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Peritoneal lavage with povidone-iodine solution

in colorectal cancereinduced rats

Hua-Li Song, MM,a Dong-Mei Zhang, PhD,b,* Heng Wen, MM,c

Meng Wang, MM,b Na Zhao, MM,b Yu-Hua Gao, MM,b and Ni Ding, MMa
Department of Anesthesiology, Ningxia Medical University, Yinchuan, Ningxia, China
Department of Anesthesiology, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China
Department of Anesthesiology, The Second Affiliated Hospital of Zhejiang Chinese Medical University,
Hangzhou, Zhejiang, China

article info abstract

Article history: Background: Although peritoneal lavage with povidone-iodine (PVPI) is frequently per-
Received 6 November 2017 formed after surgery on the gastrointestinal tract, the effects of PVPI on the intestinal
Received in revised form epithelial barrier are unknown. The purpose of this study was to investigate the effects of
3 February 2018 abdominal irrigation with PVPI on the intestinal epithelial barrier in a colorectal cancer
Accepted 27 February 2018 (CRC)einduced rat model.
Available online 25 April 2018 Materials and methods: The CRC model was induced in rats with azoxymethane and dextran
sodium sulfate. Next, a total of 24 male CRC-induced rats were randomly divided into three
Keywords: groups (n ¼ 8): (1) a sham-operated group, (2) an NS group (peritoneal lavage 0.9% NaCl),
Peritoneal lavage and (3) a PVPI group (peritoneal lavage with 0.45%-0.55% PVPI). The mean arterial pressure
Povidone-iodine was continuously monitored throughout the experiment. The levels of plasma endotoxin
Intestinal mucosa barrier and D-lactate, blood gases, and protein concentration were measured. The ultrastructural
Shock changes of the epithelial tight junctions were observed by transmission electron
Results: The mean arterial pressure after peritoneal lavage was lower in the PVPI group than
that in the NS group. The protein concentration and levels of endotoxin and D-lactate were
higher in the PVPI group than they were in the PVPI group. In addition, PVPI treatment
resulted in a markedly severe metabolic acidosis and intestinal mucosal injury compared
with NS rats.
Conclusions: Peritoneal lavage with PVPI dramatically compromises the integrity of the in-
testinal mucosa barrier and causes endotoxin shock in CRC rats. It is unsafe for clinical
applications to include peritoneal lavage with PVPI in colorectal operations.
ª 2018 Elsevier Inc. All rights reserved.

Introduction Peritoneal lavage is frequently performed after the surgeries

of the gastrointestinal tract.2,3 Povidone-iodine (PVPI) is a
Colorectal cancer (CRC) is the third most common cancer and polymer of iodine complexed with polyvinylpyrrolidone (PVP)
the fourth most common cause of cancer death worldwide. and exhibits antiseptic and tumoricidal benefits.4 PVPI is the
The main cornerstone of treatment for CRC is surgery.1 most common iodophor and is available globally. PVP can

* Corresponding author. Department of Anesthesiology, General Hospital of Ningxia Medical University, Yinchuan Shengli Road #1160,
Yinchuan 750004, Ningxia, China. Tel.: þ86 13995086686; fax: þ86 09514073090.
E-mail address: (D.-M. Zhang).
0022-4804/$ e see front matter ª 2018 Elsevier Inc. All rights reserved.
94 j o u r n a l o f s u r g i c a l r e s e a r c h  a u g u s t 2 0 1 8 ( 2 2 8 ) 9 3 e9 9

