Center for Surgical Technologies, KULeuven and Department of Obstetrics and Gynaecology, University Hospital Gasthuisberg, Herestraat 49, B-3000 Leuven Belgium
1 To whom correspondence should be addressed. e-mail: philippe.koninckx{at}med.kuleuven.ac.be
Dear Sir,
We thank Dr Yesildaglar et al. for their comments about our paper concerning the systemic effects of adding small amounts of oxygen to the CO2 used for the pneumoperitoneum during endoscopic surgery.
We fully agree that they never performed nor published experiments concerning the effects of adding oxygen to the CO2 used for the pneumoperitoneum. In the discussion of a rather long manuscript we deliberately chose to be brief when describing the hypothesis of mesothelial damage through hypoxia caused by the CO2 pneumoperitoneum, and its prevention by adding small amounts of oxygen, as derived from experiments in rabbits and mice. Since the concept was progressively developed by our group, references were grouped in order to give credit to previous and actual co-workers. There certainly never has been any intention to misleadingly quote any of their work, and we trust that also the referees must have considered that the references referred to the concept and the group, not with the details of each previous publication.
The concept that CO2 pneumoperitoneum enhanced adhesion formation is mediated through mesothelial hypoxia and subsequent angiogenesis is based upon the following observations. In rabbits, adhesion formation increases with the duration of pneumoperitoneum (Ordonez et al., 1997; Molinas and Koninckx, 2000
) and with the insufflation pressure (Yesildaglar and Koninckx, 2000
), and decreases after the addition of a small percentage (36%) of oxygen (Molinas and Koninckx, 2000
). This was observed using both CO2 and helium as insufflation gases (Molinas and Koninckx, 2000
). Similar effects were observed in mice (Molinas et al., 2001
). In transgenic mice partially deficient for hypoxia inducible factors HIF-1
or HIF-2
(Molinas et al., 2003a
) the effect of pneumoperitoneum-enhanced adhesions is no longer present. In mice knockout for the genes encoding for VEGF-A, VEGF-B or PlGF we could demonstrate the important role of these angiogenic factors in pneumoperitoneum-enhanced adhesions (Molinas et al., 2003b
). Adhesions caused by a surgical lesion with the minimum duration of the pneumoperitoneum, so-called basal adhesions, are mainly mediated by the plasminogen system, as demonstrated in tPA, uPA and PAI-1 knockout mice (Molinas et al., 2003c
). All data together strongly support the hypothesis of mesothelial hypoxia as the driving mechanism. Moreover this is logical, since 3% of oxygen at a pressure of 775 mmHg, determines a partial pressure of oxygen (PO2) of 23 mmHg, which is the normal physiologic PO2 in peripheral cells according to the oxygen cascade model in mammals.
According to the physics laws of gases, gases will diffuse until an equilibrium is reached, i.e. when the partial tensions are similar. Therefore, during CO2 pneumoperitoneum some diffusion of oxygen from the blood stream into the peritoneal cavity, and of CO2 into the blood stream must occur. We still do not know how rapid and how important this phenomenon of diffusion of oxygen is. In order to ascertain a constant pneumoperitoneum environment, we consider it prudent to replace slowly but continuously the gas of the pneumoperitoneum, as we did.
The observations of Mynbaev et al. were for us unexpected (Mynbaev et al., 2002). We fully admit that the hypothesis of pneumoperitoneum-induced mesothelial damage and subsequently enhanced CO2 resorption, is not yet proven. We therefore invite Dr Yesildaglar and colleagues to disclose any data they might have and which could shed more light on this phenomenon.
Indeed the clinical implications are important. The simple addition of a small percentage (36%) of oxygen to the CO2 used for the pneumoperitoneum, could decrease postoperative adhesion formation, and could decrease CO2 resorption especially during endoscopic surgery of longer duration.
References
Molinas, C.R. and Koninckx, P.R. (2000) Hypoxaemia induced by CO(2) or helium pneumoperitoneum is a co-factor in adhesion formation in rabbits. Hum. Reprod., 15, 17581763.
Molinas, C.R., Mynbaev, O., Pauwels, A., Novak, P. and Koninckx, P.R. (2001) Peritoneal mesothelial hypoxia during pneumoperitoneum is a cofactor in adhesion formation in a laparoscopic mouse model. Fertil. Steril., 76, 560567.[CrossRef][ISI][Medline]
Molinas, C.R., Campo, R., Elkelani, O.A., Binda, M.M., Carmeliet, P. and Koninckx, P.R. (2003a) Role of hypoxia inducible factors 1 and 2
in basal adhesion formation and in carbon dioxide pneumoperitoneum enhanced adhesion formation following laparoscopic surgery in transgenic mice. Fertil. Steril., in press.
Molinas, C.R., Campo, R., Dewerchin, M., Ericksson, U., Carmeliet, P. and Koninckx, P.R. (2003b) Role of vascular endothelial growth factor and placental growth factor in basal adhesion formation and in carbon dioxide pneumoperitoneum-enhanced adhesion formation following laparoscopic surgery in transgenic mice. Fertil. Steril., in press.
Molinas, C.R., Elkelani, O.A., Campo, R., Luttun, A., Carmeliet, P. and Koninckx, P.R. (2003c) The role of the plasminogen system in basal adhesion formation and in CO2 pneumoperitoneum-enhanced adhesion formation following laparoscopic surgery in transgenic mice. Fertil. Steril., in press.
Mynbaev, O.A., Molinas, C.R., Adamyan, L.V. Vanacker, B. and Koninckx, P.R. (2002) Reduction of CO(2)-pneumoperitoneum-induced metabolic hypoxaemia by the addition of small amounts of O(2) to the CO(2) in a rabbit ventilated model. A preliminary study. Hum. Reprod., 17, 16231629.
Ordonez, J.L., Dominguez, J., Evrard, V. and Koninckx, P.R. (1997) The effect of training and duration of surgery on adhesion formation in the rabbit model. Hum. Reprod., 12, 26542657.[Abstract]
Yesildaglar, N. and Koninckx, P.R. (2000) Adhesion formation in intubated rabbits increases with high insufflation pressure during endoscopic surgery. Hum. Reprod., 15, 687691.