To the Editor:
Although the influence of CO2 insufflation on adhesion formation remains controversial, its non-physiological effects include tissue acidosis combined with metabolic hypoxemia and other respiratory and cardiovascular alterations. Therefore, the suggested hypothesis in a recent article by Corona et al. (1) that CO2-pneumoperitoneum should be supplemented by N2O seems to be promising.
The beneficial effect of 5% N2O added to the CO2 was stated by the authors as “unexplained by current knowledge” (1). This phenomenon, however, has a very simple explanation: this impact of a small concentration of N2O is the result of its diffusion to the adjacent tissues, due to its high solubility and its absence in the tissues at the onset of the insufflation. This means that, in a short time, an equilibration of gases in the peritoneal cavity occurs. According to Munson, “the rate of gas transfer between blood and the cavity depends on the same factors that control anesthetic uptake or excretion at the alveolar-capillary interface: solubility in blood, air cavity blood flow, and the blood-to-gas-space anesthetic partial pressure difference” (2), and the administration of N2O under pressure would result in an infinite increase in gas-space volume. The reverse effect of this condition, the so-called “second gas effect,” has already been described by Fink in 1955 (2).
We believe that the adhesion prevention property of N2O is possibly related to its well-known side effects: N2O oxidizes the cobalt atoms of the vitamin B12, inactivating the methionine synthase causing a dose-dependent increase in plasma homocysteine (Hcys) concentrations. This may activate the metabolic pathway responsible for the conversion of Hcys to cysteine, which could result in a decreased cross-linkage of collagen (3) or a caspase-3 activation (4) – an apoptotic pathway-induced by N2O.
Besides, the N2O metabolic side effects are well-known: N2O, by activating a complex of intracellular signaling pathways through Hcys, can trigger unexpected consequences. An increased Hcys concentration is known mainly as a risk factor for the possible development of thromboembolism, deep vein thrombosis, and atherosclerosis.
In order to confirm the benefits of N2O as an efficient additive, one should analyze the results of current clinical trials which are designed to investigate the metabolic disorders related to B12 mediated processes, reduction of cobalamin function, methionine synthase levels, and other long-term clinical N2O side effects. Therefore, application of N2O for the pneumoperitoneum in individuals with vitamin B12 dysfunctions or its deficiency should be avoided. N2O application for the pneumoperitoneum should be considered when it is used for anesthesia to avoid its possible over-dosage.
The authors claim that acute inflammation as the driving mechanism for adhesion formation is their own concept, while it was mentioned clearly in our previous study (5). Furthermore, we believe that the number of animals in their groups is too small to draw evidence based conclusions.
We believe that any surgical tool, procedure, or gas-mixture should be introduced only after it has been proved to add value to existing ones. Therefore we should continue to examine the effect of gas-mixtures as potential agents in adhesion free endoscopy.
Ospan A Mynbaev, M.D., Ph.D., Sc.D., Moscow Institute of Physics & Technology (State University), Moscow State University of Medicine and Dentistry, Peoples’ Friendship University of Russia, Moscow, Russia
Michael Stark, M.D., The New European Surgical Academy, Berlin, Germany
Peter Biro, M.D., Ph.D., Institute of Anaesthesiology, University Hospital Zürich, Switzerland
1. Corona R, Binda MM, Mailova K, Verguts J, Koninckx PR. Addition of nitrous oxide to the carbon dioxide pneumoperitoneum strongly decreases adhesion formation and the dose-dependent adhesiogenic effect of blood in a laparoscopic mouse model. Fertil Steril. 2013; 100(6): 1777-83.
2. Munson ES. Transfer of nitrous oxide into body air cavities. Br J Anaesth. 1974; 46(3): 202-9.
3. Baum VC. When nitrous oxide is no laughing matter: nitrous oxide and pediatric anesthesia. Paediatr Anaesth. 2007; 17(9): 824-30.
4. Zhen Y, Dong Y, Wu X, Xu Z, Lu Y, Zhang Y, Norton D, Tian M, Li S, Xie Z. Nitrous oxide plus isoflurane induces apoptosis and increases beta-amyloid protein levels. Anesthesiology. 2009; 111(4): 741-52.
5. Pismensky SV, Kalzhanov ZhR, Eliseeva MYu, Kosmas IP, Mynbaev OA. Severe inflammatory reaction induced by peritoneal trauma is the key driving mechanism of postoperative adhesion formation. BMC Surg 2011; 11: 30.
The authors respond:
We thank you for your comments, your interest in our work, and your attempt to explain our findings related to the effect of the N2O upon postoperative adhesions. Some comments, however, are suggestive without data, and some are incorrect.
Corona et al. (1) published the role of acute inflammation during and after surgery in March 2011, whereas your reference clearly was published later in November 2011 (2).
You start your comments with “the influence of CO2 insufflation on adhesion formation remains controversial.” Although the exact quantitative effect can be discussed, the data that peritoneal trauma, including CO2 pneumoperitoneum, is a cofactor enhancing adhesions at a surgical trauma site through acute inflammation, seems to be firmly established. A full discussion is beyond the scope of this answer.
Some comments are speculation. Although N2O is highly soluble in water, to the best of our knowledge, transport through the intact mesothelial layer has never been demonstrated. Anyway, this does not explain the effect. Also, the relationship between “N2O oxidizes the cobalt atoms of the vitamin B12, inactivating the methionine synthase causing a dose-dependent increase in plasma homocysteine (Hcys)” and the prevention of adhesion formation is speculation. Also, your suggested experiments are highly speculative.
Dr. Mynbaev and co-authors “believe that the number of animals is too small to draw evidence based conclusions.” Although the sample size was small, the data showed significant differences. Increasing the sample size would have decreased the p value—that doesn’t add any value to the final conclusion of the experiment.
Concerning the clinical effect, we invite you to read our paper, “Peritoneal full-conditioning reduces postoperative adhesions and pain: a randomised controlled trial in deep endometriosis surgery” (3), where we confirmed in the human the effectiveness of full conditioning in preventing adhesion formation, in decreasing pain, and in accelerating recovery. Moreover, we confirmed in the human the increase of CO2 resorption during pneumoperitoneum, which you described in the rabbit (4), and the prevention by full conditioning.
Roberta Corona, M.D., Ph.D., M. Mercedes Binda, Ph.D., Philippe R. Koninckx, M.D., Ph.D.
Free University Brussels, Centre for Reproductive Medicine, Brussels, Belgium
1. Corona R, Verguts J, Schonman R, Binda MM, Mailova K, Koninckx PR. Postoperative inflammation in the abdominal cavity increases adhesion formation in a laparoscopic mouse model. Fertil Steril. 2011 Mar 15;95(4):1224-8.
2. Pismensky SV, Kalzhanov ZhR, Eliseeva MYu, Kosmas IP, Mynbaev OA. Severe inflammatory reaction induced by peritoneal trauma is the key driving mechanism of postoperative adhesion formation. BMC Surg 2011; 11: 30
3. Koninckx PR, Corona R, Timmerman D, Verguts J, Adamyan L.J Peritoneal full-conditioning reduces postoperative adhesions and pain: a randomised controlled trial in deep endometriosis surgery. Ovarian Res. 2013 Dec 11;6(1):90.
4. Mynbaev OA1, Adamyan LV, Mailova K, Vanacker B, Koninckx PR. Effects of adding small amounts of oxygen to a carbon dioxide-pneumoperitoneum of increasing pressure in rabbit ventilation models. Fertil Steril. 2009 Aug;92(2):778-84.