form stable complexes with iodine, which is slowly released to normal drinking water for the subsequent 14 d (Fig. 1). All rats
the environment as free iodine with concomitant bactericidal were randomly divided into three groups at week 16: (1) a
activity.5 In addition, a previous study demonstrated that PVPI sham group with no intraperitoneal lavage (n ¼ 8), (2) an NS
had an antitumoral effect on colon cancer cells,6 and this ef- group with peritoneal lavage with 7 mL/kg of warm saline
fect is associated with the superoxide dismutase activity that (0.9% NaCl, 37 C) solution (n ¼ 8), (3) a PVPI group with peri-
is caused by the oxidizing effects of its free iodine.7 For these toneal lavage with 7 mL/kg of warm 0.45%-0.55% PVPI (37 C;
reasons, PVPI has been widely popularized for clinical use as a n ¼ 8).12
therapeutic agent for the purpose of minimizing post-
operative septic complications and reducing cancer recur- Surgical procedures
rence.8 Although PVPI possesses a broad spectrum
microbicide against bacteria and is lethal to CRC cells, concern At the end of week 16, rats were anesthetized with an
about its potential toxicity still remains. Peritoneal fibrosis has intraperitoneal injection of 2% sodium pentobarbital (60 mg/
been reported after intraperitoneal lavage with PVPI in clinical kg). Ventilation was maintained with a ventilator (VT ¼ 6.0-
practice.9 However, if PVPI is administered after the induce- 7.0 mL, respiratory rate ¼ 70 bpm, I:E ¼ 1:2). After anesthesia,
ment of appendicitis-peritonitis, the survival of dogs is abso- the caudal vein and the right carotid artery were isolated
lutely shortened.10 Moreover, other experimental studies have and cannulated with sterile polyethylene catheters (PE-50).
demonstrated that PVPI solution results in high mortality and All surgical procedures were performed under sterile con-
causes serious peritoneal damage.11,12 We hypothesized that ditions. The catheter was placed in the caudal vein for the
peritoneal lavage with PVPI may compromise the integrity of drug administration and fluid supplement (4 mL/kg/h). The
intestinal mucosal barrier. However, until now the effects of heart rate and mean arterial pressure (MAP) were continu-
PVPI on the intestinal epithelial barrier have rarely been ously monitored by connecting the right carotid artery
investigated. Therefore, the aim of the present study was to catheter to a pressure transducer and a computerized
determine the effects of abdominal irrigation with PVPI on the physiograph (BL-420S; Techman Soft, Chengdu, China).
intestinal epithelial barrier in a CRC-induced rat model. Then, a laparotomy was performed through a 2.0 cm midline
incision followed by peritoneal lavage for 3 min. The irrigant
solution was dispersed into the abdominal cavity after
Materials and methods abdominal massage for 30 s as previously described. Sub-
sequently, the irrigant fluid was suctioned out, and the
Rats wound was then aseptically covered with gauze. The irri-
gant fluid and blood samples were collected for biochemical
Five-wk-old male Sprague-Dawley rats were purchased from analyses before the peritoneal lavage and at 30 min after the
the Laboratory Animal Center of Ningxia Medical University peritoneal lavage.
(Yinchuan, China). The rats were maintained under controlled
conditions of humidity (50  10%), light (12 h light/12 h dark),
and temperature (23  2 C) according to the Institutional
Blood gas analysis
Animal Care Guidelines. All experiments were approved by
Arterial blood samples were collected at the baseline and
the Animal Care and Use Committee of Ningxia Medical
30 min after the peritoneal lavage. Approximately 200 mL of
carotid blood was used for the measurement of potential of
Rat model of CRC and grouping hydrogen (pH), the base excess (BE), HCO‾3, and the blood
lactate level (i-STAT 300 G Blood Gas Analyzer; Abbott, Denver,
The rat model of CRC was created as previously described.13,14 CO).
A total of 24 male Sprague-Dawley rats were subjected to a
single intraperitoneal injection of azoxymethane (AOM) Protein concentration measurement
(15 mg/kg, SigmaeAldrich Chemical Co, St. Louis, MO) at 5 wk
of age. After the administration of the injection, the animals Protein concentration was determined with a BCA protein
were exposed to three cycles of 3% dextran sodium sulfate (MP assay kit (KeyGen Biotech, Nanjing, China) using bovine
Biomedicals, Aurora, OH) in the drinking water for 7 d and plasma albumin as the standard. Before irrigation and 30 min

