1 Section of Reproductive and Developmental Medicine, The Jessop Wing, Central Sheffield University Hospitals, Tree Root Walk, Sheffield S10 2SF and 2 Division of Biomedical Sciences/BMRC, Sheffield Hallam University, City Campus, Sheffield, S1 1WB, UK
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Abstract |
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METHODS: Peritoneal fluid, collected from eight patients following laparoscopy and again at 12, 36 and 48 h after surgery, was analysed using enzyme-linked immunosorbent assay (IL-1 and IL-6) and bioassay (TNF-). At 48 h, a second look laparoscopy was performed to inspect the pelvis for adhesion formation/reformation. RESULTS: Three patients had adhesion reformation >10% at 48 h after surgery. The mean adhesion score 48 h after adhesiolysis was 5 (range 017). The mean reduction in adhesion score was 88% (range 83100%). Newly formed adhesions were filmy, relatively soft and avascular in nature. Adhesion reformation of >10% was associated with (i) high concentrations of IL-6 at 12 h (P < 0.01) and (ii) high concentrations of IL-1 at 48 h (P < 0.001). CONCLUSIONS: Results from this preliminary study suggest that future treatment strategies for adhesion prevention could be aimed at the control of cellular mediators in the peritoneal fluid during the initial adhesion formation period.
Key words: adhesiolysis/adhesions/cytokines/peritoneal fluid
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Introduction |
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As the peritoneal fluid is in constant contact with the peritoneal surface, the cellular mediators that exist in the peritoneal fluid reflect the biochemical dynamics of adhesion formation. Evidence from current literature suggests that pro-inflammatory cytokines such as interleukin (IL)-1, IL-6 and tumour necrosis factor (TNF)- are released into the abdominal cavity after abdominal surgery (Shenkin et al., 1989
; Baigre et al., 1991
; Tsukada et al., 1993
). These cytokines may play a role in adhesion formation/reformation. Pro-inflammatory cytokines may be involved in adhesion formation/reformation in a number of ways: IL-1 and TNF-
are both pro-inflammatory cytokines important in the early phase of wound healing (Lowry, 1993
), and are produced by activated macrophages in the peritoneal fluid (Halme, 1986
; Mori et al., 1991
), whereas IL-6 is expressed by activated macrophages and its production is up-regulated by IL-1 during the inflammatory process (Hirano, 1998
). Both IL-1 and TNF-
are potent inducers of IL-6 (Bauer et al., 1988
). These cytokines are thought to be important as they interact extensively with the fibrinolytic pathway and contribute directly or indirectly to the remodelling of the extracellular matrix (ECM) (Cheong et al., 2001b
); the abnormal control of ECM remodelling may be responsible for the formation of adhesions after peritoneal injury.
A number of previous studies have examined cytokine concentration in peritoneal fluid of well-established adhesions in humans (Buyalos et al., 1992; Chegini et al., 1994
; Holmdahl et al., 1996
). However, no studies have investigated the relationship between the changes in peritoneal fluid cytokine concentrations immediately after adhesiolysis and the surgical outcome and pelvic adhesion reformation. The objective of this study was therefore to examine the concentrations of IL-1, IL-6 and TNF-
in the peritoneal fluid at periods throughout the 48 h post-operative period following adhesiolysis, and correlate the results to the extent of adhesion reformation. This is the first human study attempting to correlate the concentration of peritoneal fluid cytokines with post-operative pelvic adhesion reformation.
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Materials and methods |
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The subjects were recruited from the gynaecological outpatients and consented in the pre-operative assessment unit 2 weeks before their surgery. All the subjects had undergone a previous laparoscopy which confirmed the presence of adhesions and were scheduled for laparoscopic adhesiolysis. All subjects had adhesions as a consequence of previous surgery and seven subjects had previously undergone hysterectomy. All of the subjects had their ovaries conserved. None had a history of pelvic inflammatory disease or endometriosis. Adhesiolysis was the sole procedure performed in these patients and was performed by one surgeon. No suturing was required during the operation. None of the patients had adhesion barriers administered during and/or after their initial laparoscopy.
The subjects were admitted a day prior to their surgery for bowel preparation. Women recruited into the study underwent laparoscopic adhesiolysis performed by one laparoscopic surgeon and a further second look laparoscopy 48 h later under local or general anaesthetic by the same surgeon. Prior to any surgery, the pelvic cavity was inspected for adhesion formation/reformation, and the adhesions were scored using the well-validated adhesion scoring method (MCASM) (Adhesion Scoring Group, 1994). The laparoscopic procedure was video-recorded and subsequently analysed by a separate investigator.
