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Oxychlorine species suppress postsurgical adhesions in rats

Juan M. Zavala-Rodriguez, MSc,a Jose M. Correa Rovelo, MD,a,b

Noe Martinez-Morales, MD,c Carlos Muñoz-Arce, MD,c Rosa A. Bobadilla-Lugo, MD,a
Robert D. Kross, PhD,d Roberto Medina, MD,a and Cleva Villanueva, MDa,*
a
Departamento de Posgrado e Investigacion, Instituto Politecnico Nacional, Escuela Superior de Medicina, Mexico City, Mexico
b
Departamento de Cirugia, Fundacion Medica Sur, Mexico City, Mexico
c
Escuela Militar de Graduados de Sanidad, Universidad del Ejercito y Fuerza Aerea, Mexico City, Mexico
d
Kross-Link Laboratories, Bellmore, New York

article info abstract

Article history: Background: Surgically induced adhesions complicate up to 100% of abdominal surgeries.
Received 5 May 2013 Food and Drug Administrationeapproved treatments are generally not only less effective
Received in revised form than desired but they also have major contraindications. Oxychlorine species, including
24 June 2013 chlorine dioxide (ClO2), suppress scar formation in infected wounds without affecting
Accepted 23 July 2013 keratinocytes while reducing fibroblast proliferation. The aim of the present study was to
Available online 14 August 2013 evaluate the effect of oxychlorine solutions containing ClO2 on adhesion formation.
Methods: Male Wistar rats were subjected to Buckenmaier model of surgical adhesions and
Keywords: treated with either oxychlorine solutions containing ClO2 (40e150 ppm) or isotonic saline
Surgical adhesions solution. To increase the severity of adhesions, peritonitis was produced by intraperitoneal
Chlorine dioxide administration of a diluted nonlethal dose of feces (50 mg/kg). Wound strength of the
Free radical scavenger healed wound was measured to evaluate the effects of oxychlorine solutions. In addition,
Peritonitis an oxychlorine solution of lesser efficacy (at 100 ppm) was compared with three available
Antisepsis anti-adhesion materials.
Results: Reproducibility of the model was validated in 26 rats. Oxychlorine solutions con-
taining ClO2 (40e110 ppm) significantly reduced postsurgical adhesion formation without
affecting the strength of the healed wound. Higher concentrations (120 and 150 ppm) had
no effect. Fecal peritonitis significantly increased, and solutions with ClO2 at 110 ppm
significantly reduced adhesion formation. The effect of the oxychlorine solution was
significantly greater than that of Interceed, Guardix, Seprafilm, and isotonic saline solution.
Conclusions: ClO2-containing oxychlorine solutions could be an innovative strategy for the
suppression of surgical adhesion formation, with the additional advantage of contributing
antiseptic properties.
ª 2014 Elsevier Inc. All rights reserved.

1. Introduction almost any type. Up to 100% of patients submitted to abdom-

inal surgery will develop adhesions [2]. The clinical symptoms
An adhesion is a fibrous bridge between two or more tissues of abdominal adhesions range from nothing (asymptomatic)
that blocks their normal free movement [1]. The main cause of to chronic abdominal pain, female infertility and bowel
adhesions is a surgical procedure (surgical adhesions) of obstruction [1e3]. Bowel obstruction produced by adhesions

* Corresponding author. Instituto Politecnico Nacional, Escuela Superior de Medicina, Plan de San Luis y Salvador Diaz Miron S/N, Colonia
Casco de Santo Tomas, Mexico DF, CP 11340, Mexico. Tel./fax: þ52 55 5729 6000x62794.
E-mail address: cleva_villanueva@yahoo.com.mx (C. Villanueva).
0022-4804/$ e see front matter ª 2014 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.jss.2013.07.043
 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 1 8 6 ( 2 0 1 4 ) 1 6 4 e1 6 9 165

