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N2O strongly prevents adhesion formation and postoperative pain in open surgery through a drug-like effect Corona, Roberta; Binda, Maria M; Adamyan, Leila; Gomel, Victor; Koninckx, Philippe R Nov 7, 2017

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ORIGINAL ARTICLEN2O strongly prevents adhtn3ninbeaf esmall. In women of reproductive age, follicular exudationincreases the volume and adds high concentrations ofthe duration and severity of the trauma. Identified trau-mas are surgical manipulation, mesothelial cell hypoxiaxidative stressed by expos-and saline asration of thisal cavity cre-Gynecological SurgeryCorona et al. Gynecological Surgery  (2017) 14:21 DOI 10.1186/s10397-017-1024-2mation through a reduction in tissue plasminogen ac-tivator (tPA) and an increase in plasminogen activator5KU Leuven, Vuilenbosstraat 2, 3360 Bierbeek, BelgiumFull list of author information is available at the end of the articleate an inversely proportional reduction of fibrinolysis.This, in turn, increases the potential of adhesion for-* Correspondence: pkoninckx@gmail.com1Department of Obstetrics and Gynaecology, KU Leuven – CatholicUniversity of Leuven, 3000 Leuven, Belgiumlong to the body homeostasis. Any trauma in theperitoneal cavity causes an inflammatory reaction and amesothelial cell retraction, exposing the basal mem-brane. This abolishes the blood-peritoneal fluid barrierischaemia-reperfusion at desufflation [4], o[5] or reactive oxygen species (ROS) inducure to air with 20% of oxygen, desiccationirrigation liquid. The severity and the duacute inflammation of the entire peritonesteroid hormones. The peritoneal cavity is not vascu-larised and constitutes a sterile cavity that does not be-by CO2 pneumoperitoneum, deeper ischaemia at an in-traperitoneal pressure of more than 8 mmHg andN2O during LS and OS.In OS, 30- and 60-min exposure to non-humidified CO2 caused mortality of 33 and 100%, respectively. Mortality wasprevented by humidification, by dry N2O or dry CO2 + 4%O2. Adhesions increased with the duration ofexposure to CO2 (p < 0.0001) and decreased slightly by humidification or by the addition of 4% O2. N2Ostrongly decreased adhesions at concentrations of 5% or greater. With humidified CO2 + 10% N2O, adhesionformation was similar in OS and LS.Conclusions: The drug-like and strong beneficial effect of low concentrations of N2O is confirmed in OS.Keywords: Postoperative adhesions, N2O, Conditioning, Humidification, Microsurgery, Microsurgical principleBackgroundThe peritoneal cavity with its peritoneal fluid is a spe-cific environment different from that of plasma. Themesothelial cell lining of the peritoneal cavity and its or-gans facilitates the gliding of the bowels and actively reg-ulates homeostasis and transport of fluids, moleculesand cells. In males, the volume of peritoneal fluid isand permits the entry of immunocompetent cells andfacilitates diffusion of larger molecules as immunoglo-bins, which is an efficient defence mechanism to in-truders [1, 2].The large and flat mesothelial cells react within sec-onds to any trauma by retraction and bulging [1, 2]causing an acute inflammation [3] which increases withevaluated the dose-response curve of adding N2O to CO2. Experiment III compared humidified CO2 + 10%and postoperative pain inthrough a drug-like effecRoberta Corona1,2, Maria Mercedes Binda1, Leila AdamyaAbstractBackground: Microsurgical tenets and peritoneal conditioadhesions and pain. For a trial in human, the strongopen surgery (OS).Results: In a mouse model for OS, the effect of the gExperiment I evaluated desiccation and the duration o© The Author(s). 