Introduction
The pleura is a serous lining derived from the mesoderm whose function is related to allowing the coupling of the movement of the thoracic cage with the lung during respiratory movements, the pleural fluid being the lubricant for such movement [1]. The accumulation of pleural fluid is attributed to 3 possible factors: alteration of transpleural pressures, alteration of lymphatic drainage, or increased permeability of mesothelial and endothelial capillaries; of these, the former is the only one that does not alter protein concentrations [2]. This chapter discusses pleurodesis, especially in the setting of malignant pleural effusion, its history, indications, complications, and benefits, giving general guidelines and indicating some particularities when relevant.
Pleurodesis
It comes from the Greek roots pleurá (pleura) and desmos (union), referring to the obliteration of the pleural space by the adherence of the visceral pleura with the parietal pleura, through a stimulus that generates inflammation and fibrosis. It’s indicated for the management and prevention of pleural effusions and pneumothorax [3].
History
The first description of this procedure is attributed to Luios Spengler in 1906 when he administered glucose solutions and silver nitrate in the pleural cavity to favour the adhesions as management of pneumothorax [4]; Noman Bethune in 1935 proposed the use of iodized talc after lobectomy for bronchiectasis [5]; pleurodesis by abrasion was described by Dr Edward Delos in 1941 [6], and only in 1958 was described the use of talc in malignant disease by Dr J. Chambers [7]. Multiple substances or interventions on the pleura have been used to achieve pleurodesis, all with the purpose of generating fibrosis and adhesion between pleurae, starting with talc [8–10], iodized talc [7, 11], silver nitrate [12], iodine [13], extending to the use of antimicrobials such as tetracycline [14, 15], doxycycline [16–20], minocycline [18, 21] tigecycline [22, 23], quinacrine [24], mepacrine [25], cytotoxics such as bleomycin [18, 19], mitomycin [26, 27], mitoxantrone [28, 29], platinum derivatives [30, 31], bacterial agents such as Corynebacterium parvum [32], OK-432 (a derivative of Streptococcus) [26, 33], Staphylococcus superantigens [26, 34, 35], lipoteichoic acid [36], reaching haematic patches [37–39], hypertonic glucose [40–42], mistletoe-derived substances such as Viscum album [43–45] and thermal ablation [46]; with new tools in the future such as the use of natural glues such as sericin [47] and the use of transforming factor b [48]. Emerging closed variations by thoracotomy, thoracoscopy, pleuroscopy, and even hybrid techniques of permanent pleural catheters with talc with and without thoracoscopy [49].
Pleural involvement due to cancer
The diagnosis of malignant pleural effusion is based on documentation of malignant cells in the fluid or on pleural biopsy. Closed biopsy achieves a yield of about 45%, cytology of the liquid about 60%, biopsy guided by computed axial tomography (CT) 87%, biopsy guided by ultrasound 90%, and reaching values of 95% thoracoscopy and pleuroscopy [50].
Chronic pleural effusion, absence of fever, haemorrhagic features of the fluid, and some findings on CT scans predict malignant aetiology [51]. Pleural involvement by cancer is attributed to a local invasion by contiguity or haematogenous or lymphatic dissemination [52], most of them being metastatic [53].
Situations in which pleural effusion associated with cancer can be found are (1) direct involvement of the pleura, (2) lymphatic or venous obstruction, (3) bronchial obstruction with atelectasis, (4) post-obstructive pneumonia with parapneumonic effusion, (5) hypoalbuminemia (Fig. 1) [54]. Most malignant pleural effusions are attributed to adenocarcinomas, especially of the lung [55–58].
According to necropsy reports, 28% of patients with cancer present pleural metastases and 15% pleural effusion [3]. Malignant pleural effusion is characterized by a lymphocytic exudate [59, 60]. However, a non-negligible percentage, between 5% to 10% of malignant pleural effusions, are transudates considered as a superposition of both or false transudates [61]. They can also occur as histiocytic [62] or neutrophilic exudates [63], the latter being a marker of poor prognosis [64]; therefore, it is important to keep this possibility in mind when performing thoracentesis [54, 65, 66].
Patient selection
Dyspnoea is the main marker of pleural involvement due to malignant effusion; its presence impairs patient survival [67], and the basis of its management is the systemic treatment of the disease [68]. However, some chemosensitive tumours, despite having a good response to systemic management, may persist with pleural effusion [69]. Therefore, early pleurodesis is advised to avoid recurrences [70].
