Original Article

Asian Cardiovascular & Thoracic Annals

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ß The Author(s) 2018
The effect of iodopovidone versus Reprints and permissions:
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bleomycin in chemical pleurodesis DOI: 10.1177/0218492318778485
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Reza Bagheri1, Marzieh Noori2, Maryam Rajayi1,

Davood Attaran1, Amir Mohammad Hashem Asna Ashari1,
Shahrzad Mohammadzadeh Lari1, Reza Basiri1,
Fariba Rezaeetalab1, Reza Afghani3 and Maryam Salehi4

Abstract
Background: Malignant pleural effusion continues to be a common problem in patients with metastatic disease.
This study was conducted to compare the efficacy and safety of bleomycin pleurodesis with povidone-iodine pleurodesis
through a chest drain as palliative treatment for recurrent malignant pleural effusion.
Methods: Sixty cancer patients (36 males and 24 females) with recurrent malignant pleural effusion were enrolled
in a prospective randomized trial. Thirty patients received povidone-iodine pleurodesis and 30 received bleomycin
pleurodesis. Age, sex, side of the primary pathology, treatment outcome (recurrence and relapse time), and complica-
tions were analyzed.
Results: The mean age was 59.63  7.68 years in the povidone-iodine group and 57.97  9.27 years in the bleomycin
group (p ¼ 0.452). The complications were identical in both groups: 2 (6.7%) patients had chest pain, 2 (6.7%) had fever,
and one (3.3%) had hypotension. There was a good response to therapy in 20 (66.7%) patients in the bleomycin group
and 25 (83.3%) in the povidone-iodine group (p ¼ 0.136).
Conclusion: The results of this study indicate that povidone-iodine should be considered as a selective chemical agent
to perform pleurodesis in patients with recurrent malignant pleural effusion because it has the same effect but costs less
than bleomycin.

Keywords
Bleomycin, Palliative care, Pleural effusion, malignant, Pleurodesis, Povidone-iodine, Treatment outcome