2017 Open Access This articleInternational License (http://creativecommons.oreproduction in any medium, provided you givthe Creative Commons license, and indicate ifOpen Accessesion formationopen surgery, Victor Gomel4 and Philippe R. Koninckx1,5*g during laparoscopic surgery (LS) decrease postoperativeneficial effects of N2O needed to be confirmed ins environment upon adhesions was evaluated.xposure to CO2, N2O or CO2 + 4%O2. Experiment IIis distributed under the terms of the Creative Commons Attribution 4.0rg/licenses/by/4.0/), which permits unrestricted use, distribution, ande appropriate credit to the original author(s) and the source, provide a link tochanges were made.Corona et al. Gynecological Surgery  (2017) 14:21 Page 2 of 8inhibitor (PAI) [6, 7]. During laparoscopic surgery,the retraction and bulging of mesothelial cells cause aprogressive increase in CO2 resorption. The acute periton-eal inflammation increases postoperative C-reactiveprotein concentrations (CRP) and causes postoperativepain [2].During laparoscopic surgery, prevention of themesothelial cell retraction and the subsequent acuteinflammation effectively prevents or decreases the as-sociated consequences including postoperative adhe-sion formation and postoperative pain. In addition, itaccelerates recovery and in animal experiments de-creases tumour metastasis. The most effective pre-ventive factors are the addition of more than 5% ofnitrous oxygen to the CO2 pneumoperitoneum, cool-ing of the peritoneal cavity below 31 °C, minimalisingmechanical trauma and ROS production, usingRinger’s lactate instead of saline and administeringone or two doses dexamethasone postoperatively [2].If used together with a barrier [8], this approach re-sults in virtually adhesion free surgery [9].The similarity between our current knowledgederived largely from animal experiments, and themicrosurgical tenets developed in the early 1970s em-pirically, but controlled by systematic second-looklaparoscopy, 8–12 weeks after the initial operation, isstriking. These principles were developed for opensurgery and soon after applied in laparoscopic surgery[10]. These microsurgical principles indeed are acombination of gentle tissue handling, judicious useof electrical and/or laser energy, use of inert sutures,continuous irrigation with Ringer’s lactate at roomtemperature during the procedure to avoid desicca-tion, shielding the bowels from the ambient air, thor-ough lavage of the peritoneal cavity at the end of theprocedure, instillation of Ringer’s lactate solution con-taining a minimum of 500 mg of hydrocortisone suc-cinate into the peritoneal cavity before closure andadministration of one or two doses of dexamethasoneafter surgery.Microsurgical tenets were proven to decrease adhe-sion formation and to increase pregnancy rates inopen and laparoscopic surgery [10, 11]. The relativeimportance of each of these factors that decreaseacute inflammation and adhesion formation was in-vestigated only recently in a laparoscopic mousemodel with proof of concept trials in human [9].However, the addition of low doses of N2O which isthe single most effective factor was investigated dur-ing laparoscopic surgery with an insufflation pressureonly. Since there is no insufflation pressure in opensurgery, we, therefore, decided to evaluate the effectof N2O in a mouse model for open surgery beforeundertaking a trial in human.MethodsAnimals and the experimental set-up (anaesthesia, venti-lation, laparoscopic surgery, adhesion induction andscoring) were as previously described [3, 12, 13].AnimalsInbred 9 to 10-week-old female BALB/c OlaHsd mice of18 to 20 g (Harlan Laboratories B.V., Venray, TheNetherlands) mice were used to decrease experimentalvariability. They were kept under standard laboratoryconditions and diet at the animal facilities of theKatholieke Universiteit Leuven (KUL). The study wasapproved by the Institutional Review Animal Care Com-mittee (KUL: P040/2010).The laparoscopic mouse modelFollowing anaesthesia and pneumoperitoneum induction(Thermoflator, Karl Storz, Tüttlingen, Germany) withhumidified gas (Humidifier, 204,320 33, Karl Storz) andstandardised 10 × 1.6 mm bipolar lesions (20 W,standard coagulation mode, Autocon 350, Karl Storz,Tüttlingen, Germany) were made on both right and leftuterine horns and on abdominal walls using a 2 mmendoscope (Karl Storz, Tüttlingen Germany) and two14-gauge catheters (Insyte-W, Vialon, Becton Dickinson,Madrid, Spain) as secondary ports. The insufflation pres-sure was 15 mmHg. Since adhesion formation increaseswith body temperature, the latter was strictly controlled[13]. Therefore, mice and equipment were placed in aclosed chamber at 37 °C (heated air, WarmTouch, Pa-tient Warming System, model 5700, Mallinckrodt Med-ical, Hazelwood, MO). Anaesthesia