Peritoneal fluid collection
Pre-operatively
Peritoneal fluid was collected during laparoscopy using a follicular aspiration needle under direct vision, at the beginning of the procedure, prior to the commencement of any pelvic surgery. In some cases a palpiteur was used to move away bowel to expose the pouch of Douglas for collection of the peritoneal fluid. Care was taken not to contaminate the peritoneal fluid with blood. The fluid collected was snap-frozen in liquid nitrogen and stored at 70°C.
Post-operatively
After the operation, a size 16 Robinson's drain was inserted via the suprapubic port site. This drain was left in situ in the pouch of Douglas for the next 48 h. The drain entry sites were kept clean with regular changes of dressings. Peritoneal fluid was collected from the drain for 1 h at 12 h intervals on three occasions (12, 24 and 36 h) before the patient went back to theatre for a second look laparoscopy at 48 h. On each occasion, the drain was emptied 1 h before the designated fluid collection time to ensure that the peritoneal fluid collected was freshly drained from the abdominal cavity.
The last peritoneal fluid sample (at 48 h after surgery) was collected from the pelvic cavity during the second look laparoscopy using the follicular aspiration needle as described before.
Second look laparoscopy
Second look laparoscopy was performed under local (n = 3) or general anaesthesia (n = 5), mainly depending on patient preference. Carbon dioxide (CO2) insufflation was performed via direct connection of the carbon dioxide gas tubing to the Robinson's drain. In the three women in whom the procedure was performed under local anaesthesia, a mini-laparoscope (5 mm) was inserted via the Robinson's drain after ~1 l of CO2 was introduced into the peritoneal cavity. In the remaining women, after the removal of the suture at the subumbilical site, the laparoscope was introduced along with the laparoscopic cannula directly through the sub-umbilical site, thus avoiding the introduction of a sharp instrument into the abdominal cavity. The pelvic cavity was inspected for adhesion formation/reformation, and scored as previously using MCASM; the nature of deperitonealised areas, colour and volume of the peritoneal fluid were noted. Adhesion reformation was expressed as a percentage of the adhesion present during the first laparoscopy.
Surgical techniques
All patients had four laparoscopic ports for surgical access: a camera port (10 mm) at the subumbilical site; and three additional 5 mm ports over the iliac fossae and suprapubically. The bands of adhesions were gently stretched by a pair of graspers to allow for the identification of the tissue plane. To facilitate adhesiolysis, a combination of blunt, sharp and hydro-dissection was used. In the presence of fine, avascular adhesions, blunt dissection using the tip of the scissors as well as hydro-dissection were used. This method avoids thermal injury to the peritoneum and the surrounding tissues. In the presence of thick, cohesive omental adhesion, the bipolar diathermy was used to diathermize the omental adhesions together with any blood vessels hidden in them, and the scissors were then used to cut the coagulated tissue. The process was repeated until all the adhesion bands were separated from their attachment. Microsurgical techniques including atraumatic handling of tissue, constant irrigation and meticulous haemostasis were employed in all cases.
Cytokine assays
IL-1 and IL-6 were measured by enzyme-linked immunosorbent assay using Duoset kits (R&D Systems Ltd, Abingdon, Oxon, UK) according to the manufacturer's instructions. Samples and standards were assayed in duplicate. TNF- was measured by bioassay using L929 cells (Aarons and Borish, 1993
; Gaines Das and Meager, 1995
). These cells were split the day before the start of the assay to ensure that they were in log-phase growth. Cells were plated into all wells of a 96-well plate at a density of 2.2x105 cells per ml (100 µl per well) and grown overnight at 37°C in an atmosphere of 5% CO2. The next day, 100 µl of sample or standard TNF-
(8500 pg/ml) (R&D Systems Ltd) was added and the cells were incubated as before for a further 24 h. Cells were then washed twice in phosphate-buffered saline, fixed in methanol for 15 min and stained using Crystal Violet. After staining, the cells were solubilized using 10% acetic acid and the absorbance at 570 nm was read. All samples and standards were assayed in triplicate. The sensitivity of the assays was 1, 1 and 2 pg/ml for IL-1, IL-6 and TNF-
respectively. The inter-assay and intra-assay variation was 10 and 5% for the IL-6 and IL-1 immunoassay and 15 and 5% for the TNF-
bioassay respectively. To ensure that the other constituents of the peritoneal fluid did not interfere with the assays, known amounts of each cytokine were added to a single peritoneal sample and assayed in parallel to the unspiked sample.
Ethical issues
Ethical approval was obtained from the South Sheffield Research Ethics Committee. Patient information leaflets were given to the women recruited into the study and written consent was obtained from all women.