In patients with epidermal growth factor receptor (EGFR) driver mutations, pleurodesis may be deferred according to reports, of similar recurrence when early pleurodesis was performed [71–73].
The management choice depends on the clinical scenario, where the type of tumour, the functionality and characteristics of the pleural fluid, and some other parameters stratify survival [64, 74]. The LENT (Tab. 1) [55] and PROMISE (Tab. 2) [75] scores are used to evaluate survival. Once the patient’s probability of survival has been stratified, the possibility of expectant management, pleurodesis, permanent pleural catheter, or thoracentesis can be considered if necessary [76, 77]. A decision that should be based on multidisciplinary monitoring and management, seeking to improve the quality of care according to the guidelines and, probably, improving outcomes [78–80].
|
Variable |
Points |
|
Lactate dehydrogenase (pleural fluid) |
|
|
< 1,500 IU/L |
0 |
|
>/= 1,500 IU/L |
1 |
|
ECOG score |
|
|
0 |
0 |
|
1 |
1 |
|
2 |
2 |
|
3–4 |
3 |
|
Neutrophil to lymphocyte ratio (serum) |
|
|
< 9 |
0 |
|
≥ 9 |
1 |
|
Tumour type |
|
|
Lowest risk: mesothelioma, haematologic |
0 |
|
Moderate risk: breast, gynaecologic, renal cell carcinoma |
1 |
|
Highest risk: lung, other types |
2 |
|
Risk category (median survival in days) |
Total score |
|
Low (319 days) |
0–1 |
|
Moderate (130 days) |
2–4 |
|
High (44 days) |
5–7 |
|
Previous chemotherapy |
|
|
No |
0 |
|
Yes |
4 |
|
Previous radiotherapy |
|
|
No |
0 |
|
Yes |
2 |
|
Haemoglobin (g/dL) |
|
|
16 |
0 |
|
14–16 |
1 |
|
14–12 |
2 |
|
12–10 |
3 |
|
< 10 |
4 |
|
White blood cells (10^9 cells/uL) |
|
|
< 4 |
0 |
|
4–6.3 |
2 |
|
6.3–10 |
4 |
|
10–15.8 |
7 |
|
> 15.8 |
10 |
|
C-reactive protein IU/L |
|
|
< 3 |
0 |
|
3–10 |
3 |
|
10–32 |
5 |
|
32–100 |
8 |
|
> 100 |
11 |
|
ECOG score |
|
|
0–1 |
0 |
|
2–4 |
7 |
|
Cancer type |
|
|
Mesothelioma |
0 |
|
All other cancers |
4 |
|
Lung cancer |
5 |
|
Risk category |
|
|
Category A (< 25%) |
0–20 |
|
Category B (25% to 50%) |
21–27 |
|
Category C (50 to 75%) |
28–35 |
|
Category D (> 75%) |
> 35 |
Pathophysiology of pleurodesis
Pleurodesis is achieved through two types of interventions, the first of them is the direct injury of the pleura with mechanical or physical interventions or through the administration of different substances that favour the development of pleural adhesions [81].
Four primary factors are required: adequate apposition and contact between the pleurae, development of inflammation, activation of coagulation with limitation of fibrinolysis, and involvement of the mesothelium [82].
Such is the response to the foreign body phenomenon generated by some substances such as talc, that pseudomasses or thalcomas can subsequently develop, an element that can generate recurrence concerns in patients undergoing lobectomy for malignant causes [83], with the particularity of showing glucose consumption almost 20 years after the intervention [84].
Respiratory alterations due to pleural involvement
The main symptom attributed to pleural involvement with effusion is dyspnoea, explained by multiple mechanisms such as atelectasis and loss of thoracic distensibility, which generate an increase in respiratory drive and alter ventilatory mechanics [85]. The development of hypoxemia is supported by the appearance of a shunt [86]. In patients with pleural effusion, oxygen consumption (VO2) is low, reaching only 37% of the predicted value; this limitation pattern shows an alteration of ventilatory efficiency with elevated respiratory equivalents for oxygen (VE/VO2) and carbon dioxide (VE/VCO2) and high heart rates with a decrease in oxygen beats (VO2/HR) [87]. This limitation in exercise performance seems to be related to a restrictive component with a drop in forced vital capacity (FVC) [88–90].