and ventilation [14]and the timing between anaesthesia (T0), intubation (at10 min, T10) and the onset of the experiment (at 20 min,T20) were standardised.The only variable in this model of adhesion formationthus was the duration of the pneumoperitoneum andthe type and humidification of the gas used.A mouse model for open surgeryAll factors validated for the laparoscopic model werekept identical, i.e. animals, anaesthesia, intubation, venti-lation, temperature control, timing, type of lesions, theequipment used for gas insufflation and humidificationand the scoring of adhesions. The only difference wasthat instead of a laparoscopy with a pneumoperitoneum,a laparotomy was performed and the mice were keptwith the open abdomen in a box exposed to the specificgas environment.Following some pilot experiments, the model wasstandardised as follows. Following anaesthesia (T0), shav-ing and disinfection of the abdomen, the mouse wasplaced on a warm pillow in a transparent plexiglas boxmeasuring 22 ×10 ×30 cm, closed with a slidingtransparent cover that could be removed to perform at20 min, T2 surgery and lesions (Fig. 1). The box had onehole that accommodates the ventilation tube without gasleaks and two holes of 1 cm diameter each. The upperhole permitted escape of gas without pressure. Thelower hole permitted insufflation of gas standardised inthese experiments at 2 L/min. Since densities of CO2and N2O are higher than air (δCO2 = 1.842,δN2O = 1.872, δair = 1.205 at room temperature and at-mospheric pressure), the box fills progressively until thegas escapes by overflow. In order to perform the surgicalprocedure, the box had to be opened; this causes theinsufflated gas to partially mix with the ambient air. Amidline xyphopubic incision was performed, and the ab-domen kept open with two pins. Standard 10× 2 mm bi-polar lesions were created similar to the laparoscopicmodel. Following surgery, the cover was placed over thebox and the mouse kept with the abdomen open ex-posed to the insufflated gas. This cover was necessary,since otherwise the insufflated gas would mix partiallyStudy designRandomisation and factorial designAll experiments were block randomised by day as donein all previous experiments. Thus, one animal of eachexperimental group was operated at random on thesame day in order to avoid eventual differences by day.A factorial design [16] was used since a two by twofactorial design results for each of the two variables inan almost similar statistical power as if two experimentshad been performed with the same total number of ani-mals in each experiment.Mixture of N2O and CO2In these experiments, we used either premixed gas with90% CO2 and 10% N2O (Ijsfabriek, Strombeek, Belgium)or two Thermoflators one delivering CO2 and the otherN2O, or the premixed gas. The gases from both insuffla-tors were subsequently mixed in a mixing chamber, andthe excess gas was permitted to escape from a watervalve, the flow of both gases entering the box was lim-Corona et al. Gynecological Surgery  (2017) 14:21 Page 3 of 8with the ambient air varying with the height of the box,the diameter of the opening and the flow rate of the gasinsufflated. At the end of the experiment, the abdomenwas closed with nylon 3-0 sutures.Scoring of adhesionsPostoperative adhesions were scored blindly after 7 daysas previously described during a second laparotomyusing a stereomicroscope. The terminology of Poulyet al. [15] was used to describe de novo adhesion forma-tion as adhesions formed at non-surgical sites.Fig. 1 The mouse model for open surgery. Image modified from Binda etited to 2 L/min with a stopcock.Pilot experimentsThe first pilot experiment for open surgery consisted ofmice (n = 3) with the abdomen open exposed to the am-bient air at 37 °C (chamber at 37 °C) for 60 min. After60 min, bowels were macroscopically dry and all micedied within 2 days. Mortality was thought to be causedby desiccation and maybe the damaging effect of 20% ofO2 in air. Therefore, the box was designed as describedin order to control the gas environment, and CO2 wasal. [13], Corona R et al, Gynecol Surg, 2017 + refStatisticsDifferences were calculated with the SAS System (SASInstitute, Cary, NC) [17] using Wilcoxon/Kruskal