Introduction

Pleural effusion still remains as a clinical problem that always occurs in

malignancy. (1) Approximately 75% of pleural effusion occurs due to the
malignant process. (2) Malignant Pleural effusion is the accumulation of fluid
in the pleural cavity due to malignant process, evidenced by the discovery of
malignant cells in pleural fluid or pleural tissue. Paramalignant plural effusion
is related to a pleural effusion which allegedly associated with the
malignancy process, but no malignant cells is found in pleural fluid or pleural
tissue. (1.2) Malignant cells can be found through cytology examination of
pleural fluid or fine needle biopsy of the pleural tissue, or thoracoscopic
biopsy, thoracotomy, or autopsy. (1,2)
In the United States, the incidence of malignant pleural effusion is estimated
reaching 150,000 new cases every year and continues to increase in each
subsequent decade, in accordance to the increase in the incidence of lung,
breast, ovarian, lymphoma, and gastric cancer. Based on preliminary studies
which conducted in Hasan Sadikin Hospital, 22 inpatients who were
diagnosed as malignant pleural effusion was obtained during July to
September 2011. Approximately, 80% of them underwent pleurodesis. (1,3)
Pleurodesis is the adherence process of visceral pleura and parietal pleura so
the layers stick permanently, either through chemical process or mechanical
process. Pleurodesis is indicated for malignant pleural effusion. (4-6) In
general, the objective of pleurodesis is to prevent recurrent effusions

(especially when it occurs quickly), need of following thoracocentesis and

recurrent chest tube insertion, and decrease morbidity. Pleurodesis is a longterm palliative therapy in patients with malignant pleural effusion, which is
expected to improve the quality of life of patients. (4)
Pleurodesis accomplishment is not only seen by whether there has been a
perfect adhesion, but also by the absence of re-accumulation fluid in the
pleural cavity, so that the patient is no longer having dyspnea and
thoracocentesis will no longer required. Pleurodesis response is divided into
complete and partial responses. Complete response is described when there
is no re-accumulation of pleural fluid on chest radiograph and patients have
no symptoms which associated with effusion. Otherwise, partial response is
described if there is re-accumulation fluid in the pleural cavity, but
thoracocentesis is not required (aspiration). Pleurodesis can be failed if there
is re-accumulation of fluid in the pleural cavity which thoracocentesis is
needed to be performed. (7)
Oxytetracycline is pleurodesis chemical substance which is routinely used in
Cardiothoracic-surgery Sub-Division, Hasan Sadikin General Hospital. The
success of oxytetracycline as a pleurodesis agent varies between 65%-92%
with high recurrence rate. (2-4) Recurrence rate of pleurodesis in the Hasan
Sadikin General Hospital is not yet known.
In addition to oxytetracycline, there is other substance that can be used for
pleurodesis, povidone iodine. Povidone iodine is a topical antiseptic that has

been proven to be effective as a pleurodesis agent. The use of povidone

iodine was first proposed in 1991, and has been published in several studies.
(7-9) Mechanism of action of povidone iodine for pleurodesis is still unclear.
The mechanism of action is allegedly associated with its low pH or its strong
cytotoxic and oxidative effects of that induce inflammatory process.
Povidone iodine also has anti-exudative properties that related to protein
binding. (9.10)
Based

on

theory,

the

mechanism

of

action

of

povidone

iodine

is

hypothetically similar to talk, which is by producing fibroblast growth factor.

