc poudrage, could best predict a successful result. However, these cut-off points should be considered as indicative because the efficacy of talc as a sclerosant (success rate = 92%) might produce a bias, due to the small number of patients in the F group. The results from the current study imply that cases that tend to have a different pattern of response to talc than that summarised in figure 3 will probably fail. In such cases additional measures could be considered to enhance local reactions, such as the application of an additional dose of talc through the thoracic tube (slurry) or the prolongation of pleural drainage for a few days with increased suction.
The present authors conclude that talc, shortly after its instillation, induces a neutrophilic reaction and causes a decrease of the fibrinolytic activity into the pleural cavity. The intensity of these reactions, reflected by the levels of polymorphonucleate and D-dimer in pleural fluid after talc poudrage, seems to correlate with the outcome of pleurodesis. Since the measurement of both polymorphonucleate and D-dimer values can be performed by simple and easily available techniques, the current authors believe that these parameters can be useful in monitoring the ongoing pleurodesis process after the application of talc.
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) the PMN rose significantly and reached a plateau at 24 h (***: p<0.001). The failed pleurodesis group (•) followed a similar, but significantly less intense, pattern of response (#: p = 0.005). The difference of the mean PMN values between the two groups was not significant at 0 and 3 h, but it was significant at 24 and 48 h. ***: p<0.001; #: p = 0.005; ¶: p = 0.023; +: p = 0.027.
) mean values, in the successful pleurodesis group of patients. - - -: The cut-off values for PMN and DD, respectively, that gave the best prognosis for the outcome of pleurodesis.