Wallisunpaired test for comparison of individual data and a two-way analysis of variance (Proc GLM) for experiments witha factorial design. Results are expressed as a mean andstandard deviations unless indicated otherwise.ResultsExperiment IAs observed in the pilot experiment for open surgery withnon-humidified air for 60 minutes, open surgery withnon-humidified CO2 for 60 min resulted in 100% mortal-Corona et al. Gynecological Surgery  (2017) 14:21 Page 4 of 8used as a carrier gas in order to be comparable withlaparoscopy and because CO2 is heavier than air andthus will fill the box progressively from the bottom.A second pilot experiment was performed to evaluatein open surgery gas conditions known from thelaparoscopy model. Humidified CO2 for 60 minconfirmed the absence of mortality with humidification;humidified 50% CO2 + 50% N2O and humidified 100%N2O confirmed the strong adhesion preventing theeffect of N2O in concentrations over 5% (six mice, twomice per group).Experiment IThe first experiment was designed to evaluate in opensurgery the effect of humidification and of the durationof exposure to either 100% CO2 or 100% N2O or 96%CO2 + 4%O2 upon adhesion formation. A factorial de-sign was used with non-humidified or humidified gas(two factors), during 30 or 60 min (two factors), and thethree gas compositions (three factors). With three mice/cell for two humidification factors and two duration fac-tors and three gas factors (total mice = 3×2×2×3 = 36),an almost similar statistical power for each variable wasobtained as if in three consecutive experiments with 36mice each would have been done.Experiment IIA dose response of the addition of various concentra-tions of N2O to the CO2 was evaluated in open surgery.Mice were exposed for 30 min to humidified CO2 withconcentrations of N2O varying from 0 to 0.3, 1, 3, 10and 100%. For 100% CO2, 100% N2O and 10%N2O + 90% of CO2, a Thermoflator was used with CO2,N2O or a premixed gas (10% N2O + 90% CO2), respect-ively. For the other concentrations two Thermoflatorswere used, one with CO2 and the other with premixedgas (10% N2O + 90% CO2). The final concentrations of3, 1, and 0.3% N2O were obtained by combining variousflow rates of 4 and 2 L/min, 9 and 1 L/min and 14.5 and0.5 L/min of 100% CO2 and premixed gas with 10% ofN2O (six mice/group, total mice = 36).Experiment IIIThe third experiment was designed in order to compareadhesion formation following laparoscopic and open sur-gery and to evaluate whether the addition of 4% of O2had an additive effect when 10% of N2O had been addedto the CO2. Using a factorial design, mice were exposedfor 60 min to humidified 90% CO2 + 10% N2O or to86% CO2 + 10% N2O + 4% O2 either during laparoscopyor during open surgery. Since adhesions were known tobe very low with 10% of N2O, 10 mice per cell were usedin order to have a power of almost 40 mice for each fac-tor (total mice = 40).ity (3/3). Even exposure to 30 min non-humidified CO2resulted in 33.3% mortality (1/3) (Fig. 2). As expected,there was no mortality when humidified gas was used. Toour surprise, there was also no mortality when 10% ofN2O or 4% of O2 were added to the non-humidified CO2.Adhesions at the surgical lesion site increased when theduration of exposure was longer (p < 0.0001) and whennon-humidified gas was used (p < 0.0001) When 100%N2O was used, adhesions were very scant in comparisonwith 100% CO2 and 96% CO2 + 4%O2 with and withouthumidification (all comparisons p < 0.0001). When 96%CO2 + 4% O2 was used, adhesions were slightly less thanwith 100% CO2 (non-humidified gas for 30 minp < 0.0001; humidified gas for 30 min p = 0.0011 and for60 min p = 0.003).Whereas in the laparoscopic mouse model, de novoadhesions in the upper abdomen have never been ob-served; in this experiment, de novo adhesions were seenin the upper abdomen between bowels, and betweenbowels and sidewalls when non-humidified CO2 or non-humidified 96% CO2 + 4%O2 were used (Fig. 2).Experiment IIThe addition of increasing concentrations of N2O toCO2 decreases exponentially adhesion formation, with aFig. 2 Effect of duration, humidification and gas type upon mortality andadhesion formation during open surgery: 30 or 60 min of non-humidifiedor humidified CO2, N2O or 96% CO2 + 4%O2 Corona R et al, Gynecol Surg,2017 + ref were used. Proportions of adhesions are given (mean and SD)half maximum effect around 2.5% and a maximal effectfrom 5% onwards (Fig. 3). The difference between 10and 100% N2O was not significant (p = 0.1551). Differencesbetween 0 and 3%, 0 and 10% and between 3 and 10% N2Owere p = 0.0061, p = 0.0006 and p = 0.03, respectively.Experiment IIIWhen humidified CO2 with 10% of N2O was used, adhe-sion formation was as expected very low in all groups(Fig. 4). The extent of adhesions was similar after bothlaparoscopic and open surgery with (NS) or without (NS)4% of oxygen. The addition of 4% of oxygen to CO2 with10% of N2O had a very small additive effect which how-ever turned out to be significant (p < 0.01) caused by thehigh power of 20 mice in each group (factorial design, 10mice/cell) and the low variability of inbred strains,of which is unknown. It is also not understood why mor-tality is 100% after exposure for 60 min to non-humidifiedCO2 and no mortality when non-humidified N2O is used,although the desiccated aspect of the bowels is the same.We only can speculate that mortality is not only caused bythe desiccation but mainly by the severity of the inflam-matory process since N2O strongly and O2 slightly de-crease the inflammatory reaction [18].The observed effects of 5 to 10% of N2O in open surgeryat atmospheric pressure shed new light on the pathophysi-ology of adhesion formation. CO2 pneumoperitoneum atan insufflation pressure of 15 mmHg decreases peritonealoxygenation, triggers hypoxemia inducible factor (HIF) anddecreases tissue plasminogen activator and upregulates PAIfor several days. These effects of CO2 pneumoperitoneumare less and/or of shorter duration at lower insufflationpressures and disappear at insufflation pressures below8 mmHg in human and 2 mmHg in mice [3, 6–8]. Takinginto account the differences in size between man and miceand Pascal’s law, these pressures are considered the pres-sures at which vascular compression of the peritoneum,hypoxia and oxidative stress start. Since at atmosphericpressure N2O still decreases adhesion formation caused byCorona et al. Gynecological Surgery  (2017) 14:21 Page 5 of 8Fig. 3 Dose-response curve of the addition of 0.3 to 100% N2O tohumidified CO2 upon adhesion formation during open surgerydemonstrating the drug-like effect. In inset, the dotted yellow lineindicates adhesion formation if the effect of N2O would have beenDiscussionThese experiments confirm that the prevention of adhe-sion formation by conditioning is similar in both openand laparoscopic surgery. The main damaging effect ofCO2, thus, is caused by mesothelial cell hypoxia and re-traction, and less by tissue and ischaemia-reperfusion. Ad-hesions indeed increase with the duration of exposure toCO2 and with desiccation. N2O in concentrations of morethan 5% appears to be the single most effective factor witha marginal beneficial effect when 4% of oxygen is added tothis gas mixture. Although not all observations made dur-ing laparoscopic surgery were repeated in open surgery,we conclude that the mechanisms involved are similar inboth open and laparoscopic surgery. The key factors aremesothelial cell damage and acute inflammation in theby replacing CO2 irritation. Proportions of adhesions are given (meanand SD) Corona R et al, Gynecol Surg, 2017 + refentire peritoneal cavity, as a reaction to trauma, hypoxia,ROS, oxidative stress and desiccation.The exact mechanisms involved in the peritoneal cavitythat enhance or prevent adhesion formation are not fullyunderstood. The half maximal effect around 2.5% of N2Oindicates that N2O has a drug-like effect, the mechanismFig. 