Povidone iodine is also alleged to have cytotoxic characteristic that has the
ability to against tumor cells. Ritesh Agarwal et al reported a success rate of
pleurodesis povidone iodine in India reached 88.5% in pleural effusion and
93.5% in pneumothorax. Primary side effect of povidone iodine was pleuritic
pain. At another study conducted by Olivarres Torres et al, from total 52
samples in Mexico, there was one case of hypotension and blindness
(1.92%). Allegedly, the blindness outcome was raised due to the use of 200500 ml dose of povidone iodine, which exceeds the threshold of iodate
toxicity. This side effect did not occur in other studies and recent studies
which using 20 cc of 10% povidone iodine dissolved in 80 cc of 0.9% NaCl.
There was no mortality reported due to the use of this substance. (8)
Currently, injection of oxytetracycline is increasingly difficult to obtain.
Therefore, it is necessary to find other substances that can be chosen as an

alternative to pleurodesis agent. 10% povidone iodine is a low-priced

alternative and it is easily available. This study was comparing the success of
10% povidone iodine and oxytetracycline as chemical pleurodesis substances
in patients with malignant pleural effusion.

Method
The study was a cross-sectional study, comparing the success of pleurodesis
using oxytetracycline and 10% povidone iodine as a sclerosan substance.
The

subjects

were

malignant

pleural

effusions

patients

treated

in

Cardiothoracic-surgery Sub Division, Hasan Sadikin Hospital (RSHS) Bandung

in period of February - May 2015. The inclusion criteria were included
patients with malignant pleural effusion with breast carcinoma primary
tumor, lung carcinoma, and ovarian carcinoma (who has been diagnosed
with clinical, radiological or histopathological), has been already qualified to
performed pleurodesis, and no history of pleurodesis before. Exclusion
criteria were Karnofsky score <70%, has allergic to a substance pleurodesis
(obtained from anamnesis) and serum albumin <2.0 mg / dl. Research plot is
described in chart 1.
The sample size was determined according to the type of analysis of 2
unpaired data groups with categorical variables as measurement scale.

Thirty four subjects were obtained, and the subjects were then divided into 2
groups, pleurodesis using 10% povidone iodine and pleurodesis using
oxytetracycline. The success of pleurodesis then recorded and assessed.

Result
Table 1 shows the characteristic data of the study. Patients range of age in
10% povidone iodine group (n = 17 patients) was 16-72 years with mean of
47.2 13.5 years old and median of 45 years old; while in the
oxytetracycline group (n = 17 patients) was 29-69 years with mean of 50.8
11.0 years old and a median of 51 years old. Sex of the patient was
distributed almost equally in both groups, where women were more
dominant, both in 10% povidone iodine group (76.5%) and oxytetracycline
group (88.2%). The primary tumor type in patients was dominated by
mammary

carcinoma,

both

in

10%

povidone

iodine

(41.2%)

and

oxytetracycline (52.9%). Patients in 10% povidone iodine group has a range

of albumin level between 2.1 to 3.3 with mean of 2.6 0.4 and the median
2.5; while in the oxytetracycline group has albumin level ranges between
2.3 to 4.4 with mean of 2.9 0.5 and median of 2.8. As for the Karnofsky
scores, both groups had the same Karnofsky score range, which were
between 70-90 with a median of 70 in 10% povidone iodine and 80 in
oxytetracycline.

Results of homogeneity test between groups showed that the patient

characteristics between 10%povidone iodine and oxytetracycline were the
same or homogeneous, either based on the median of age (p = 0.409), the
distribution of gender (p = 0.656), the distribution of the primary tumor (p =
0.685 ), the median level of albumin (p = 0.085), and the median Karnofsky
score (p = 0.231).
Table 2 shows the success of pleurodesis. The proportion of pleurodesis
success in 10% povidone iodine group amounted to 82.4% (14 patients in a
total of 17 patients); while in the oxytetracycline group was 88.2% (15
patients in a total of 17 patients). Descriptively, it appears that the
proportion of pleurodesis success in the oxytetracycline group was slightly
greater than 10% povidone iodine group. Nevertheless, Fisher test results
showed that this difference was not significant (p = 1.000).
Table 3 shows the pleuritic pain side effects caused by sclerosant substances
which were given. The median level of pain of patients in the 10% povidone
iodine was the same as in the oxytetracycline group, which was equal to 1,
with a range between 1 to 2. Mann-Whitney test results also showed that the
level of pain in 10% povidone iodine group did not differ significantly with
oxytetracycline (p = 0.786).

