1 Centre for Surgical Technologies and 2 Department of Obstetrics and Gynaecology, University Hospital Gasthuisberg, Leuven, Belgium
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Abstract |
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Key words: adhesions/helium/hypoxaemia/laparoscopy/pneumoperitoneum
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Introduction |
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In humans, laparoscopy was claimed to be less adhesiogenic than laparotomy (Lundorff et al., 1991). More and large clinical studies have not been performed because of the obvious difficulties and ethical concerns for follow-up and scoring of adhesions. In animals, some studies failed to show differences between laparoscopy and laparotomy (Filmar et al., 1987
; Marana et al., 1994
; Jorgensen et al., 1995
) whereas others did show significantly less adhesions after laparoscopy in rats (Schäfer et al., 1998
), dogs (Schippers et al., 1998
), pigs (Fowler et al., 1994
) and rabbits (Luciano et al., 1989
).
CO2 pneumoperitoneum was recently shown to play a role in peritoneal adhesion formation in rabbits (Ordoñez et al., 1997) and mice (Yesildaglar et al., 1999
). This could be important since CO2 is generally used for pneumoperitoneum for safety reasons because of its high solubility in water and exchange rate in the lungs. CO2 induces local changes such as intraperitoneal acidosis (Volz et al., 1996
, 1997
; West et al., 1997
). In the absence of moistening, desiccation of mesothelial layers will occur (Ryan et al., 1973
), whereas the intraperitoneal pressure will induce adverse effects upon peritoneal microcirculation (Taskin et al., 1998
, 1999
) possibly inducing hypoxaemia. The hypothesis of hypoxaemia in the peritoneal superficial layers was moreover suggested by the observations that adhesions decrease when oxygen is added to the CO2 during pneumoperitoneum (P.R. Koninckx et al., unpublished).
In order to confirm that superficial mesothelial hypoxaemia is a key adhesiogenic factor, this prospective, randomized trial in a rabbit model was designed using helium instead of CO2. This experiment should confirm the effect of duration of pneumoperitoneum and evaluate the relative importance of acidosis and hypoxaemia upon adhesion formation.
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Materials and methods |
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The anaesthesia was induced with i.m. ketamine (50 mg/kg, Ketalin®; Apharmo, Duiven, The Netherlands) and xylazin (6 mg/kg, XYL-M 2%®; VMD, Arendonk, Belgium) and maintained with inhalational halothane (2%, Fluothane®; Zeneca, Destelbergen, Belgium) and oxygen (1.5 l/min).
The surgery was performed under strict aseptic condition and no antibiotics were administered. The rabbits were placed in supine position and the abdomen was shaved and disinfected with polyvidone iodine (iso-Betadine®; Asta Medica, Brussels, Belgium). A 12 mm trocar (Apple®; Medical Corporation, Bolton, MA, USA) was introduced by open laparoscopy through a 1 cm incision caudal to the sternum. The pneumoperitoneum was created using 100% of CO2 or helium or a mixture of 96% of CO2 or helium with 4% of oxygen. This was achieved using two insufflators (Thermoflator®; Karl Storz, Tuttlingen, Germany), one for CO2 or helium and one for oxygen. To obtain a homogeneous mixture, the output of both insufflators was mixed in a mixing chamber which was connected to a water valve to limit the insufflation pressure at 10 cm of water (Koninckx and Vandermeersch, 1991). Therefore a slightly higher insufflation pressure was used for both insufflators (8 mm Hg), whereas 4% of oxygen was achieved using 24 l/min of CO2 or helium and 1 l/min of oxygen. For reasons of standardization 25 l/min was used for pure CO2 or helium, knowing that all excess gas would escape from the water valve. A 12 mm 0° endoscope (Karl Storz), connected to a single chip video camera (Karl Storz) and light source (Karl Storz), was used. After the establishment of the pneumoperitoneum a 5 mm trocar (Apple®; Medical Corporation) was introduced, under direct laparoscopic vision, at the level of the umbilicus to allow the introduction of the necessary instruments. Taking into account the high exchange capacity of the peritoneum and to maintain the concentration of the gases used, a continuous flow rate through the abdominal cavity of 1 l/min was used to remove constantly any oxygen which could be diffused from the circulation. To achieve this an 18 gauge catheter (Insyte-W®, Vialon®; Becton Dickinson, Madrid, Spain) was inserted in between the first and second trocars.
The rabbits were placed in 45° Trendelenburg position. Standardized opposing lesions of 2 cm2 were performed randomly on the uterine horns and in the pelvic side walls by bipolar coagulation in one side, using a 5 mm forceps (Ethicon Endo-Surgery, Cincinnati, OH, USA) with a power of 10 watts (Force 30®; Valley Lab, Longbow Drive Boulder, CO, USA) and in the other side by CO2 laser (Sharplan 1040, Tel Aviv, Israel) with a spot diameter of 1 mm and a power of 10 watts in the continuous super-pulse mode. Laser and bipolar lesions were used since the former was a lesion leaving a layer of some 100 µm of damaged cells only, whereas a bipolar lesion would induce necrosis up to at least a few mm. Since differences in healing between these lesions cannot be ruled out, the effect of pneumoperitoneum was investigated using both. The procedures took some 56 min and the pneumoperitoneum was maintained subsequently up to 10 or 45 min. At the end of the surgery the abdominal incisions were sutured with polyglactine 30 (Vicryl®, Ethicon®; Johnson and Johnson, Brussels, Belgium). Adhesion formation was scored after 7 days by second look laparoscopy since it was assumed that the laparoscopic evaluation might be more precise than a post-mortem evaluation by laparotomy because of the magnification and because of the distended abdomen by the pneumoperitoneum. This, however, will have to be validated since it cannot be excluded that adhesions might be separated by the pneumoperitoneum.