Statistical analysis
The data were analysed using SPSS. Results were expressed as the mean and SEM. The difference in the concentrations of the cytokines was analysed by the general linear model repeated measures multivariate analysis of variance (MANOVA), with P < 0.05 taken as the level of significance.
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Results |
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Adhesion scores
Figure 1 summarizes the mean and individual adhesion scores of all eight patients assessed at the first treatment operation and the second look laparoscopy. The mean (range) of the adhesion scores at the first operation was 42 (2556). Six patients had reformation of adhesions and two had no adhesions reformed at the second look laparoscopy. The mean adhesion score 48 h after adhesiolysis was 5 (range 017). The mean reduction in adhesion score was 88% (range 83100).
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Morphological description of newly reformed adhesions
Appearances in subjects with adhesions
Newly formed adhesions at 48 h post-laparoscopic adhesiolysis were filmy, relatively soft and avascular in nature. They were easily lysed by gentle traction to the surrounding organs to which they were attached, such as bowel or ovaries. They were present in areas where the peritoneum had been denuded or traumatized. The areas where adhesions were reformed were bloodless, with the occasional old blood clot but no active bleeding/ooze.
Varying amounts of peritoneal fluid were present and the fluid was blood-stained in five patients. In patients with >10% adhesions reformed (n = 3), the peritoneal fluid was heavily contaminated with blood compared with the other samples which were clear but pink in colour.
Appearance in subjects with no adhesions (n = 2)
During the second look laparoscopy, the previously denuded area of the peritoneum was covered with a layer of yellow and shiny exudate. There was no active bleeding/oozing and the peritoneal fluid was clear but pink.
De-novo adhesions
In this study, we did not observe the formation of any adhesions at sites where none were previously present.
Biochemical findings
Figure 2 shows the concentrations of IL-1, IL-6 and TNF-
in peritoneal fluid from individual patients 12, 24, 36 and 48 h after adhesiolysis. Figures 35
shows the mean of IL-1, IL-6 and TNF-
between those with significant adhesions and those with no adhesions. The concentration of IL-1 after surgery in patients who had adhesion reformation >10% appeared higher after 24 h than patients who had minimal/no adhesion reformation and this was significant at 48 h after surgery (P < 0.001). Levels of IL-6 appeared greater in patients with significant (>10%) adhesion reformation compared with those with minimal/no adhesion reformation at all time points except zero, although this was only significant 24 h after surgery (P < 0.01). The concentration of TNF-
in the 48 h after surgery in patients who had significant adhesions reformed was not significantly different from that of patients who had minimal/no adhesions reformed.
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Discussion |
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Sample size
Due to the highly experimental nature of this study, it was designed as a pilot study; thus the findings in this study consisted of our preliminary observations. The study could be made more robust by the recruitment of more patients. However, to increase the power of the study, the number of patients recruited would need to be substantially increased, the precise number to be determined by a proper power calculation. Our study is really a pilot study necessary to help in the planning of future substantive studies.
Timing for the second look laparoscopy
Previous studies that attempted to correlate peritoneal fluid cytokine concentration and adhesion formation/reformation obtained peritoneal fluid from women with chronic well-established adhesions. However, adhesion formation/reformation is a dynamic process, therefore a single sample of peritoneal fluid obtained after adhesions have already formed is unlikely to provide valuable information on the dynamic process of adhesion reformation. In animal studies, the peritoneum is known to heal within the first week from the initial insult (Ellis et al., 1965). The prime time to examine the biochemical kinetics and the adhesion reformation process is therefore within the first few days after the operation. In our current study, we obtained biochemical data and correlated the results with the appearance of the pelvis 48 h after surgery. Whilst animal data suggest that the cellular mechanisms of peritoneal healing would be most critical during the first few days after the initial trauma (diZerega, 1990
), there are no firm human data to suggest that observations at 48 h accurately reflected subsequent evolution of adhesion formation/reformation. The only way to obtain data on subsequent adhesion formation/reformation would be to perform a third look laparoscopy. In the current study, one can only infer from animal data that what appears in the early post-operative phase is of critical importance to the subsequent development of adhesions.
It is known that IL-1 precedes IL-6 response after abdominal surgery and that IL-1 concentrations are raised during the operation (Baigre et al., 1991). This first rise in IL-1 may not have been seen in our study. The continued increase in IL-1 concentration after the 24 h seen in some patients and not in others in our study might represent the difference in individual response to peritoneal insult/trauma.
