Title of the project: To assess the role of respiratory physiotherapy in the effectiveness of pleurodesis in adult patients with malignant pleural effusion.

Background:

            Certain primary or metastatic cancer causes pleural effusions and causes  severe respiratory symptoms. Malignancy is the major cause of both exudative pleural effusions and massive recurrent pleural effusions.[1] These effusions tend to recur in more than 90% of patients.[1] A confirmed malignant pleural effusion requires palliative treatment aimed mainly at alleviating the dyspnea caused by the tendency of the effusion to recur. In view of the limited life span in patients with malignant pleural effusion, the goal of management is aimed at sustained symptom relief, shortening the length of hospitalization, improvement of quality of life and minimizing the number of invasive procedures. A number of treatment strategies for the pleural effusion are available.  The most cost-effective method of controlling a malignant pleural effusion is chest tube or catheter drainage and intrapleural instillation of a chemical agent. [1,2]

            Pleurodesis is an accepted palliative management for patients with symptomatic or recurrent malignant pleural effusion.[3] Pleurodesis involves instilling an irritant into the pleural space to cause inflammatory changes that result in bridging fibrosis between the visceral and parietal pleural surfaces, effectively obliterating the potential pleural space.  

            Simple small bore drainage catheters have been used effectively for drainage of pleural fluid. There are emerging data on the use of small-bore tubes for chemical pleurodesis.[2,4,5]. Pigtail catheter is considered a safe, easy, tolerable and effective alternative method in comparison to the traditional intercostal tubes in pleurodesis of malignant pleural effusions.[2]

            Before a sclerosing agent is injected, the ability of the lung to reexpand should be confirmed. Also, increase duration of chest tube drainage is associated with increased hospital stay and increase risk of potential infection. So, it is warranted to decrease the duration of pleural fluid drainage prior to pleurodesis. The physiotherapy intervention has been reported to enhance the pleural fluid drainage. It also helps in lung reexpansion and this aids in faster pleural fluid drainage and resolution of symptom of dspnoea.[6] Physiotherapy is an important intervention that prevent and reduces the negative effects of prolonged bed rest during hospitalization and improves the respiratory function in patients with pleural effusion. Some authors have proposed treatment of pleural effusion with physiotherapy, however no definitive conclusion could be drawn about the success of this treatment on malignanat pleural effusion and pleurodesis.[6,7]

Lacunae in existing Knowledge: 

·         Though physiotherapy intervention has been well described for lung expansion after surgical intervention but it is not known whether such intervention can produce similar kind of re-expansion in subjects with unilateral malignant pleural effusion. Since lung expansion is paramount for the effectiveness of pleurodesis, there exists a need to compare the effectiveness of respiratory physiotherapy intervention with deep breathing exercises, purse lip breathing and incentive spirometry on the chest expansion in patients with unilateral pleural effusion and thus the effectiveness of pleurodesis.

Research Question:

·         Do respiratory physiotherapy increases the effectiveness of pleurodesis for malignant pleural effusion in adult patients?

Aim of the study:

·         To evaluate the effect of the respiratory physiotherapy on  effectiveness of pleurodesis in adult patients with malignant pleural effusion.

Hypothesis:

·         Respiratory physiotherapy in adult patients with malignant pleural effusion improves the effectiveness of pleurodesis.

Study design and methodology:

Study design – Prospective randomized study

Method: After ethical approval, this prospective randomized study will be carried at Pain and Palliative Care Clinic, Dr BRA Institute Rotary Cancer Hospital, AIIMS, New Delhi, India. Adult patients with diagnosed cancer of any site, having malignant pleural effusion [confirmed by pleural fluid cytology and/or either computed tomography (CT)-guided biopsy or tissue biopsy] and requiring pleurodesis will be recruited for the study. The diagnosis of pleural effusion will be based on the presence of consistent radiological findings in posteroanterior (PA) and lateral chest (ipsilateral) radiographs in addition to the clinical presentation (dyspnea, pleuritic chest pain). Informed consent form will be signed prior to participation and ‘patient information’ sheet will be provided and explained to all participants. Visual analog scale score (VAS) (0-no pain to 10-worst pain) for assessment of pain will be explained to the patient.