Fig. 1 e Experimental schedule. Rats at 5 wk of age were given a subcutaneous injection of AOM at 15 mg/kg body weight
(black arrow). One wk after the AOM injection they were given three cycles of 3% dextran sodium sulfate (black box) in
drinking water for 1 wk and normal drinking water for 2 wk.
song et al  povidone-iodine and colorectal cancer 95

after irrigation, the peritoneal fluid was sampled to calculate Statistical analysis
the protein concentration.
All data were analyzed with IBM SPSS Statistics version 23 and
Measurement of plasma endotoxin levels are expressed as mean  standard deviation. One-way anal-
ysis of variance was used to determine the significant differ-
Blood samples from the portal vein were stored in ences between the different groups. Analysis of the
endotoxin-free tubes for endotoxin determination. The differences within groups was performed using analysis of
plasma endotoxin was measured with a limulus ameobatic variance with repeated measures. The value of P <0.05 was
lysate test using enzyme-linked immunosorbent assay kits considered to be statistically significant for all tests.
(purchased from Elisa Biotech Co, Ltd, Shanghai, China)
according to the instructions. The method has a sensitivity
of 1.0 EU/mL. Results

Measurement of plasma D-lactate levels Hemodynamic parameters

The plasma from the blood samples from the portal vein was The MAP values after peritoneal lavage were calculated and
assayed for the D-lactate concentration by an enzymatic are presented in Figure 2. There were no significant differ-
spectrophotometric method with a D-lactate enzyme-linked ences in the MAP values at the baseline in any animals. After
immunosorbent assay kit (Elisa Biotech Co, Ltd). The sensi- the lavage administration, the MAP of the PVPI-treated rats
tivity of this assay is 1.0 mmol/L. decreased to 39.44  6.81 mm Hg, which was significantly
lower than the values of the sham- and NS-treated rats at all
Transmission electron microscopy time points (P <0.05, Fig. 2). However, there were no significant
differences between the sham group and the NS group after
Specimens of the small intestine (1 mm2) were cleaned with peritoneal lavage (Fig. 2). These findings indicate that perito-
ice-cold phosphate buffer saline and fixed with 2% glutaral- neal lavage with PVPI elicited persistent hypotension.
dehyde for 2 h. Then, tissues of the small intestine were
postfixed with 1% osmium tetroxide. Subsequently, the Blood gas analysis
specimens were dehydrated with graded ethanol and
embedded in epoxy propane. Ultrathin sections were cut and The pH, BE, and HCO 3 values were significantly decreased
stained with uranyl acetate and lead citrate. Finally, the ul- 30 min after peritoneal lavage with PVPI compared with the
trastructure of the small intestine was examined with a sham and NS group (Table). Moreover, the lactic acid content
transmission electron microscope (Hitachi H-7650, Hitachi, in the PVPI group increased to 6.61  0.77 mmol L1, which
Naka, Japan). was significantly higher than the values in the sham and NS

Fig. 2 e Effects of PVPI on the MAP after peritoneal lavage. (A) Temporal trends in mean arterial pressure. (B) Changes in
mean arterial pressure after peritoneal lavage. The data are presented as the means ± the standard errors of the mean (n [ 8
for each group). *P <0.05 versus the zero point of the same group; #P <0.05 versus the sham at the same time point; xP <0.05
versus the NS group at the same time point. NS [ rats exposed to warm saline irrigation; PVPI [ rats exposed to warm
povidone-iodine irrigation.
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Table e Effect of PVPI on blood gas parameters after

peritoneal lavage.
Variables Groups Time points

Baseline 30 min after

pH Sham 7.387  0.033 7.394  0.032
NS 7.400  0.021 7.408  0.068
PVPI 7.392  0.023 7.196  0.021*,y,z
BE (mmol,L ) Sham 1.63  1.30 1.50  1.20
NS 1.75  1.39 1.63  1.30
PVPI 1.50  1.31 13.00  2.00*,y,z
3 (mmol,L ) Sham 23.05  1.50 22.71  1.54
NS 23.24  1.15 22.80  1.18
PVPI 22.98  1.05 10.56  1.05*,y,z
LA (mmol,L ) Sham 1.97  0.07 1.98  0.08
NS 1.96  0.08 1.98  0.06
PVPI 1.96  0.05 6.61  0.77*,y,z

Data presented as means  standard errors of the mean (n ¼ 8 for

each group).
NS ¼ rats exposed to warm saline irrigation; PVPI ¼ rats exposed to
warm povidone-iodine irrigation.
P <0.05 versus baseline of the same group.
P <0.05 versus sham at the same time point.
P <0.05 versus NS at the same time point.
Fig. 3 e Effects of PVPI on the protein concentration in the
peritoneal fluid after peritoneal lavage. The data are
groups (P <0.05, Table). No significant differences in the pH,
presented as the means ± the standard errors of the mean
BE, HCO 3 , or lactic acid values were observed between the
(n [ 8 for each group). *P <0.05 versus the protein
sham group and NS group that underwent lavage. There were
concentration before lavage of the same group; #P <0.05
no significant differences in the pH, BE, HCO 3 , or lactic acid
versus the sham at the same time point; xP <0.05 versus
values at baseline.
the NS group at the same time point. NS [ rats exposed to
warm saline irrigation; PVPI [ rats exposed to warm
Protein concentration measurement of peritoneal fluid povidone-iodine irrigation.