Discussion

This study included 34 subjects of malignant pleural effusion patients who

met the inclusion and exclusion criteria. The research subjects were then
divided into 2 groups, ie groups which pleurodesis was using 10% povidone
iodine and groups which pleurodesis was using oxytetracycline (according to
standard procedures in Cardiothoracic-Surgery Sub Division RSHS).
International Agency for Research on Cancer showed that the most common
malignant pleural effusion was in 30-65 years old women. (1,2,6,7,9,10)
There were no differences in terms of age and gender compared to this
study, which showed 47.2 years old of mean age at 10% povidone iodine
group, while 50.8 years old of mean age at oxytetracycline group. Both group
showed they had more female patients compared to male with 10%
povidone iodine group (13: 4) and the oxytetracycline group (15: 2).
The mean value of the albumin level was 2.6 mg / dl in the 10% povidone
iodine group, while in the oxytetracycline group the mean was 2.9 mg / dl.
Karnofsky score in 10% povidone iodine group was 70 and in oxytetracycline
group was 80. Based on statistical test in the overall research subjects, the
subjects had same homogeneity, either based on the median of age (p =
0.409), the distribution of gender (p = 0.656), the distribution of the primary
tumor (p = 0.685), median levels of albumin (p = 0.085), and the median
Karnofsky score (p = 0.231).
One of the factors that determine the success of pleurodesis is the type of
sclerosant that used in the pleurodesis. Various substances reported to have

been used as pleurodesis agents include talc, oxytetracycline, cuinacrine,

bleomycin, mitomycin, and povidone iodine. The ideal sclerosant is
subtances which has high molecular weight and polarity, low local
elimination, rapid systemic elimination with minimal side effects. The use of
povidone iodine as a pleurodesis agent began in 1991. In a meta-analysis
conducted by Ritesh Agarwal et al. showed that the success rate of povidone
iodine for pleurodesis reach 88-95% in India, while the success of
oxytetracycline ranged between 65-92%. In another study conducted by
Carlos Olivares et al., it demonstrated the success of povidone iodine
pleurodesis reached 96% in Mexico. Mechanism of action of povidone iodine
as a pleurodesis agent allegedly associated with its oxidative effect that is
able to induce inflammation. There are also allegations because cytotoxic
effects that has the ability to against tumor cells. (6,7,9,10) The success of
povidone iodine was also seen in this study, in which 14 of the 17 research
subjects (82.4%), while the success of pleurodesis using oxytetracycline was
in 15 of 17 research subjects (88.2%). It showed that the success rate of
povidone iodine slightly smaller than oxytetracycline, but based on Fisher's
exact test this difference was not significant (p = 1.000).
The ideal pleurodesis agent is still not yet discovered. Selection of
pleurodesis agent nowadays is still based on the availability and local
experience of local institutions, especially in the terms of side effects. (10)
The side effects that can arise include fever, pleuritic pain, acute respiratory
distress syndrome (ARDS). Side effects of Povidone iodine can be seen in the

study were pleuritic pain. Analgesic is recommended to be given in the

patients before pleurodesis, to reduce discomfort due to pain. (5-10,19,20) In
accordance to the literature, in 34 patients both in the povidone iodine group
or oxytetracycline group, pleuritic pain was minimal which proven by the
grade of pain was 1-2 using a VAS scale. There were no significant
differences between the povidone iodine and oxytetracycline after tested by
using the Mann-Whitney test (p = 0.786).
Conclusion
Povidone iodine 10% had the same success as compared to oxytetracycline
as a pleurodesis agent in malignant pleural effusion, with minimal pleuritic
pain as side effects.
Suggestion
Further research is needed, with a longer time span for follow-up periodically
after pleurodesis, so a clearer representation of the success of povidone
iodine and its complications can be obtained.