and ovarian carcinomas account for less than 5% of

Introduction
Malignant pleural effusion is detected by malignant
cells in pleural fluid or pleural tissue obtained by
needle biopsy through the skin, or by thoracoscopy,
thoracotomy, or autopsy. In some patients with
proven malignancy and related pleural effusion, malig-
nant cells are not found in the fluid or pleural tissue;
this is referred to as para-malignant effusion. Almost all
cancers can metastasize to the pleura. Lung cancer is
the most commonly diagnosed pleural tumor due to its
proximity to the pleural surface and tendency to invade
the pulmonary arteries and embolize the visceral
pleura. Breast cancer, which commonly metastasizes
to the pleura, was responsible for approximately 25%
of malignant pleural effusions in a large series. Gastric
malignant pleural effusions.1 Disrupted lymphatic
drainage of the pleural space is the main mechanism
for accumulation of a large volume of pleural fluid in
1
Lung Diseases Research Center, Mashhad University of Medical Sciences,
Mashhad, Iran
2
Endoscopic and Minimally Invasive Surgery Research Center, Mashhad
University of Medical Sciences, Mashhad, Iran
3
5th Azar Hospital, Golestan University of Medical Sciences, Gorgan, Iran
4
Society Medicine, Ghaem Hospital, Mashhad University of Medical
Sciences, Mashhad, Iran
Corresponding author:
Reza Bagheri, Lung Diseases Research Center, Mashhad University of
Medical Sciences, Mashhad, Iran.
Email: Bagherir@mums.ac.ir
2 Asian Cardiovascular & Thoracic Annals 0(0)
malignancies. The inflammatory response to pleural
invasion leads to increased microvascular permeability
and variable degrees of effusion. Oxygen radicals,
arachidonic acid metabolites, proteases, lymphocytes,
immune complexes, and vascular endothelial growth
factor are also involved.
The most common clinical manifestation in patients
with carcinoma or pleural lymphoma and bulky pleural
effusion is exertional dyspnea. Due to the fact that
malignant pleural involvement is an indicator of
advanced disease, these patients often have weight
loss and an ill appearance. Patients with pleural carcin-
omas may complain of chest pain due to involvement of
the parietal pleura, ribs, or chest wall.1 On examining
many cases of malignancy, cytology of the pleural fluid
gave a diagnostic result of 66%, and percutaneous
pleural biopsy had a diagnostic result of 46%. If both
methods are used, the result is reported positive in 73%
of cases. When pleural effusion is proven malignant or
para-malignant, and the patient is not a suitable candi-
date for surgery, palliative care and treatments should
be considered. The factors in this decision are overall
condition, symptoms, and expected survival. The range
of treatments varies from observation of symptom-free
patients to thoracotomy and pleurectomy.1 For most
patients, the greatest effect with the lowest morbidity
can be achieved with chest tube drainage and infusing a
sclerosing substance into the pleural space. The accu-
mulation of malignant fluid in the pleural cavity is due
to advanced malignancy, and most patients undergo
chemotherapy or alternative treatments. When fluid
accumulation is resistant to chemotherapy or recurs
after chemotherapy, local treatments such as thoracent-
esis, pleurodesis, pleurectomy or pleuroperitoneal
shunting are used.2
Pleurodesis is a process to create adhesion and pre-
vent the accumulation of air or fluid in the pleural
cavity. This technique is also used in cases of recur-
rence. Pleurodesis can be carried out with chemical
agents or physical abrasion of the pulmonary mem-
brane during thoracotomy or thoracoscopy. The ideal
chemical agent for pleurodesis should be very effective
with a high molecular weight and high chemical
polarity, cheap, affordable, safe, and have minimal
side-effects. At present, no agent has been found to be
optimal, and research is still ongoing. Many chemicals,
including tetracycline derivatives (doxycycline or mino-
cycline), talc and bleomycin, mitoxantrone, nitrogen
mustard, silver nitrate, and povidone-iodine (PVP-I)
have been used, each with its own advantages and
disadvantages. The most widely used material for this
purpose in countries such as the United States, Britain,
Canada, and Australia is talc with tetracycline and
bleomycin. Due to some complications such as acute
respiratory distress syndrome as well as cost and
sometimes lack of access in developing countries,
studies have been conducted to find alternatives with
lower cost and greater accessibility.3 In our country,
because talc is not available, bleomycin is used for
this procedure. PVP-I, which is used as a local disin-
fectant, has been considered an effective agent for
chemical pleurodesis in recent years.4 PVP-I is cheap
and available and might be a good alternative to
other chemicals.5 The aim of this study was to evaluate
the efficacy and safety of PVP-I for chemical pleurod-
esis in patients with malignant pleural effusion, and to
compare it with bleomycin.
Patients and methods
A clinical trial was conducted between 2015 and 2017 at
Ghaem Hospital in Mashhad, Iran. All human-related
issues were in accordance with the guides derived from
the Helsinki Statement. Full consent was obtained from
all patients after the nature of the substances and
their possible side-effects had been fully explained.
This study was also approved by the ethics committee of
Mashhad University of Medical Sciences. This research
was proposed and approved by the Department of
Organizational Ethics of the School of Medicine/
Region of Mashhad University of Medical Sciences,
with code 931250, and registered with IRCT code
IR.MUMS.REC.1394.410.
Sixty patients with metastatic pleural effusion (all
had positive cytology), who were candidates for pleur-
odesis, were randomly assigned to one of two groups,
using block randomization and a table of random num-
bers. Initially, a chest tube was inserted. If the lung was
completely expanded on chest radiography after chest
tube insertion and the volume of secretions was less
than 100 mL, the patient entered the study. The inves-
tigators and patients were unaware of the assigned
group. In the bleomycin group, 15 mg of bleomycin
dissolved in 100 mL of normal saline was injected into
the chest tube, and the chest tube was clamped for 6 h.
In the PVP-I group, 20 mL of 10% PVP-I dissolved in
80 mL of normal saline was injected, and the chest tube
was clamped for 6 h.
Data were collected on age, sex, primary pathology,
outcome of treatment (recurrence and timing), and
complications. Chest radiographs were obtained
before and 24 h after the procedure, and at 2 weeks,
1 and 6 months after discharge. A positive response
to treatment was recorded when there was no fluid
accumulation detected on radiographs obtained
6 months after pleurodesis.
Descriptions of data were performed using descrip-
tive statistics. Mean and standard deviation were used
for quantitative data, and tables and charts were used
for qualitative data. To compare quantitative variables
Bagheri et al. 3