Experimental design
Six groups of eight animals were used. In group I pneumoperitoneum was maintained for 10 min and in group II for 45 min using 100% of CO2 and in group III for 45 min using 96% of CO2 with 4% of oxygen. In group IV pneumoperitoneum was maintained for 10 min and in group V for 45 min using 100% of helium and in group VI for 45 min using 96% of helium with 4% of oxygen.
A 2x2 factorial design (groups I, II, IV and VI) was used to evaluate the effect of duration of pneumoperitoneum (10 and 45 min) and the effect of insufflation gas (CO2 and helium) upon adhesion formation. Similarly a 2x2 factorial design (groups II, III, V and VI) was used to evaluate the effect of the addition of oxygen (100% of CO2 or helium or 96% of CO2 or helium with 4% of oxygen) and the effect of the insufflation gas (CO2 or helium). Groups I, II and III moreover should confirm the previous observation of an increase in adhesion formation with the duration of CO2 pneumoperitoneum (I versus II) and a decrease with the addition of oxygen (II versus III).
Block randomization by days was used. Each block of six animals thus was operated on during the same day. All surgery was performed by the same surgeon during 8 consecutive days for the first and the second look respectively.
All second look laparoscopies were video-recorded and subsequently adhesion formation was scored blindly by two independent observers taking into account extent (0: no adhesions, 1: 125%, 2: 2650%, 3: 5175%, 4: 76100%), type (0: no adhesions, 1: filmy avascular, 2: dense avascular, 3: dense with capillaries, 4: dense with larger vessels) and tenacity (0: no adhesions, 1: essentially fall apart, 2: required traction, 3: required sharp dissection).
Since the lesions inflicted in either the right or the left side were performed in the same way (laser or bipolar), scoring was done separately for right and left side, thus obtaining separate laser (L) and a bipolar (B) lesions adhesion scores.
Laser total (L-total) adhesion score was obtained adding laser extent (L-extent), laser type (L-type) and laser tenacity (L-tenacity) adhesion scores. Bipolar total (B-total) adhesion score was obtained adding bipolar extent (B-extent), bipolar type (B-type) and bipolar tenacity (B-tenacity) adhesion scores. Extent, type, tenacity and total adhesion scores were defined as the sum of L-extent and B-extent, L-type and B-type, L-tenacity and B-tenacity and L-total and B-total, respectively.
Statistics
Statistical analysis was performed with the SAS system (SAS Release 6.12, 1998) using Wilcoxon analysis and two-way analysis of variance. Since data were not normally distributed because of 0 scores, the general linear model (Proc GLM) was used instead of analysis of variance. All data are presented as mean ± SEM. The advantage of the 2x2 factorial design was that to achieve the same statistical precision as with a one at a time approach, twice as many observations would have been needed. The power of the observed effect of duration of CO2 and helium, and the effect of adding oxygen thus is comparable to experiments with 16 animals in each group. This increase in power of the factorial design was only valid when the effects of the two factors were additive, i.e. when no interaction between the two factors was present. The possibility of detecting an interaction, i.e. a different effect of one factor at different levels of the other factor, could however also be considered an advantage of the factorial design, since this effect could otherwise easily be missed. When the number of observations is low, one should be aware that a positive interaction (with subsequent reduction of power to demonstrate the effect of the two factors) could be missed, especially when the between subject variability is high (Armitage and Berry, 1987
).
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Results |
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Laser and bipolar lesions were evaluated separately. By two-way analysis of variance, increasing duration of the pneumoperitoneum increased L-total (P = 0.0001), L-extent (P = 0.0001), L-type (P = 0.0001) and L-tenacity (P = 0.003) adhesion scores, as well as B-total (P = 0.05), B-extent (NS), B-type (NS) and B-tenacity (NS) adhesion scores (Table I).
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Laser lesions induced more adhesions than bipolar lesions as evidenced by higher total scores (P = 0.0001), and higher scores for extent (P = 0.0001), type (P = 0.0001) and tenacity (P = 0.0001).