frequently requires subsequent surgery to sever the adhesions a publication comparing four different techniques to produce
(adhesiolysis) and liberate the bowel [3]. Although it is known abdominal surgical adhesions in the rat, and the authors
that as many as 53% of patients submitted to adhesiolysis will concluded that Buckenmaier model was the most consistent
have a recurrence, there is no way to predict who will develop and reproducible [11]. In addition, analyzing the variability in
adhesions after their first abdominal surgery [4]. The 1994 a group of 26 rats validated reproducibility (see Results
National Hospital Discharge Survey estimated that in the United section). In brief, the animals were anesthetized with sodium
States, adhesiolysis procedures cost $1.3 billion annually pentobarbital (45 mg/kg, intramuscularly), the abdomen was
(hospitalization and surgical expenditures) [5], which clearly shaved and disinfected with povidone iodine, a middle inci-
underscores the need for an effective treatment that could sion was made, and the parietal peritoneum wall was then
reduce or even potentially eliminate postsurgical adhesions. exposed. Four vessels were located on the left side of the
Different oxychlorine species have been used extensively parietal peritoneum (the distance between the vessels was at
as disinfectants [6]. Hypochloriteehypochlorous acid (bleach) least 1 cm) and then ligated with 3-0 silk suture to produce
is the most well-known example. Chlorine dioxide (ClO2), ischemia. The peritoneum around the suture was gently
another oxychlorine species which has come into prominence abraded with the tip of scissors, and the incision was then
more recently, is a stable, free radical molecule capable of closed in two layers. The peritoneum and abdominal muscles
oxidizing organic and inorganic species [6]. Apparently, the were closed with continuous 3-0 prolene suture, and the skin
disinfectant effect of ClO2 is attributable to the oxidation of was closed with continuous 3-0 Dermalon (Kendall Co) suture.
certain microbial biomolecules containing SeH and/or SeS Before the peritoneum was completely closed, 10 mL of
groups (in certain sulfur amino acids), the amino acids control or treatment solutions was infused into the peritoneal
phenylalanine and tryptophan, and other labile species. Tet- cavity: either a sterile ISS (control) or a sterile oxychlorine
rachlorodecaoxide complex, a chloriteeperoxide oxychlorine saline (40e150 ppm ClO2).
species, first used as an antimicrobial agent for wound infec-
tions was also found to affect wound repair in humans [7]. In 2.3. Evaluation of adhesions
an investigation for preventing surgical adhesion formation in
rabbits [8], the authors found that tetrachlorodecaoxide Seven days after surgery, the animals were sacrificed by
decreased adhesions by 25% compared with saline solution overdoses of sodium pentobarbital (200 mg/kg, intraperito-
controls [8]. Kenyon et al. [9] studied the effect of a composi- neally); the abdominal cavity was opened carefully, photo-
tion named “Alcide” (an acidified chlorite system: a mixture of graphed, and the adhesions then counted (and confirmed in
oxychlorine species) on wound repair in guinea pigs. They the photographs). For each rat, an adhesion score was recor-
found that Pseudomonas-infected wounds treated with Alcide ded as follows: 1 point was assigned to each adhesion formed
as an antiseptic gel after healing had formed less collagen and on the ischemic buttons (Buckenmaier model) and addition-
less scarring than isotonic saline solution (ISS) controls, ally 2 points assigned to any of the following cases: adhesions
although both had the same epithelialization. The authors formed between portions of the intestines, adhesions to the
postulated that Alcide decreased fibroblast stimulation by liver, or adhesions to the peritoneal wound. In this way, the
activated macrophages. maximum adhesion score per rat would be 10 (1 point per each
The aim of this study was to determine whether certain of the four ischemic buttons plus 2 points for adhesions
proprietary ClO2-containing oxychlorine solutions can prevent between the intestines plus 2 points for adhesions to the liver
abdominal surgical adhesion formation in an experimental plus 2 points for adhesions to the peritoneal wound).
animal model, even in the presence of contaminating micro-
organisms, such as associated with nonlethal fecal peritonitis. 2.4. Contamination of the peritoneal cavity
Additionally, the study compared the new technology with
three available anti-adhesion compositions. Because contamination of the peritoneal cavity is known to
aggravate adhesion formation [12], a modification to Buck-
enmaier model was carried out. One hour before surgery (see
2. Methods 2.2. Surgical procedure), 44 rats were treated intraperitoneally
with a solution made with their own feces (50 mg/kg, diluted
2.1. Animals in 400 mL of ISS). Previous experiments were run, at decreasing
concentrations, until a dose was established that did not kill
All the experiments were performed according to the Institu- the animal but did induce significant peritonitis (nonlethal
tional Ethical Committee for Animal Research (Comite para la fecal peritonitis). The animals were divided into four groups
Investigacion, Cuidado y Uso de Animales de Laboratorio (at least seven animals per group): one received ISS (after the
[CICUAL]). Male Wistar rats (230e250 g, 10-wk old) were used in surgical and treatment procedures mentioned above) and the
the experiments. The animals were kept at the Institutional other three were treated with the oxychlorine solution con-
Animal House, fed with Purina Chow (Purina, Mexico) and taining ClO2 at 40, 70, or 110 ppm. Sacrifice and evaluation of
water ad libitum, and subjected to lightedark cycles of 12  12 h. the adhesions were done as described previously.