The protein concentration in the peritoneal fluid before lavage

did not differ significantly among the three groups (Fig. 3). The transmission electron microscopy. In the sham group, the TJs
protein concentration in the peritoneal fluid after lavage was and desmosome were intact and clear between adjoining
significantly higher in the PVPI group than those in the sham cells, and epithelial cell surface microvilli were arranged in
and the NS groups (P <0.05, Fig. 3). Compared with the sham neat rows (Fig. 5A). After PVPI treatment, the TJs were
and PVPI groups, the protein concentration was significantly obscured or had disappeared. Moreover, the paracellular
decreased in the NS group (P <0.05, Fig. 3). spaces were wider (Fig. 5C), and the microvilli were damaged
and sparse with irregular lengths and arrangements (Fig. 5C).
In the NS-treated rats, the TJ and microvilli morphologies
Plasma levels of endotoxin and D-lactate
exhibited no observable changes and remained similar to
those of the sham group (Fig. 5B).
The levels of endotoxin and D-lactate in the plasma were
measured 30 min after peritoneal lavage (Fig. 4A and B). The
peritoneal lavage with PVPI resulted in significantly higher
levels of endotoxin and D-lactate compared with the values Discussion
observed in the sham and NS groups (P <0.05, Fig. 4A and B).
The levels of endotoxin and D-lactate were markedly lower in The results of this study confirmed that peritoneal lavage with
the NS group than in the PVPI group after peritoneal lavage PVPI is harmful to CRC-induced rats and lead to significantly
(P <0.05, Fig. 4A and B). more severe metabolic acidosis compared with the NS group
(P <0.05, Table). In addition, the rats that were treated with
Morphological ultrastructure analysis of small intestines PVPI exhibited significantly lower MAP compared with the NS
and sham groups (P <0.05, Fig. 2). When the plasma was
As tight junctions (TJs) contribute to the maintenance of the subsequently evaluated at 30 min after peritoneal lavage, the
intestinal mucosa barrier permeability, the ultrastructural levels of D-lactate and endotoxin were higher in the PVPI rats
changes of intracellular TJs were observed with the than in the NS rats, which indicated an increased intestinal
song et al  povidone-iodine and colorectal cancer 97

Fig. 4 e Effects of PVPI on endotoxin and D-lactate after peritoneal lavage. (A) Representative endotoxin levels from different
groups. (B) Representative D-lactate levels from different groups. The data are presented as the means ± the standard errors
of the mean (n [ 8 for each group). *P <0.05 versus sham; #P <0.05 versus NS. NS [ rats exposed to warm saline irrigation;
PVPI [ rats exposed to warm povidone-iodine irrigation.

permeability compared with the NS rats (P <0.05, Fig. 4A and and is associated with sepsis.17 When epithelial TJs are dis-
B). Moreover, the protein concentration in the peritoneal fluid rupted, the intestinal epithelial permeability increases, which
was increased in the PVPI rats (P < 0.05, Fig. 3). Taken collec- leads to the release of bacterial endotoxins into the circula-
tively, our results indicate that peritoneal lavage with PVPI can tion, which further aggravates septic shock.17-19
aggravate the intestinal mucosal injury, damage TJs in the PVPI is a polymer of PVP that is complexed to iodine. The
intestinal epithelium, and even provoke endotoxin shock. iodine is slowly released into the environment through the
The gut barrier, which is composed of the intestinal oxidative reaction in which I2 is converted to I, which con-
epithelium and intercellular TJs, can prevent pathogenic in- tributes to the bactericidal effect of PVPI.12 PVPI has long been
testinal microorganisms, antigens, and toxins from entering accepted as a disinfectant, tumoricidal agent, and a broad-
the blood. Failure of intestinal barrier function often occurs in spectrum antiseptic against aerobic, anaerobic, and spore-
hemorrhage shock, severe burn injury, and surgically critical forming bacteria as well as against protozoa, fungi, and vi-
illness and results in the increased intestinal permeability and ruses.9 Until now, PVPI has been widely recommended for
subsequent translocation of bacteria and endotoxins from the clinical use within the contaminated peritoneal cavity and for
gut.15 A previous study indicated that TJ proteins play a critical colorectal operations for the purpose of minimizing post-
role in paracellular permeability.16 Intestinal barrier operative septic complications and reducing cancer recur-
dysfunction is characterized by an increased gut permeability rence, although the advantages and side effects of PVI

