{"paper_id":"4ab5dd2b-2504-4870-b5ff-1850ed4babd5","body_text":"B R I E F C O M M U N I C A T I O N Open Access\nA surgical polypragmasy: Koninckx PR, Corona R,\nTimmerman D, Verguts J, Adamyan L. Peritoneal\nfull-conditioning reduces postoperative adhesions\nand pain: a randomised controlled trial in deep\nendometriosis surgery. J Ovarian Res. 2013\nDec 11;6(1):90\nOspan A Mynbaev 1,3*, Peter Biro 2, Marina Yu Eliseeva 3, Andrea Tinelli 4, Antonio Malvasi 5, Ioannis P Kosmas 6,\nMykhailo V Medvediev 7, Tatiana I Babenko 8, Madina I Mazitova 9, Sergei S Simakov 1 and Michael Stark 10\nDear Sir,\nIn clinical trials most adhesion prevention methods\nfail. Therefore we have read the article by Koninckx\net al. [1] with great interest. They aim “… to perform a\ntranslational proof of concept trial to investigate the ef-\nfect of full-conditioning (FC) in the human upon CO 2\nresorption during surgery, …”.\nCongratulations to the authors are in order for their\nvaluable clinical results which have demonstrated the\nefficiency of their attempts to prevent postsurgical adhe-\nsions, reducing pain and modulated posttraumatic in-\nflammation with lower postoperative C-reactive protein\n(CRP) values and accelerated recovery. Since huge obsta-\ncles in the setup of clinical studies are met when\nsecond-look laparoscopy (SLL) is required, most studies\nevaluate the efficiency of adhesion prevention adjuvants\non the basis of experiments only. It is indeed difficult to\norganize such kind of clinical trials due to both severe\nethical and financial issues and patient requirement diffi-\nculties. Therefore, clinical trials aimed to evaluate post-\nsurgical adhesion formation by SLL should be based on\na well-defined study question, a distinct design and\nstrictly specified patient selection, all of which may lead\nto evidence-based conclusions, albeit in a limited num-\nber of homogenous population.\nHowever, some shortcomings of this study [1], which\nmight lead to misleading conclusions, and the authors ’\ndisregard of well-known undesirable N\n2O side effects\nhave coerced us to write this letter.\nProfessor Koninckx is an outstanding, worldwide au-\nthority in this field who performs high-quality surgical\ntreatment of deep endometriosis. Therefore we may\nsafely assume that for deep endometriosis excision in\nboth groups, identical surgical procedures were per-\nformed and that presurgical randomization and post-\nsurgical follow-up were also done up to standard.\nHowever, the patients in the FC group experienced\nsurgical polypragmasy, namely: 1) a humidified pneumo-\nperitoneum gas mixture (86% CO\n2 + 10% N 2O + 4% O 2)\nwith controlled gas temperature (31°C); 2) peritoneal\ncooling (up to 30°C) by sprinkling 2 –3 ml/min of\nRingers lactate with heparin (1000 IU/L) at room\ntemperature; 3) a Hyalobarrier gel (HBG) application,\nand 4) 5 mg of dexamethasone administered intramus-\ncularly at the end of surgery. The women in the control\ngroup however, were operated by standard laparoscopy\nwith humidified CO\n2 only and these two completely dif-\nferent treatment approaches were compared. Subse-\nquently, according to the authors ’ conclusions, successful\nadhesion prevention treatment was estimated by FC only.\nWe quote: “This translational research confirms in the\nhuman the efficacy of FC in reducing CO\n2 resorption\nand adhesions with in addition less postoperative pain,\n* Correspondence: ospanmynbaev@hotmail.com\n1The International Translational Medicine & Biomodeling Research Group,\nDepartment of Applied Mathematics, Moscow Institute of Physics &\nTechnology (State University), 9 institutsky per, Dolgoprudny, Moscow\nRegion 141700, Russia\n3The Department of Obstetrics, Gynecology & Reproductive Medicine,\nPeoples’ Friendship University of Russia, 21/3 Miklukho-Maklay str, Moscow\n117198, Russia\nFull list of author information is available at the end of the article\n© 2014 Mynbaev et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative\nCommons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and\nreproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain\nDedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article,\nunless otherwise stated.