2.2. Surgical procedure 2.5. Measurement of wound strength

Surgical adhesions were produced following the model re- One of the concerns using a treatment that could affect
ported by Buckenmaier [10]. We chose this model based on fibroblast growth (to reduce adhesion formation) is that it
166 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 1 8 6 ( 2 0 1 4 ) 1 6 4 e1 6 9

could adversely affect normal healing of surgical wounds. dioxide and unconsumed chlorite ion. This is accomplished by
After sacrifice and before opening the abdominal cavity of the judicious selection of the levels of chlorite, hypochlorite, and
fecally contaminated animals, wound strengths were mea- citric acid, to create our oxychlorine system, consisting of
sured according to the method reported by Marques Batista chlorine dioxide and chlorite ion. The two species form
et al. [13]. In brief, a surgical glove finger, attached to a mercury a particularly effective oxidation pair, the [Cl2O4] ion. The
sphygmomanometer through a 16-F Foley catheter, was level of ClO2 used to characterize the specific oxychlorine
introduced into the peritoneal cavity through a 0.5-cm inci- solution prepared was measured by its ultraviolet absorption
sion of the skin and peritoneal wounds. The incision was at 360 nm, using an extinction coefficient of 1243 L/M cm.
carefully closed around the Foley catheter and the glove finger
inflated until the surgical wound was forced open and the 2.9. Statistical analysis
finger emerged. The pressure needed to open the wounds was
recorded in millimeters of mercury. All values are presented as the mean  standard error of the
mean. The adhesion index was evaluated using the Krus-
2.6. Comparative study kaleWallis test (Dunn multiple comparison test post hoc) or
ManneWhitney test; wound strength was evaluated using the
To have a more clinically useful evaluation, an oxychlorine unpaired t-test. Differences were considered significant if
solution was compared (n at least 6 per group) with three P was <0.05. All the statistical analyses were performed using
available anti-adhesion compositions: Guardix (Hanmi Medi- Prism 5.0b (GraphPad Software Inc, San Diego, CA).
care Inc, hyaluronic acid and sodium carboxymethyl cellulose
gel) [14], Interceed (Johnson and Johnson Co, oxidized regen-
3. Results
erated cellulose) [15], and Seprafilm (Genzyme Corp, hyalur-
onic acid and carboxymethyl cellulose barrier) [2,15]. An
The reproducibility of the model was demonstrated with
additional control group (ISS) was used in this series of
26 rats treated with ISS. The adhesion score was 4.0  0.2
experiments. After surgery (see above), the animals received
(ISS, Fig. 1).
10 mL of ISS (control group), 10 mL of an oxychlorine solution
A doseeresponse curve was performed for oxychlorine
(containing ClO2 at 100 ppm), Guardix (400 mL per rat), Inter-
solutions containing ClO2 from 40e150 ppm. Concentrations
ceed (1.5 cm2 applied on each ischemic button), or Seprafilm
from 40e110 ppm significantly reduced adhesion formation
(1.5 cm2 applied on each ischemic button). One hundred mL of
(Figs. 1 and 2A and B), whereas oxychlorine solutions con-
ISS was applied on each Interceed or Seprafilm square after
taining ClO2 at 120 or 150 ppm did not change the adhesion
they were placed on each ischemic button. The experiment
score (compared with control).
was finished and the evaluation of adhesion scores was per-
Adhesions significantly increased in control animals
formed as mentioned previously.
(treated with ISS) with fecal peritonitis (adhesion score of
4.0  0.3 without fecal peritonitis and 5.6  0.3 with fecal
2.7. Experimental groups

1. Seven groups (at least n ¼ 6 per group): Treated with ISS

(control) or oxychlorine solutions containing 40, 70, 96, 110,
120, or 150 ppm of ClO2.
2. Four groups with abdominal cavity contamination: Control
(n ¼ 21, ISS) and three groups treated with oxychlorine
solutions containing ClO2 at 40, 70, or 110 ppm (n ¼ 9, 7, and
8, respectively).
3. Five groups were used for the comparative study: Control
(n ¼ 8, ISS), Interceed (n ¼ 8), Guardix (n ¼ 8), Seprafilm
(n ¼ 6), and an oxychlorine solution containing ClO2 at
100 ppm (n ¼ 9).