Table 1. Comparison of variables in the bleomycin and PVP-I Mesothelioma, breast cancer, and lung cancer are the
groups. major causes of pleural effusion due to malignancy.
Based on the background disease, patients may survive
PVP-I Bleomycin
group group for several months to several years. The quality of life
of these patients is important, and the aim of treatment
Variable (n ¼ 30) (n ¼ 30) p value should be to reduce symptoms in addition to the
actions taken for the primary illness. Performing aspir-
Sex
ation repeatedly to resolve dyspnea causes physical and
Male 20 (66%) 16 (53%) 0.292
psychological damage and creates a huge workload for
Female 10 (33%) 14 (46%) the healthcare system. Therefore, most patients need to
Mean age (years) 59.63  7.68 57.97  9.27 0.452 have this fluid removed and its accumulation prevented.
Primary pathology Treatment options for pleural effusion due to malig-
Primary lung cancer 10 (33%) 12 (40%) 0.901 nancy are determined by several factors: the magnitude
Metastatic lung cancer 9 (30%) 9 (30%) of the symptoms and the patient’s functional status, the
(bone sarcoma) type of primary tumor and its response to systemic
Metastatic lung cancer 6 (20%) 4 (13%) therapy, and the amount of pulmonary re-dilatation
(soft tissue sarcoma) after discharge of the pleural fluid.6 Pleurodesis is
Metastatic lung cancer 5 (16%) 5 (16%) regarded as the best treatment to prevent recurrent
(uterine sarcoma) pleural effusion induced by malignancy.7 Various tech-
Response to treatment niques and materials have been used with different
Yes 25 (83%) 20 (66%) 0.136 effects and complications.8 Recent studies have shown
No 5 (16%) 10 (33%) the benefits of PVP-I to achieve this goal.9 Bleomycin is
Complications commonly used to treat malignant pleural effusion due
None 25 (83%) 25 (83%) 0.999 to its antineoplastic properties and effect similar to
Fever 2 (6%) 2 (6%)
tetracycline. In a study by Vargas and colleagues10 on
a mouse model, intrapleural injection of bleomycin did
Chest pain 2 (6%) 2 (6%)
not have the appropriate efficacy to produce pleural
Hypotension 1 (3%) 1 (3%)
fibrosis. Because bleomycin is expensive and has less
PVP-I: povidone-iodine. effect than other treatments,11 it is recommended for
patients with nonneoplastic pleural disease such as
pneumothorax, congestive heart failure, or cirrhosis
in the 2 groups, the t test or equivalent nonparametric of the liver.10 PVP-I is a local disinfectant that has
test was used, and the chi-square test was used to been shown to have fewer complications and less
compare qualitative variables. The significance level effect in numerous previous studies. For pleurodesis,
was considered to be less than 0.05. a solution containing 20 mL of 10% PVP-I in 80 mL
of normal saline is used.12 The mechanism of stimula-
tion of the pleura by PVP-I is unknown but it seems to
Results
be associated with the low pH of diluted PVP-I solution
Of the 60 patients, 36 (60.0%) were male and 24 (pH 5.0). In addition, PVP-I has oxidative and cyto-
(40.0%) were female. The mean age was 58.80  8.48 toxic properties that can cause an inflammatory
years (range 41–76 years). The primary pathology was response followed by pleural symphysis.8 We did not
lung cancer in 22 (36.7%) patients and metastatic lung see any serious side-effects associated with PVP-I.
cancer in the other 38 (63.3%). Twenty (66.7%) Agarwal and colleagues8 found in a meta-analysis of
patients in the bleomycin group and 25 (83.3%) in observational studies that PVP-I was effective and
the PVP-I group responded to treatment; there was safe with no mortality, and the most commonly
no significant difference between groups. The main reported complications were chest pain and a systemic
finding of this study was that there was no significant blood pressure drop. However, in a study on 5 patients
difference in the response to treatment or complications with high serum creatinine, Singalavanija and col-