\nMynbaev et al. Journal of Ovarian Research 2014, 7:29\nhttp://www.ovarianresearch.com/content/7/1/29\n\nlower postoperative CRP concentrations and an acceler-\nated recovery ” [1].\nIt is difficult to identify the cause of the beneficial adhe-\nsion prevention impact because of the excessive combin-\nation of several factors. Indeed, it is difficult to accept the\nauthors’ conclusion that the adhesion prevention effect is\nrelated with FC only, since in these patients HBG was also\napplied and dexamethasone was administered. Therefore,\nthe abstract section does not reflect their results at all and\nmay lead JOR readers astray.\nAnother limitation of this study lies in the small number\nof patients and the complexity of the adhesion score. In\nthe compared groups it is difficult to distinguish between\nsize and severity of adhesions separately. Moreover, upon\ninitial surgery, most patients had already had adhesions\nresulting from previous surgery. It is a well-known fact\nthat the adhesion score analysis after adhesiolysis is differ-\nent from that of adhesions after first surgery. It is quite\nclear that all of these factors, combined with the popula-\ntion heterogeneity in these groups which only have a small\nnumber of patients, may lead to biased results.\nWe previously demonstrated that reduced blood gas\nchanges during CO\n2 pneumoperitoneum are associated\nwith mixed gas insufflation (MGI) since even a small\nconcentration of O\n2 added to CO 2 results in lower end\ntidal CO 2 (PETCO2) values and slight changes in blood\ngas parameters in comparison with those of pure CO 2\ninsufflation in rabbits [2,3]. Also, MGI has a significant\nimpact on ventilation parameters [4]. Subsequently, it is\nobvious that during surgery, patients in the FC group re-\nquire less increased tidal volume (TV) and lower ventilation\nfrequency than patients in the standard pneumoperitoneum\ngroup. However, this conclusion should be drawn based\nupon a comprehensive analys is of anesthesiological ma-\nnagement including full respiratory and blood gas, acid base\nparameters without combining raw data of P\nETCO2, TV and\nfrequency of ventilation.\nIn comparison with the traditional mechanism of ad-\nhesions (Figure 1A), N 2O impact on adhesion formation\nmay be related with the activation of several N 2O-\ninduced pathways (Figure 1B) with rise of Hcys content\n[5] and an increased cysteine concentration [6], which\nthen possibly results in weakened collagen cross-linking\nin the collagen network between fibroblasts [7]; N 2O\ninduced-oxidative stress and DNA damage [8]; apop-\ntosis by caspase-3 activation [9] in adhesion fibroblasts\nwith increased genome instability.\nThe authors stated that N 2O is safer than CO 2 due to\nits high solubility in water and the higher lung exchange\ncapacity [1]. However, according to available literature,\nthe administration of N\n2O is associated with neuro-\napoptotic/neurotoxic [5,6] genotoxic effects [8] and\nchanges in cobalamin (Vitam in B12), methionine syn-\nthase and Hcys metabolism [5,6] the latter being an\nα-amino acid biosynthesized from methionine by\ncatabolism.\nThrough these signaling pathways an increased concen-\ntration of blood N 2O [5,6] is associated with the expan-\nsion of air-filled spaces such as bowel, and pneumothorax\n[10,11]; a dose-dependent depression of the ventilatory re-\nsponse to hypoxemia [12]; increased DNA damage [8];\nendothelial dysfunction with elevated procoagulant status\n[13] with increased risk of thromboembolism, atheroscler-\nosis and cardiovascular diseases [5,6,13,14] and long term\nrisk of myocardial infarctions [15].\nIt can be put forward that multiple blood clots in the le-\nsion sites will be stabilized as long-term fibrinogenic adhe-\nsions transforming later to fibrotic adhesions (Figure 1C)\ndue to changes of the vascular endothelium surface from\nan anti- to a procoagulant status, the reactivation of blood\nplatelets involving several intrinsic and extrinsic targets in\ncoagulation and fibrinolysis, resulting in alterations of\nblood clot/fibrin clot structure, and its increased resist-\nance to fibrinolysis [13].