2.8. Preparation of the proprietary ClO2-containing

oxychlorine solutions

The proprietary solution (Kross-Link Laboratories, Bellmore, Fig. 1 e Doseeresponse curve of oxychlorine solutions.
NY) [16] is prepared in a sterile bag of ISS by sequential addi- Reproducibility of Buckenmaier model is evident in the
tion of sodium chlorite, a solution of sodium hypochlorite control group (ISS, n [ 26). The oxychlorine solutions
combined with sodium carbonate, and then a citric solution. (ClO2 concentration from 40e110 ppm, n at least 6 per
This acidity converts hypochlorite ion to hypochlorous acid concentration) significantly prevented adhesion formation
and oxidizes part of the chlorite ion to chlorine dioxide. At the (P < 0.0001, KruskaleWallis test; *P < 0.05 compared with
same time, the combination of citric acid and the alkalinity ISS, **P < 0.05 compared with 150 ppm, Dunn multiple
from the hypochlorite forms a citrate buffer. We therefore comparison test), whereas ClO2 concentrations of 120 and
have two physiological buffers present in the saline solution 150 ppm had no effect (P > 0.05 compared with ISS). Data
mixture that now contains the desired amount of chlorine are shown as the mean ± standard error of the mean.
 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 1 8 6 ( 2 0 1 4 ) 1 6 4 e1 6 9 167

Fig. 2 e Representative photographs showing the effect of oxychlorine solutions on adhesion formation. The four animals
were subjected to Buckenmaier model. (A) and (C) are from control animals (treated with ISS), whereas (B) and (D) were
treated with an oxychlorine solution containing ClO2 at 110 ppm. (A) and (B) are without fecal contamination, whereas
(C) and (D) are with fecal contamination. The arrows show adhesions. There are four adhesions (to ischemic buttons) in (A);
(B) shows no adhesions; (C) shows adhesions to the ischemic buttons, the liver, and the peritoneal wound (the later is
a thick adhesion); and (D) shows one thin adhesion to one of the ischemic buttons.

peritonitis; P ¼ 0.003). Even in the presence of fecal peritonitis, managed, adhesions are still formed. It now appears reason-
the oxychlorine solution (containing ClO2 at 110 ppm) signif- able to suggest that the process of adhesion formation begins
icantly reduced adhesions (Figs. 2C and D and 3A). Oxy- at the very moment of the surgical incision, when tissues are
chlorine solutions containing ClO2 at 40 or 70 ppm did not exposed to environments to which they had never been
change the adhesion score obtained in the control group with exposed. Additionally or alternatively, the incision interrupts
contaminated peritoneal cavities (Fig. 3A). Treatment with the blood circulation, leading to the production of hypoxia.
oxychlorine solution (containing ClO2 at 110 ppm) did not Indeed, postsurgical tissue attachments have been demon-
change the wound strength (Fig. 3B). strated as early as 2 h after surgery in a rodent model [17],
The results of the comparative study (Fig. 4) showed no which suggests that the actual process of adhesion formation
difference between ISS, Interceed, Guardix, and Seprafilm, begins earlier. It has been postulated that hypoxia plays an
whereas the oxychlorine solution significantly reduced the important role in adhesion formation [18]. In fact, when
adhesion score. normal fibroblasts are subjected to hypoxia, their phenotype
is changed, resembling adhesion fibroblasts [19].
It is known that hypoxia triggers superoxide production and
4. Discussion inflammation [20]. Superoxide acts as a signal transduction
factor inducing inflammation [21]. Chlorine dioxide is a para-
The main finding of the study was the capacity of ClO2-con- magnetic stable-free radical with powerful oxidant properties
taining oxychlorine (40e110 ppm) solutions to suppress and [22,23]. Our hypothesis is that oxychlorine species, including
even prevent the development of surgically induced adhesions. ClO2, function by stabilizing superoxide and decreasing the
The limitation of the study was the experimental model inflammatory cascade triggered by hypoxia. Indeed, it was
requirement for permanent silk sutures in the peritoneal previously demonstrated, by electron paramagnetic spectros-
cavity, which is not a condition in the clinical field. However, copy, that an oxychlorine solution containing 15 ppm of ClO2
the model has been shown to be reproducible, and it was scavenged 100% of superoxide produced by xanthine and
chosen based on a publication analyzing different models of xanthine oxidase (an effect comparable with that produced by
surgical adhesions in which the authors concluded that Buck- superoxide dismutase and catalase) [24]. The half-life of ClO2 is
enmaier model was the most consistent and reproducible [11]. very brief (within minutes), in the presence of oxidizable
Certain factors have been identified in the past as triggers organic matter, suggesting that the effect is produced very early
of adhesion formation. Such factors include foreign material in the process of adhesion formation, thereby leaving the
(e.g., starch, surgical gloves, certain sutures), infection, and subsequent healing process intact. Indeed, the wound strength
duration of surgery [2]. Even when these factors are carefully was not affected by the oxychlorine solution.
168 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 1 8 6 ( 2 0 1 4 ) 1 6 4 e1 6 9