Pleural effusion is associated with an increased percentage of N1 stage sleep and decreased REM sleep, which decreases sleep efficiency and impairs sleep quality; management of pleural effusion restores sleep architecture, increases REM sleep, and therefore sleep efficiency and rest [90, 91].
Pleurodesis indications
The indications for pleurodesis are aimed at treating: the recurrence of pneumothorax [92], malignant pleural effusion [76], and exceptionally benign pleural effusion pathologies [93, 94].
The outcomes after pleurodesis in malignant pleural effusion can be classified as follows [95]:
- Complete success: when there is long-term relief of effusion-related symptoms, with an absence of fluid reaccumulation on chest radiographs until death.
- Partial success: decrease in dyspnoea related to the effusion with only partial fluid reaccumulation (less than 50% of the amount of fluid seen on the initial radiograph), without requiring thoracentesis for the rest of the patient’s life.
- Failed pleurodesis: when the definitions previously described are not met.
Selection of the intervention
Particularly for malignant pleural effusion, surgical interventions by thoracoscopy are not superior to drainage and administration of substances by catheter [96, 97]. Bonding agent selections are based on specialist experience who perform the procedure, substance efficacy, whether it can be used for benign and malignant causes, and whether it is widely available, economical, and easy to use; these characteristics have traditionally been achieved by talc and iodine [94, 98, 99].
Adjuvant conditions for pleurodesis
Considering the physiopathogenesis of the procedure (which generates pain), the need to leave a thoracostomy tube to evacuate the air and liquid that enters during the different pleurodesis manoeuvres is imperative to keep in mind to provide measures to reduce the pain burden of the procedure. As an initial measure, administering lidocaine into the cavity is an option [100], and some systemic absorption may occur [101].
The use of smaller calibre drainage tubes improves comfort and pain and is not inferior to larger calibre tubes [102]. Contrary to what occurs with corticosteroids [103], the provision of analgesia with NSAIDs or opioids does not correlate with recurrence or failure of the procedure, but with symptomatic control [104], especially when talc slurry is used, which is particularly painful [105]. Another practice that has been re-evaluated in the procedure is the need to rotate the patient after the administration of the substance, since it has not been associated with any benefit and, on the contrary, it can perpetuate discomfort during pleurodesis [106, 107]. Strikingly, haematic patches have better pain control than the other strategies [37].
After administration of the substance, it is suggested to occlude the drainage for one to four hours and then open it with controlled negative pressure of −10 to −20 cm of water, to allow adequate interaction of the substance with the pleura, favours apposition between the pleurae, and prevent oedema by reexpansion [108]. In addition, the patient should be followed daily with ultrasound guidance to review the evolution of the pleurodesis and define the removal of the tube when the drainage is less than 100 to 150 cc [109], thus impacting hospitalization times [110].
Predictors of response and additional strategies
Traditionally, the importance of nutritional status in the performance of pleurodesis has been emphasized, based on the need to mount a good inflammatory response, for which there are not many studies that support patient nutrition as a marker of response. However, having decreased albumin values does correlate with lower survival rates [111].
The following factors are predictors of successful pleurodesis, some of which are specific to the aetiology of the effusion, such as those secondary to lymphoma, primary ovarian, primary breast, mesothelioma; having an ECOG (Eastern Cooperative Oncology Group) score less than or equal to 2; having performed the procedure by medical thoracoscopy; and having high levels of protein, albumin, and eosinophils in the pleural fluid [112, 113].
Recently, a meta-analysis found that high pH fluid, low amount of fluid at the time of pleurodesis, and complete re-expansion after drainage are the strongest predictors of successful pleurodesis. There are other weaker markers or contradictory reports such as short duration of tube drainage, use of thoracostomy tube, high glucose levels in the fluid, low pleural LDH, and low tumour burden during thoracoscopic evaluation [95, 114]. Achieving a marked elevation of C-reactive protein is related to achieving a good response to pleurodesis, explained by mounting an adequate inflammatory response [115].
Among the different substances used to perform pleurodesis, the performance of all of them is variable. Talc is used as a comparator in many scenarios [116] due to its availability and cost could become one of the substances that achieve greater success in pleurodesis [117]. However, there is retrospective evidence of greater effectiveness with silver nitrate [118], making it a proven rescue option for those who have failed with talc [119]. Atypically, pleurodesis with Corynebacterium parvum is not affected by the pH of the fluid to induce pleurodesis, this being another option in patients with no predictors of response [120, 121].