\nSurprisingly, several risk factors are related with repro-\nductive functioning, such as: a reduced fertility [16]; an\nelevated risk of spontaneous abortion [17]; in rats,\nchanges in the luteinizing hormone releasing hormone\n[18]; N\n2O-induced teratogenicity [19], are claimed to be\na result of N 2O administration.\nThese N 2O effects, combined with other factors due to\npolypragmasy with multiple compounds of surgical pro-\ncedures, may lead to unexpected and undesirable side\neffects when, in various circumstances, its action path-\nways remain unclear.\nAlthough the clinical relevance of the unfavorable side\neffects of N\n2O remains undetermined [12,20] we should\nbe prudent in introducing N 2O as a safe additive com-\npound for the pneumoperitoneum. Moreover, if we take\ninto account the metabolic, procoagulant and DNA\ndamaging properties of N\n2O it is clear that a spectrum\nof beneficial and undesirable effects of N 2O being in-\nsufflated intraperitoneally under pressure have not yet\nbeen fully appreciated.\nWe suggest that the influence of N\n2O as an additional\ncomponent gas for the pneumoperitoneum should be in-\nvestigated in different animal models evaluating a wide\nrange of physiological parameters including blood gases,\nacid base balance, oxygen/oximetry and metabolite values\nand this in well-designed experimental studies. Special at-\ntention should be given to local intraperitoneal changes\nsuch as oxidative stress parameters, the response of peri-\ntoneal macrophages and the role of immune reaction\npathways. These studies are needed to demonstrate the\nimpact of both, CO\n2 and N 2O on postsurgical adhesions\nand the homeostasis. This combination might indeed re-\nduce or even solve the adhesion problem, but as long as\nexperimental studies by other research groups do not\nMynbaev et al. Journal of Ovarian Research 2014, 7:29 Page 2 of 4\nhttp://www.ovarianresearch.com/content/7/1/29\n\nprove the benefits nor examine the calculated risks, we\nshould continue to use CO 2, which is a well-established\ngas with known pathophysiological mechanisms.\nAt NESA, we believe in, and are initiating evidence-\nbased studies toward the standardization of surgical\nprocedures in order to avoid the implementation of su-\nperfluous technologies instead of relying on surgical ex-\ncellence. The concept of simple surgical procedures\nperformed with a limited number of instruments and\nsurgical equipment was suggested in cases where an\nFigure 1 Disputable mechanisms of the addition of N 2O to the CO 2 pneumoperitoneum impact on adhesion formation. A) Traditional\nmechanism of multiple severe adhesion formation, which is not related with N 2O. B) The antiadhesiogenic impact of N 2O. Metabolic pathways\naffected by N 2O included interactions with the cobalt atom (Co), betaine, methyltransferase, methionine synthase with increased homocysteine\n(Hcys) and decreased methionine [5,6]. Then, several enzyme deficiencies can also be a pathway for decreased postsurgical adhesions such as\nacystathionine synthetase, tetrahydrofolate methyltransferase and 5,10-methylenetetrahydrofolate reductase (MTHFR), which catalyze the syn thesis\nof cystathionine from Hcys [5,6] with subsequent increased cysteine concentration, which then results in weakened collagen cross-linking [7] in\nthe collagen network between fibroblasts; N 2O induced-oxidative stress, DNA damage [8] and apoptosis by caspase-3 activation [9] in these virgin\nadhesion fibroblasts with increased genome instability. C) A possible mechanism of the adhesiogenic impact of N 2O: The following changes are\nassociated with increased Hcys concentration: shift of vascular endothelium surface from anti- to pro-coagulant status; reactivation of blood\nplatelets; alterations of several intrinsic and extrinsic targets in the coagulation and fibrinolysis system with modification of the blood clot/f ibrin\nclot structure; increased resistance of fibrin clot to fibrinolysis [13] with increased adhesion formation potential.\nMynbaev et al. Journal of Ovarian Research 2014, 7:29 Page 3 of 4\nhttp://www.ovarianresearch.com/content/7/1/29\n\nadhesion prevention strategy should be implemented by\na personalized approach taking into account individual\ngenetic and constitutional predispositions. Any surgical\ntool, procedure or combination of gases should be intro-\nduced only after it has been proved to add value to exis-\nting ones; therefore we should continue to examine the\neffect of gas mixtures as potential agents leading to\nadhesion free endoscopy.