Fig. 4 e Comparative study. Interceed, Guardix, and

Seprafilm had the same effect as ISS. The oxychlorine
solution containing ClO2 at 100 ppm significantly reduced
adhesion formation (P [ 0.003, KruskaleWallis test;
*P < 0.05 compared with ISS, Dunn multiple comparison
test). Data are shown as the mean ± standard error of the
mean.

When competing oxidizable targets, such as manifest by fecal

contaminants, are present, the lower levels of 40 and 70 ppm
of ClO2 in the treatment solutions are being partially vitiated
by those targets. Only at 100 ppm level, there is sufficient
remaining activity available to quash the superoxide and
suppress the hypoxia-triggered inflammatory cascade. In
contrast, when considering the decrease in adhesion
suppression, where the score for the 40 ppm system shows
Fig. 3 e Effect of oxychlorine solutions on adhesion remarkable activity compared with the proportionately
formation and wound strength. All the animals were diminishing suppression at higher levels of ClO2-containing
subjected to nonlethal fecal peritonitis. The oxychlorine oxychlorines, it is a reasonable conclusion by these authors
solution (ClO2 at 110 ppm, n [ 8) significantly reduced that the known cytogenic effects of excess chlorite ions are
adhesion formation in (A) (*P [ 0.0003, ManneWhitney increasingly coming into play. The higher the chlorite level,
test, compared with ISS, n [ 7), whereas it did not change above what is needed to function as component of the [Cl2O4]
the wound strength in (B) (P [ 0.19, unpaired t-test). The ion, the greater is the competitive adverse effect on adhesion
oxychlorine solutions containing ClO2 at 40 and 70 ppm suppression. Clearly, the choice of treatment solution to be
had no effect (P > 0.05, A). Data are shown as the used in a surgical intervention must reflect the condition of
mean ± standard error of the mean. the subject. These authors are now undertaking the obvious
next phase of the studies, whereby the relative ratio of oxy-
chlorine components [ClO2:chlorite ion] will be optimized for
the intended surgery. In the bulk of surgical interventions,
Intriguingly, we observed an inverse doseeresponse curve sans organic contaminants (e.g., bacterial infections), the
for the oxychlorine solutions depending on ClO2 concentra- choice will be easier. Future studies will be directed to provide
tion. The higher the concentration the smaller is the effect. It more detailed understanding of these complex but obviously
should be noted, however, that these results were obtained in highly effective oxychlorine systems.
the absence of peritoneal contamination, wherein the study The Food and Drug Administration has approved at least
using an oxychlorine composition containing 100 ppm of ClO2 three synthetic products that presumably function by sepa-
showed superior efficacy compared with the three commer- rating the surgically injured tissue from other tissue surfaces
cial products. The fecal (organic) contaminants significantly during surgery [2]. However, these products are often poorly
depleted the efficacy of the lower level ClO2-containing oxy- effective and actually contraindicated if there is infection or
chlorine solutions. It is reasonable to conclude, based on our bleeding in the surgical subjects. Oxychlorine solutions,
experience with these complex oxychlorine systems, that two which are powerful germicides [24], in contrast, could be
competing actions are at play. In the absence of significant favorably used in these circumstances. In fact, oxychlorine
organic matter, the full oxidative capacity of ClO2echlorite solutions were demonstrably effective even in the presence of
systems can be directed fully to stabilize superoxide and fecal peritonitis. This could represent a major advance in the
decrease the inflammatory cascade triggered by hypoxia. treatment of surgical adhesions.
 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 1 8 6 ( 2 0 1 4 ) 1 6 4 e1 6 9 169

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