between the PVP-I and bleomycin groups (Table 1). leagues13 noted visual impairment following oral con-
sumption of high-dose potassium iodine. Wagenfeld
and colleagues14 reported a reduction in visual acuity
Discussion
due to disturbance of the retinal pigmented epithelium
Recurrent and symptomatic pleural effusion is common in 3 patients who received 10% PVP-I solution during
in patients with malignancy, affecting 25% of patients thoracoscopic surgery; but the dose of PVP-I solution
with lung cancer and 50% of those with breast cancer. was much higher than that normally recommended.
4 Asian Cardiovascular & Thoracic Annals 0(0)
Teixeira and colleagues15 found that even the highest
concentration of PVP-I (10%) in rabbits caused no
alteration or damage to the retinal pigment epithelium.
Kovacikova and colleagues16 reported that PVP-I,
either locally or as a contrast in imaging, may interfere
transiently with thyroid function, especially in children.
High concentrations of exogenous iodine can destroy
the ability to synthesize thyroid hormone or cause
thyrotoxicosis in people who are susceptible.17
Yeginsu and colleagues18 found that intrapleural
administration of 100 mL of 2% PVP-I had no effect
on thyroid hormone levels in humans. We had no thy-
roid complications in any of our patients. Although
PVP-I may cause chest pain, the cause is unclear but
in most studies, thoracoscopy was used and the patient
has already received anesthesia, thus evaluation of pain
may be false.8 It is unclear whether hypotension is an
anaphylactic reaction or a vasovagal response asso-
ciated with pain. Iodine can cause severe allergic reac-
tions, especially in susceptible patients, so we have to be
prepared to deal with this emergency.8
Lack of fluid accumulation in our patients with
pleural effusion showed that a response to treatment
occurred in 66.7% of the bleomycin group and 83.3%
of the PVP-I group, and there was no significant differ-
ence between the 2 groups. Dey and colleagues4 studied
38 patients with recurrent or malignant pleural effusion
and pneumothorax who had pleurodesis with PVP-I; 34
(89.5%) had no fluid or air accumulation during
34 months of follow-up. Neto and colleagues19 retro-
spectively evaluated the effect of PVP-I for pleurodesis
in malignant pleural effusion in a dose similar to that in
our study; the success rate was 98.4%. Haddad and
colleagues20 evaluated the efficacy and safety of pleur-
odesis using talc and bleomycin in a prospective rando-
mized clinical trial involving 71 patients with malignant
pleural effusion; the success rate in 34 patients treated
with bleomycin for 180 days was 67.8%. Ong and col-
leagues21 found that talc was better than bleomycin for
control of malignant pleural effusions (89% versus 70%,
p ¼ 0.168). Zimmer and colleagues22 also noted that talc
gave a better result (90%) than bleomycin (74%;
p ¼ 0.388). We concluded that PVP-I can be considered
as a choice of chemical agent to perform pleurodesis in
patients with pleural effusion due to recurrent malig-
nancy, with similar efficacy and complications and less
cost than bleomycin. Further studies should be per-
formed with larger sample sizes to compare the efficacy
and complications, as well as the dosage and appropriate
concentration of PVP-I compared to bleomycin.
Acknowledgement
This study is based on the thesis of a general practitioner
course conducted at the Lung Diseases Research Center.
Thanks to Ms. Farideh Golhasani, a research specialist at
the Lung Diseases Research Center, for preparing the original
text of the article.
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with
respect to the research, authorship, and/or publication of this
article.
Funding
The author(s) received no financial support for the research,
authorship, and/or publication of this article.
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