\nIn conclusion, this FC clinical trial definitely is a step for-\nward in the surgical treatment of severe deep endometri-\nosis. Future studies with simplified MGI may cast further\nlight on the mechanism of this strategy ’s adhesion preven-\ntion impact since pure CO 2 during laparoscopic surgery\nproduces severe acidosis, blood gas and acid base changes\nwith increased intraperitoneal insufflation pressure.\nAbbreviations\nCRP: C-reactive protein; SLL: Second look laparoscopy; FC: Full-conditioning;\nMGI: Mixed gas insufflation; CO 2: Carbon dioxide; N 2O: Nitrous oxide;\nO2: Oxygen; HBG: Hyalobarrier gel; JOR: Journal of ovarian research; TV: Tidal\nvolume; Hcys: Homocysteine; DNA: Deoxyribonucleic acid; NESA: New\nEuropean Surgical Academy; Polypragmasy: The use of multiple therapeutic\nmodalities to manage a single condition. ( #Segen’s Medical Dictionary.\n© 2012 Farlex, Inc. All rights reserved).\nCompeting interests\nThe authors declare that they have no competing interests.\nAuthors’ contributions\nIn the design of this letter all authors contributed equally and approved the\nfinal manuscript.\nAuthor details\n1The International Translational Medicine & Biomodeling Research Group,\nDepartment of Applied Mathematics, Moscow Institute of Physics &\nTechnology (State University), 9 institutsky per, Dolgoprudny, Moscow\nRegion 141700, Russia. 2The Institute of Anaesthesiology, University Hospital,\n100 Rämistrasse, Zürich CH-8091, Switzerland. 3The Department of Obstetrics,\nGynecology & Reproductive Medicine, Peoples ’ Friendship University of\nRussia, 21/3 Miklukho-Maklay str, Moscow 117198, Russia. 4The Department\nof Obstetrics and Gynaecology, Division of Experimental Endoscopic Surgery,\nImaging, Minimally Invasive Therapy and Technology, Vito Fazzi Hospital,\nPiazza Muratore, Lecce 73100, Italy. 5Department of Obstetrics and\nGynecology, Santa Maria Hospital, 314/A Via Alcide De Gasperi, Bari 70125,\nItaly. 6The Department of Obstetrics & Gynecology, Xatzikosta General\nHospital, Avenue General Makriyannis, Ioannina 45001, Greece. 7The\nDepartment of Obstetrics & Gynecology, State Establishment\n“Dnepropetrovsk Medical Academy of Health Ministry of Ukraine ”,9\nDzerzhinky str, Dnepropetrovsk 49044, Ukraine. 8The Department of\nObstetrics & Gynecology, Stavropol State Medical University, 310 Mira str,\nStavropol 355017, Russia. 9The Department of Obstetrics and Gynecology,\nKazan State Medical Academy, 11/1 Mushtary, Kazan 420012, Russia. 10The\nNew European Surgical Academy, 21 Unter den Linden, Berlin 10117,\nGermany.\nReceived: 17 January 2014 Accepted: 4 March 2014\nPublished: 10 March 2014\nReferences\n1. 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Rowland AS, Baird DD, Weinberg CR, Shore DL, Shy CM, Wilcox AJ: Reduced\nfertility among women employed as dental assistants exposed to high\nlevels of nitrous oxide. N Engl J Med 1992, 327(14):993–997.\n17. Rowland AS, Baird DD, Shore DL, Weinberg CR, Savitz DA, Wilcox AJ:\nNitrous oxide and spontaneous abortion in female dental assistants.\nAm J Epidemiol 1995, 141(6):531–538.\n18. Kugel G, Letelier C, Zive MA, King JC: Nitrous oxide and infertility.\nAnesth Prog 1990, 37(4):176–180.\n19. Fujinaga M, Baden JM: Methionine prevents nitrous oxide-induced\nteratogenicity in rat embryos grown in culture. Anesthesiology 1994,\n81(1):184–189.\n20. Myles PS: Nitrous oxide: deep in the zone of uncertainty. Anesthesiology\n2013, 119(1):1–3.\ndoi:10.1186/1757-2215-7-29\nCite this article as: Mynbaev et al. : A surgical polypragmasy: Koninckx PR,\nCorona R, Timmerman D, Verguts J, Adamyan L. Peritoneal full-conditioning\nreduces postoperative adhesions and pain: a randomised controlled trial in\ndeep endometriosis surgery. J Ovarian Res. 2013 Dec 11;6(1):90.Journal of\nOvarian Research2014 7:29.\nMynbaev et al. Journal of Ovarian Research 2014, 7:29 Page 4 of 4\nhttp://www.ovarianresearch.com/content/7/1/29","source_license":"CC0","license_restricted":false}