4 The additional effect of 4% of O2 on adhesion formationwhen 10% of N2O is used was investigated during laparoscopic andopen surgery using humidified CO2. Adhesion formation wascomparable between laparoscopic and open surgery. The additiveeffect of 4% of O2 was marginal (p < 0.01). Proportions of adhesionsare given (mean and SD) Corona R et al, Gynecol Surg, 2017 + refthe CO2 environment, we must conclude that key mechan-ism driving the subsequent events is mesothelial hypoxiaCorona et al. Gynecological Surgery  (2017) 14:21 Page 6 of 8and retraction. In addition, the observations that with lap-aroscopic surgery in the presence of a 10% N2O environ-ment at 15 mmHg pressure, the extent of adhesionformation is similar to open surgery at atmospheric pres-sure strongly suggests that 10% of N2O prevents mesothe-lial cell oxidative stress hypoxia and its consequencesincluding mesothelial cell retraction and decreased fibrin-olysis enhanced adhesion formation and postoperativepain. However, whether N2O also has a protective effecton oxidative stress caused by partial oxygen pressureshigher than 75 mmHg (or more than 10% O2 at atmos-pheric pressure) as in air remains to be investigated.Despite the differences that exist between oxidativestress caused by 20% CO2 in ambient air in open surgeryand the detrimental effect of the CO2 pneumoperito-neum and insufflation pressure, the prevention of adhe-sion formation and postoperative pain are similar inboth open and laparoscopic surgery. Beside the use of aproper atraumatic surgical technique and precisehaemostasis, the important adhesion preventive factorsin open surgery are to avoid ROS formation, caused bythe 20% oxygen concentration in ambient air; the use ofN2O in concentrations of 5% or more; cooling the peri-toneal cavity; avoiding desiccation; the use of Ringer’slactate solution instead of saline; being toxic for meso-thelial cells [19–25] for intraoperative irrigation and ter-minal thorough lavage and administration of one or twodoses of dexamethasone after surgery. Although, it hasnot been investigated as yet whether N2O can preventthe damaging effects of exposure to 20% of oxygen con-centration, the flooding of the surgical site in open sur-gery with 5 to 10% of N2O will require a carrier gas forwhich both CO2 and nitrogen (N2) seem suitable. Theimportance of cooling in open surgery has indirectly beenconfirmed in rats using cold saline infusions [26, 27]. Ad-hesions were also less when the abdominal cavity was ex-posed to the atmosphere of the operating theatre (21% O2,21 °C, 40–47% relative humidity) than to CO2 + 4% ofoxygen and 95–100% relative humidity at 37 °C [28]. Pre-vention of desiccation is much more important in opensurgery than in laparoscopic surgery considering the 100%mortality of mice when exposed to dry CO2 for 60 min.The toxicity of saline for the peritoneum was known sincethe early 1970s [19, 20] and has recently been confirmed[21–25]. The use of dexamethasone and another tenet ofmicrosurgery was only proven to be effective after condi-tioning in laparoscopic surgery in an animal model. In anycase, adhesion formation following open and laparoscopicsurgery appears to be remarkably similar in an atmosphereof 10% N2O in CO2 without desiccation.The implementation of these principles to open sur-gery should be carried out judiciously. That salineshould be abandoned, and a richer solution should beused for irrigation is obvious. Prevention of desiccationcan be achieved by continuous irrigation as done inmicrosurgery, by covering bowels with moistened inerttowels and/or by flooding the operative field with hu-midified CO2 [29, 30]. The latter indeed decreased adhe-sion formation in open cardiac surgery. The instillationof humidified CO2 deep into the surgical field also de-creased oxidative stress since the organs were no longerexposed to the 20% of O2 in ambient air. A similar effectwas achieved by shielding the organs in microsurgery.The exposure of the surgical field to the temperature ofthe operating theatre has never been an issue in opensurgery. We can be happy today that cooling unexpect-edly has a beneficial effect. The administration of dexa-methasone after surgery, eventually at the end ofsurgery, may be beneficial to reduce inflammation andadhesion formation and accelerate recovery, while itsuse might aggravate an eventual infection. The provenvery strong beneficial effect of 5 to 10% of N2O with noexplosion risk demands a trial in open surgery. As de-scribed for humidified CO2 in cardiac surgery, [29, 30]the deep instillation of gases heavier than air will fill andflood progressively the operation field. CO2 seems obvi-ous as a carrier gas since it is heavier than air with min-imal irritative effect at atmospheric pressure. N2O,which fortunately