Many previous studies examining the cytokine response post-operatively have investigated serum concentrations of cytokines (Kato et al., 1997, 1998
). Although serum concentrations of cytokines might reflect systemic response to the stress of surgery, the local response by the peritoneum can only be assessed by the measurement of cytokines in the peritoneal cavity. It is well known that during abdominal operations, peritoneal macrophages are activated and release biologically active substances such as IL-1, IL-6 and TNF-
, into the peritoneal fluid (Shenkin et al., 1989
; Baigre et al., 1991
). The adhesion formation/reformation process involves a combined local response of the mesothelial cells lining the peritoneal cavity and the macrophages in the peritoneal fluid (Offner et al., 1995
, 1996
; Haney, 1999
, 2000
); hence the importance of measuring peritoneal fluid cytokine concentrations immediately after the operation. Previous studies which have assessed the post-operative inflammatory response by measuring the post-operative peritoneal fluid cytokine levels unfortunately did not include any second look morphological data describing the extent of reformation of adhesions (Tsukada et al., 1993
).
Causal or casual effect of cytokines on adhesion formation
The correlation between cytokine concentration and degree of adhesion formation may reflect a cause or an effect of the adhesion formation process. There was no means of differentiating peritoneal cytokine response secondary to the different degrees of inflammation evoked by the original insult from that of the adhesion formation process itself. However, the extent of the adhesiolysis performed in the eight patients was similar as shown both by their preoperative adhesion scores and the operating time required; furthermore surgery was performed by laparoscopy, thus minimizing trauma that would have resulted from manual handling. However, it has been shown that administration of IL-1 intraperitoneally increased adhesion formation in rats (Hershlag et al., 1991). In addition, IL-1 antibody administration into the pelvic cavity reduced adhesion formation in rats (Kaidi et al., 1995a
). These results in animals suggest that IL-1 is a causative factor in the adhesion formation process.
Confounding factors
In the planning of subsequent larger studies, it would be important to take into account the following confounding factors.
Sample collection
The concentration of the cytokines in the peritoneal fluid could be influenced by a number of factors including proteases and bacterial contamination. In this study, the samples were collected an hour after the drain was emptied to ensure that there was minimal contamination.
Assessment of adhesion formation/reformation
In this study, the subjective nature of adhesion scoring by using a well-validated adhesion scoring method was minimized (Adhesion Scoring Group, 1994). In addition, the same surgeon performed the operations and the surgery was video-recorded and examined by a separate investigator, thus avoiding operator bias.
Intra-operative and peri-operative factors
Although unlikely to be significant factors influencing the peritoneal fluid cytokine concentration, any intraoperative and perioperative factors such as the effect of general/local anaesthesia or intraperitoneal carbon dioxide insufflation could act as confounders in this study. Other confounding factors not accounted for in this study include the amount of diathermy and irrigation used.
Effect of blood, proteins and menstrual cycle on peritoneal fluid cytokines
Our previous study showed that the concentrations of blood and proteins did not interfere with the cytokine concentrations (Cheong et al., 2001a). In contrast, peritoneal fluid cytokine concentrations could be influenced by the menstrual cycle; TNF-
but not IL-1 or IL-6 was shown to be menstrual cycle dependent (Cheong et al., 2001a
). Thus, our results on TNF-
could possibly be confounded.
Future implications
The findings in this study have important implications in terms of future therapeutic strategies for adhesion prevention. Many adhesion prevention strategies have been explored in the past. Recently, one of the most popular treatment strategies has been the use of adhesion barriers (Farquhar et al., 2000). The adhesion barriers are thought have their effect by mechanically separating the viscera for as long a period as possible, preventing contact between two surfaces and thus preventing adhesion formation process. The findings of our study have suggested that certain adhesion barriers could also work by diluting the inflammatory mediators such as IL-1 in the early phases of adhesion formation process. Another strategy in the future may be the use of antibodies against the pro-inflammatory mediators in the early phases of adhesion formation process. Animal studies using these strategies have shown successful reduction in adhesion reformation (Kaidi et al., 1995a
,b
), and therefore human studies are now needed.
In conclusion, the degree of adhesion reformation 48 h after adhesiolysis was related to the concentration of IL-1, IL-6 but not TNF- in the peritoneal fluid during this period. Adhesion reformation of >10% at 48 h after adhesiolysis was associated with (i) high concentration of IL-6 at 12 h, and (ii) high concentration of IL-1 at 48 h. Newly formed adhesions are avascular and could be readily lysed by gentle traction. If adhesion reformation at 48 h predicts adhesion formation thereafter, the results from this study would suggest that future treatment strategies for adhesion prevention could be aimed at the control of cellular mediators in the peritoneal fluid during the initial adhesion formation period.
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Notes |
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References |
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Submitted on June 18, 2001; resubmitted on September 24, 2001; accepted on December 4, 2001.