Inclusion criteria:

·         Recurrent and symptomatic malignant pleural effusion

·         Age more than 18 years

·         Life expectancy> 3 months

Exclusion criteria:

• Atelectasis due to endobronchial obstruction
• Previous pleural procedures (except for thoracocentesis and/or pleural biopsy).
• Cognitive impairments or comprehension deficits.
• Coagulopathies (PT INR>1.5, and/or thrombocytopenia (platelet count <80000/mm³).
• Active pleural or systemic infection.
• Unstable cardiovascular status i.e. hemodynamic instability requiring inotropes/vasopressors, recent myocardial infarction < 5 days or uncontrolled arrythmias
• Refusals.

The patients will be randomized to one of the two groups by computer generated random number concealed in opaque sealed envelope:

·         Group A (control group): Patients will receive standard therapy (thoracocentasis using pigtail catheter and pleurodesis using Bleomycin)

·         Group B (Intervention group): Patients will receive respiratory physiotherapy (deep breathing exercises, purse lip breathing and incentive spirometry) in addition to standard therapy (thoracocentasis using pigtail catheter and pleurodesis using Bleomycin)

Procedures in the two groups:

Thoracocentasis and catheter placement: The patients will be made in a sitting position on the edge of the bed, leaning forward with the patient’s arms resting on a bedside table. When the patient is not able to be placed in a sitting position, the lateral decubitus or semidecubitus position will be used. Preprocedural ultrasound evaluation will be done to localize the pleural fluid pocket and skin entry site at the posterior intercostal space. After cleaning and draping, the skin entry site will be infiltrated with 2% lidocaine with adrenaline (3-5 mL). After making a small skin incision, an 12 F pigtail catheter will be inserted by single puncture trocar technique under ultrasound guidance. Once the needle tip is positioned inside the fluid pocket, the outer soft sheath will be advanced over the metal stylet needle, which will be later removed.  A three-way stopcock will be connected to the hub, which in turn will be connected to underwater seal for drainage of pleural effusion. The serial chest x-ray will be done once daily to evaluate the lung expansion and drainage of pleural fluid. The amount of pleural fluid will be noted and when the chest drain output is less than 100 mL over 24 hours, chest x-ray will be repeated to note expansion of the lung.

Pleurodesis: Once the expansion of lung is ensured, sclerosing agent (Bleomycin) (1 IU/kg, maximally 60 units) along with 2 mg/kg of lidocaine diluted in total of 50 mL of normal saline will be injected through the catheter into the pleural space. The catheter will be clamped for 12 hours and then released for any residual pleural fluid. If during next 24 hours drain output will be less than 150mL, pigtail catheter will be removed and dressing will be done using tincture iodine. Repeat chest x-ray will be done before discharge.

Intervention:

Physiotherapy treatment: The trained physiotherapist will explain the physiotherapy intervention to all patients. Patients in intervention group will be instructed to perform the following intervention 4 times per day:

·         Deep breathing exercises [8,9]:The deep breathing will be performed in four sets of five repetitions of deep breaths, from tidal expiration to maximum inspiration (ie from functional residual capacity to total lung capacity), with a 3-second inspiratory hold followed by relaxed expiration. The physiotherapist will train the patient by providing proprioceptive feedback by placing his hands bilaterally on the patient’s lower ribs. These exercises will be completed with the patient sitting on a chair or on a bed with the head end raised. Normal breathing will be encouraged between the repetitions of deep breathing exercises.

·         Pursed lip breathing [10]: The purse lip breathing will be done in four sets of five repetitions each waking hour. The patients will be instructed to make a normal tidal volume nasal inspiration followed by expiratory blowing against partially closed lips avoiding forceful exhalation.

·         Incentive spirometer [11]: This will be performed by patients using a volume-oriented incentive spirometer, which has coloured piston for indicating volume and rattle indicator for indicating flow. After a quiet expiration, patient will be encouraged to take slow maximal inspirations through the mouthpiece of the device and to hold each breath for as long as possible. While maintaining the rattle indicator in smiley face zone (flow indicator). The patients will be encouraged to use the device for 10 breaths per hour.