also is heavier than air, should be usedin concentrations of 5 to 10% of N2O. For this reason,we used the same combination for these experiments,the efficacy of which had furthermore already beenproven in animal models. It will obviously be necessaryto prevent or reduce contamination of the operating the-atre with N2O. The suggested upper threshold for N2Ois 25 ppm [31]. We speculate that this can be achievedwith aquarium-like drapings extending above the operat-ing field with aspiration at the borders to prevent over-flow; the opening of the draping would be a compromisebetween being sufficiently large to permit surgery butsmall enough to prevent mixture with the ambient air.Indeed even without aspiration contamination with 2 L/min with 10% of N2O would result in only 15 ppm N2Oin a normal sized (e.g. 40 m3) and ventilated (e.g. refreshrate of 20 cycles/h) operating room.ConclusionsIn conclusion, the mechanisms of mesothelial cell dam-age and their prevention are the same with open andwith laparoscopic surgery. The application of microsur-gical tenets, which enabled to decrease inflammation inthe peritoneal cavity, reduce adhesion formation and im-prove fertility outcomes, can benefit further from flood-ing the operative field with 5 to 10% of N2O, which hasproven to be a most effective factor. Prevention of meso-thelial cell damage and the subsequent acute inflamma-tion may even be more important in open surgery thanin laparoscopic surgery, especially when bowels areCorona et al. Gynecological Surgery  (2017) 14:21 Page 7 of 8exteriorised and subjected to desiccation and exposed toambient air that creates oxidative stress. Since both CO2and N2O are heavier than air, it is also possible to instilhumidified CO2 with 5 to 10% of N2O deep into the ab-dominal cavity during the procedure. Given the absenceof side effects, as demonstrated in laparoscopic surgery,a study in open surgery may well demonstrate a virtuallyadhesion free surgery, a reduction of postoperative painand a shortened recovery period, as has been observedin laparoscopic surgery.AcknowledgementsWe thank Anastasia Ussia (Rome, Italy), Karina Mailova (Moscow, Russia),Jasper Verguts (Hasselt, Belgium) and Michel Camus and Herman Tournaye(Brussels, Belgium) for the review and discussions. eSaturnus NV (Sony),Fisher and Paykel and Storz AG are acknowledged for supplying theequipment for these experiments. This research did not receive any specificgrant from funding agencies in the public, commercial or not-for-profitsectors, except royalties from patents hold at the university.CondensationPeritoneal conditioning is equally important for open surgery as forlaparoscopic surgery to prevent postoperative adhesions and pain.Authors’ contributionsRC and MMB carried out the experiments (study design, data collections)coordinated by PK. RC, MMB and PK have performed the data analysis andwriting. LA made the basic observations on N2O, and all were closelyinvolved with the design and finalisation of the study. VG activelycontributed to the understanding of these observations as an update ofmicrosurgical tenets. All authors read and approved the final manuscript.Competing interestsRoberta Corona, Maria Mercedes Binda, Leila Adamyan and Victor Gomelhave nothing to declare. Philippe R Koninckx is a stockholder of EndoSATNV.Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.Author details1Department of Obstetrics and Gynaecology, KU Leuven – CatholicUniversity of Leuven, 3000 Leuven, Belgium. 2Barbados Fertility Centre,Seaston House, Hastings, Barbados. 3Department of Reproductive Medicineand Surgery, Moscow State University of Medicine and Dentistry, Moscow,Russia. 4Department of Obstetrics and Gynecology, University of BritishColumbia, Women’s Hospital, Vancouver, British Columbia, Canada. 5KULeuven, Vuilenbosstraat 2, 3360 Bierbeek, Belgium.Received: 27 September 2017 Accepted: 25 October 2017References1. Mutsaers SE, Prele CM, Pengelly S, Herrick SE (2016) Mesothelial cells andperitoneal homeostasis. Fertil Steril 106:1018–10242. Koninckx PR, Gomel V, Ussia A, Adamyan L (2016) Role of the peritonealcavity in the prevention of postoperative adhesions, pain, and fatigue. 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