Another strategy that can be useful to ensure adequate pleurodesis is to use combinations of different substances to increase effectiveness and limit toxicity, such as combining doxycycline and talc [15, 122], bleomycin and doxycycline [123], or even mechanical and chemical strategies [124], with the possibility of repeated infusions in the case of iodine [125].
Recently, a pilot study evaluated the possibility of adding low doses of tissue plasminogen activator together or after talc to avoid mini-loculations and pleurodesis failure, significantly reducing the need for a second intervention [126].
When pleurodesis is attempted using indwelling catheters, the catheter can be combined with talc [49] with daily drainage [127]. At the moment, the strategy with silver nitrate-coated catheters has not been shown to achieve an adequate pleurodesis rate compared to the usual indwelling catheter [128].
Older age, male gender, using a pigtail catheter, haemorrhagic fluid or having a very low pH seem to be related to pleurodesis failure [95, 129]. Having received chemotherapy and radiotherapy or having an ECOG score greater than 2 are predictors of poor post-procedure survival [55, 75, 130].
Exposure to antibiotics before the procedure is a risk factor for developing empyema after pleurodesis [131].
Complications
Considering the mechanism by which pleurodesis is produced, once the process is initiated, an elevation of different inflammatory mediators is expected, which have variable behaviour depending on the substance used, with nitrate and talc being the substances that generate the greatest inflammatory response with respect to iodine [132].
Several complications have been described with pleurodesis, most of them mild to moderate, the most frequent being hypoxemia [133], an event dependent on the inflammatory response, size, and dose when talking about talc [104, 134]. Complications usually tend to be mild to moderate, although anecdotally there have been reports of pneumonitis [135], respiratory failure and ARDS [136, 137], and death from this cause [138]. This phenomenon can occur regardless of the substance used [139, 140]. Risk factors described in this setting are older age and underlying interstitial disease [141].
Recently, a meta-analysis has evaluated the safety and frequency of complications after talc pleurodesis. The complications described are pain associated with the procedure, fever, dyspnoea, pneumothorax, pneumonia, emphysema, persistent leak, persistent drainage, pulmonary embolism, lung injury, respiratory failure, pulmonary oedema due to re-expansion, and ARDS, which tends to be 0% in the cohorts [142]. Chronic pain has also been reported [143].
The possibility of tumour disease has often been highlighted with the use of talc in benign diseases due to possible asbestos contamination, but current medical talc is free of this contaminant and the risk of a second malignancy has been re-evaluated in different series of benign diseases, in which favourable short and long term effects have been found, without clearly documenting a relationship with secondary malignancies [9, 11, 144, 145].
In addition, there is a possibility of developing an interstitial disease, especially in those patients who receive pleurodesis with OK-432, who receive EGFR ITK at the time of pleurodesis, or who initiate it within 30 days after pleurodesis [146]. Failure of pleurodesis with an initial strategy could be resolved by enhancing a new approach with another substance [119].
The infectious complications described after the procedure include pleural involvement and pneumonia, empyema, cellulitis, and seeding in the intervened sites. There are other complications such as pulmonary embolism, infarction, bleeding, and pulmonary oedema. Additionally, episodes of air embolism have been described [147].
Particularly with iodine, loss of vision due to retinopathy has been reported, leaving significant scotomas when large volumes of 10% iodine are used [148], being necessary to clarify that, despite this, greater toxicity due to systemic absorption has not been documented attributed to a diseased pleura that limits its absorption [125, 149].
Regarding the use of doxycycline, when used in high doses it can cause pleural burns [150] and renal failure due to systemic absorption of the drug [151].
Special care is required for patients who present communication of the airway with the pleura, as they may present complications derived from pleural instillation and subsequent passage to the airway, which poses a risk of death [152].
Benefit of pleurodesis
Pleurodesis is the standard for the control of dyspnoea generated by the recurrence of effusions as a definitive strategy, surpassing in this sense the pleural catheter [117], being more cost-effective in those patients with prolonged expected survival [153, 154].
It has been established that changes greater than 10 on the visual analogue scale of dyspnoea are clinically significant for patients submitted to pleurodesis [155, 156]. This change occurs in approximately 74% of patients, showing in some opportunities a lower tendency to adverse effects than with the use of the pleural catheter [157].
Finally, it is important to mention that the main benefit of pleurodesis lies in improving the survival of well-selected patients in whom the procedure is successful [157–160].
Declaration of conflict of interests
The authors declare that there is no conflict of interest.
Funding
None declared.