Fig. 5 e Effects of PVPI on the morphological ultrastructure of the TJs after peritoneal lavage. Typical images were acquired
from sham rats (A), NS rats (B), and PVPI rats (C). The white arrows indicate epithelial cell surface microvilli, and the black
arrows indicate TJs. Scale bars [ 1000 nM. NS [ rats exposed to warm saline irrigation; PVPI [ rats exposed to warm
povidone-iodine irrigation.
98 j o u r n a l o f s u r g i c a l r e s e a r c h  a u g u s t 2 0 1 8 ( 2 2 8 ) 9 3 e9 9

compared with normal saline or water for intraperitoneal outer membrane of gram negative bacteria, which account for
irrigation have been debated.8,20 70% of intestinal bacteria.32
Exfoliated CRC cells can be detected in the intraperitoneal
fluid. A rectal washout with 5% PVPI may prevent anastomotic
and local recurrence against the implantation of viable exfo- Conclusion
liated tumor cells.21 The only known tumoricidal effects of
PVPI are associated with the elimination of exfoliated cancer In summary, we first demonstrated that peritoneal lavage
cells during colorectal operations. Whether peritoneal lavage with PVPI dramatically compromises the integrity of the in-
with PVPI has the potential to affect intestinal epithelial bar- testinal mucosa barrier and causes an endotoxin shock by
rier is unknown. However, in the present study, we demon- disrupting epithelial TJs, which subsequently increases the
strated a clear increase in D-lactate in the PVPI rats 30 min intestinal epithelial permeability. Our results suggest that
after peritoneal lavage compared with the NS rats. The in- peritoneal lavage with PVPI is unsafe for clinical application in
crease in D-lactate that we found in the rats that were treated colorectal operations.
with PVPI appeared to be sufficient to increase the intestinal
permeability and led to diagnosable bacterial infections as has
been previously reported in a rat model.15,22 D-lactate is pro-
duced by the bacteria found in the gut. Generally, the D-lactate Acknowledgment
levels in mammals are very low. When the mucosa is injured,
and the intestinal permeability is increased, the bacteria and Funding: This work was supported by the Ningxia Medical
the products of their metabolism, including D-lactate are University scientific research project of China, No. XZ2015021.
released into the circulation.15,23 Treatment with PVPI Authors’ contributions: D.M.Z. obtained the funding.
increased the endotoxin level and aggravated septic shock. D.M.Z., H.W., M.W., N.Z., and Y.H.G. contributed to the
The increased in endotoxins by PVPI is mediated by bacterial conception and design of this study. H.L.S. and D.M.Z. con-
translocation due to damage to the intestinal mucosal bar- ducted the experiments. H.L.S. and N.D. performed the data
rier.24 We do not have direct data demonstrating that the analysis. H.L.S. and D.M.Z. wrote and revised the article. H.L.S.
bacteria were in the blood; however, previous study25 has D.M.Z., H.W., M.W., N.Z., Y.H.G., and N.D. contributed to final
clearly demonstrated that increased intestinal permeability approval of the article.
results in bacterial translocation. Our present study also
demonstrated that peritoneal lavage with PVPI caused TJ Disclosure
disruption. Therefore, the side effects of PVPI were possibly
due to the changes in the barrier integrity and permeability. The authors reported no proprietary or commercial interest in
The development of death in the two dogs may have been any product mentioned or concept discussed in this article.
caused by PVPI. It is possible that the absorbed iodine has a
direct effect on the gastrointestinal tract.26 Moreover, we also
found that the MAP was decreased after treatment with PVPI. references
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