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Discussion |
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Helium pneumoperitoneum was used in this experiment to evaluate the hypothesis that the hypoxaemia, induced by compression of the capillary flow in the superficial peritoneal layers during prolonged pneumoperitoneum, is a cause of adhesion formation. It is logical to assume that increasing duration of pneumoperitoneum and higher intra-abdominal pressures limit the peritoneal capillary flow, increasing hypoxaemia, and that the addition of oxygen could decrease hypoxaemia. This assumption is consistent with previous findings that duration of CO2 pneumoperitoneum (Ordoñez et al., 1997; Yesildaglar et al., 1999
) and that higher intra-abdominal pressures (Yesildaglar and Koninckx, 2000
) increase adhesions whereas the addition of oxygen decreases adhesion formation (P.R. Koninckx et al., unpublished). This experiment confirmed the observations using CO2 pneumoperitoneum and demonstrated the same effect using helium pneumoperitoneum whereas no differences were found between CO2 and helium. All these data together confirm the hypothesis that hypoxaemia is more important than acidosis in adhesion formation following prolonged pneumoperitoneum.
The effect of a low oxygen concentration in blood (hypoxaemia) or in tissues (hypoxia) differs between tissues, which could be explained by different microvascular flow reserves, oxidative capacity and metabolic need (Scannell, 1996). Hypoxia alters the metabolism of endothelial cells as shown by vascular damage and increased vascular permeability (Scannell, 1996
), increased expression of adhesion molecules such as vascular cell adhesion molecule (VCAM)-1 and intracellular adhesion molecule (ICAM)-1 (Setty and Stuart, 1996
) and increased polymorphonuclear (PMN) adhesion to the vascular endothelium (Kalra et al., 1996
). At the same time, hypoxia decreases T-lymphocyte production of interleukin (IL)-2, a key cytokine responsible for B-cell proliferation and inmunoglobulin secretion, and increases the release of tumour necrosis factor (TNF)-
, IL-1 and IL-8 by human macrophages (Scannell, 1996
).
Hypoxia could modulate directly or indirectly, during pneumoperitoneum, the production of cytokines and growth factors by peritoneal mesothelial cells, macrophages and fibroblasts. Macrophages secrete cytokines and growth factors, such as IL-1, IL-4, IL-6, IL-10, TNF and transforming growth factor (TGF), which are involved in peritoneal wound healing and modulate the process that leads to adhesion formation (Chegini, 1997). TGF-ß1, TNF-
and IL-1ß up-regulate plasminogen activator inhibitor-1 (PAI-1) and down-regulate tissue-type plasminogen activator (t-PA), decreasing plasmin and thus inhibiting the lysis of fibrin (Tietze et al., 1998
). TGF-ß decreases the expression of matrix metalloproteinases (MMP) and increases the expression of tissue inhibitors of metalloproteinases (TIMP), thus decreasing matrix degradation and increasing fibrous adhesions (Chegini, 1997
). The effect of hypoxaemia, however, has not been investigated as was done for mesothelial cells. Recently it was shown that human peritoneal mesothelial cells cultured under hypoxic conditions (2% oxygen) increase amounts of TGF-ß1 mRNA and collagen III mRNA after 6 h (Saed et al., 1999a
), amounts of TGF-ß1 and TGF-ß2 mRNA after 24 h (Saed et al., 1999b
) and amounts of TIMP-1 mRNA, possibly via a TGF-ß1 dependent mechanism (Saed et al., 1999c
). To interpret these data it should be realized that in some experiments hypoxaemia varies from 05% of oxygen. This could be important since it should be compared to the partial oxygen pressure in the abdominal cavity.
The effect of mesothelial hypoxaemia, induced by the pneumoperitoneum during a laparoscopic surgery, upon vascular endothelial growth factor (VEGF) expression should be considered to explain the increase in adhesion formation. Indeed, hypoxia, together with other growth factors and cytokines, stimulates the production of VEGF by a variety of normal and transformed cell types (Neufeld et al., 1999). Hypoxia up-regulates the production of VEGF by non-activated and by interferon-
(IFN
) and/or lipopolysaccharide (LPS) activated murine peritoneal macrophages (Xiong et al., 1998
). Increased concentrations of VEGF were detected, generally under hypoxic conditions, in ovarian hyperstimulation syndrome (Chen et al., 1999
), ovarian neoplasm (Yamamoto et al., 1997
), endometriosis (McLaren et al., 1996
) and ascites tumours (Luo et al., 1998
) and during the normal cyclic changes in the female reproductive system (Shweiki et al., 1993
). Furthermore, VEGF was found in peritoneal adhesions of women by immunohistochemistry (Wiczyk et al., 1998
) and of men and women by enzyme-linked immunosorbent assay (Diamond et al., 1999
) and it was shown that a polyclonal rabbit antibody to VEGF limits adhesion formation after laparotomy in a murine model (Saltzman et al., 1996
). These data indicate that VEGF has a role in the development of post-operative adhesions.
It is unclear at present why laser lesions induce more adhesions than bipolar lesions. It can only be speculated that the larger denuded area might be important, but it should be investigated what is the exact role of depth and amount of tissue necrosis and whether this effect might be specific for hypoxaemia induced adhesions.
In conclusion, this experiment confirms the key role of mesothelial hypoxaemia in adhesion formation. Recent publications indicate that this could be mediated by a growth factor such as TGF-ß or VEGF and more specific studies are currently being performed in order to clarify this point.
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Acknowledgments |
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Notes |
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References |
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Submitted on December 20, 1999; accepted on May 11, 2000.