            Pigtail catheter insertion, and pleurodesis will be performed by a trained Palliative Care physician in association with Interventional Radiologist. The physiotherapy interventions will be trained and supervised by the physiotherapist. The assessment of pleurodesis success in the follow up period will be performed by an investigator blinded to allocation.

            The duration from insertion of pigtail catheter and time of pleurodesis and duration from time of pleurodesis and time of removal of pigtail catheter will be noted. The total length of hospital stay i.e. from day of admission for pleurodesis and till date of discharge from the hospital will also be noted. Patients will be considered ’pleurodesis fit for discharge’ the day the chest tube is removed. 

            The routine follow up in such patients is done at Pain and Palliative Care clinic at Dr BRAIRCH, AIIMS, New Delhi. The chest x-ray (posteroanterior and lateral chest radiographs) will be done at baseline, at discharge and repeated at 1, 3 and 6 months in follow up. The baseline pain,  pain induced during procedure including pleurodesis, at discharge and follow up at 1, 3 and 6 months will be  recorded as per VAS score and controlled with standard management including NSAIDS, Paracetamol and opioids to keep the Visual analog scale score (VAS) <4. The severity of dyspnoea will be assessed and recorded as per Modified Medical Research Council Dyspnea Scale (MMRC) [12] at baseline, after pigtail catheter drainage, at discharge and during follow up at 1, 3, and 6 months..

            Any complications like fever, bleeding, air-leaks/pneumothorax in periprocedural period will be noted.

Primary Outcome Variable:

·         The effectiveness of pleurodesis as assessed by reaccumulation of pleural fluid on chest radiographs on follow up at 1,  3 and 6 months - Revised to follow up at 1 month.

Secondary Outcome Variable:

·         Length of hospital stay for pleurodesis.

Research variables

·         Chest radiographs grading of size of malignant pleural effusion [13]: It will be graded into three groups:

o   small-to-moderate malignant pleural effusion will be defined as occupying less than one-quarter of the hemithorax;

o   moderate-to-large malignant pleural effusion will be defined as occupying greater than onequarter, but less than the entire hemithorax; and

o   massive malignant pleural effusion will be defined as those effusions occupying the entire hemithorax

·         The effectiveness of pleurodesis will be assessed as [14,15,16]:

o   Complete response: if there will be no reaccumulation of pleural fluid in the chest radiograph in the same hemithorax, after catheter removal, during the follow up period.

o   Partial response: Small amount of fluid re-accumulation in the chest radiograph after catheter removal but not causing symptoms and not requiring repeated thoracocentesis or tube drainage.

o   Failure of pleurodesis: It will be considered if there will be difficulty to remove the catheter, because the pleural fluid drained through it is more than 250 mL/24 h (primary failure) or there was fluid reaccumulation after tube removal, that  caused symptoms to the patient or necessitated repeated thoracocentesis or intercostal tube drainage, during the follow up period (secondary failure).

·         Grading of Dyspnoea: Garding of Dyspnoea ie shortness of breath will be done as per Modified Medical Research Council Dyspnea Scale (MMRC) [12]:

Sample Size and Statistics:

·                     Sample Size:  The success rate of pleurodesis with bleomycin alone at one month documented in other studies ranges from 60-75 % [14,15,16]. However, no study has tried to combine the respiratory physiotherapy with standard therapy (thoracocentasis using pigtail catheter and pleurodesis using Bleomycin) to observe the effectiveness of respiratory physiotherapy on pleurodesis. However, if presume that physiotherapy might results in increase in success of pleurodesis at one month by 15% (i.e. from 65% to 80%), than for one sided test, considering 95% confidence interval and power of 80%, a minimum of 65 patients in each arm will be required. Also, to best of our knowledge, as per review of literature, there is no evidence available through randomized controlled trial on the added effectiveness of respiratory physiotherapy along with standard therapy (thoracocentasis using pigtail catheter and pleurodesis using Bleomycin) on pleurodesis. Hence, it was not feasible to formally explore the required sample size for the study. However keeping in view of past experience a total of 50-60 patients/year are expected to be available who fulfill inclusion criteria to be part of the study. Accordingly this study proposed for 2 years is expected to cover a total of about 130 patients which will be sufficient to generate preliminary finding in this study.

            Data collected will be collated and analyzed statistically using SPSS version 20.0 software.

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