CO² pneumoperitoneum problems with laparoscopy

Roger Molinas, MD

Daniel Kruschinski, MD

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Daniel Kruschinski, MD: “Hello, I’m Daniel Kruschinski from Germany.  I’m working in Frankfurt at the Endoscopic Gynaecology Centre or as we call it, EndoGYN and I’m going to introduce and interview Roger Molinas, who is actually in Leuven, and he’s controlling the study on adhesion prevention and adhesion problems caused by pneumoperitoneum and carbon dioxide in laparoscopy. Please, Roger, introduce yourself.”

Roger Molinas, MD:“I’m Roger Molinas. I’m originally from Paraguay, and I’m working in Leuven in the Catholic University of Leuven in the group of Philippe Koninckx. I’m finalising a PhD where the topic is post-operative adhesion formation following laparoscopic surgery, and the problems related with the CO₂ pneumoperitoneum.”

Daniel Kruschinski, MD:“What is very important, we are performing laparoscopy with CO₂ already, I don’t know, 75 years in use, but in the last 20 or 25 years suddenly we are starting to evaluate laparoscopic surgery and the problems of carbon dioxide. How did you get to this topic?”

Roger Molinas, MD: “It’s a very interesting question. I think everybody agrees that laparoscopic surgery has so many advantages in comparison with open surgery, but adhesion formation is not clearly one of these advantages. The reported data are very controversial and, if we have to summarise, we can say that the classic laparoscopic surgery, which is performed under CO₂ pneumoperitoneum does not have any advantages in terms of adhesion formation.

Therefore, our hypothesis is that on one hand if laparoscopic surgery induces  less surgical trauma than laparotomy that could lead to less adhesion formation, but it should be another factor that increases adhesion formation and this factor could be the CO₂ pneumoperitoneum. That is the reason because in our work, we are evaluating different aspects, i.e. chemical, physical and biological effects, of the CO₂ pneumoperitoneum during the laparoscopic surgery.” 

Daniel Kruschinski, MD:  “So you did a study that shows that carbon dioxide at the time of surgery is working as an adhesion formation factor or agent?  Am I correct?” 

Roger Molinas, MD:  “That’s it.  In fact, what we’ve proved and which is already published is that the pneumoperitoneum, regardless of the type of gas used, is a co-factor in adhesion formation.  When you induce a standard lesion and you keep the pneumoperitoneum for a very long time, you increase adhesions.  When you induce a standard lesion and you use higher pressure, you also increase adhesions. 

These effects have been shown with CO₂ and with helium pneumoperitoneum, and for that reason and because we have the tools to work at the molecular biology level, we have developed a laparoscopic mouse model. In this model we are studying at this moment, adhesion formation and the next step is to study endometriosis.  Because it’s a very powerful tool to evaluate some factors that are known to play a role in adhesion formation or that we think play a role in adhesion formation.” 

Daniel Kruschinski, MD:  “So it’s a very good topic because suddenly we have to think about what to change during our laparoscopic surgery because some laparoscopic surgery, especially for adhesions and endometriosis, is going to take about four to five to six hours and if you insufflate for six hours with cold CO₂ or even normal heated CO₂, you get adhesions or other problems in the body.  So what exactly is the pathophysiologic mechanism?” 

Roger Molinas, MD:  “When you introduce gas to perform laparoscopic surgery,   obviously you distend the abdomen and you compress the capillary flow in the peritoneum. This leads to cellular hypoxia at the level of the mesothelium during the pneumoperitoneum. And, after the release of the pneumoperitoneum the cells become suddenly hyperoxic. It’s a kind of ischemia re-fusion process. That means that we have to differentiate what is the process during the pneumoperitoneum and what is the process immediately after the pneumoperitoneum. 

During the normal pneumoperitoneum, our hypothesis and our preliminary data strongly support the idea that the mesothelial cells are under hypoxic conditions and this hypoxia triggers the regulation of some factors such as hypoxia inducible factors and angiogenic factors like, for instance, vascular endothelial growth factors, that play a role in adhesion formation and also in endometriosis.  That means that, during the hypoxic process, because of the pneumoperitoneum, we try to get those mechanisms that lead to the development of adhesions.” 

Daniel Kruschinski, MD:  “So it means exactly when I’m working, for example, in the Pouch of Douglas or I’m working somewhere around the ovaries, I can get adhesions somewhere completely else, where I don’t work.  Is that correct, that you can get adhesions, for example, on the liver area or in the other abdominal quadrant when you are working down in the pelvis?” 

Roger Molinas, MD:  “You can; in fact, you can.  But we failed to demonstrate that. It is important to differentiate between a factor and a co-factor. The most important factor in the development of adhesions is the direct surgical trauma.  The pneumoperitoneum has an additional effect and by inducing an indirect surgical trauma, becomes a co- factor that, according to our data, contributes to the development of adhesions.  It’s not able by itself to induce adhesions, but certainly it is a co-factor in adhesion formation.” 

Daniel Kruschinski, MD:  “You mean, if you touch the peritoneal cavity with the instrument, this is like a direct trauma to the peritoneum and if you don’t have any surgery on this side, you don’t get adhesions?  That carbon dioxide is only like a co-factor in adhesion formation on the site of the surgery?” 

Roger Molinas, MD: “This is in our animal models, but we have to admit that probably the models are not sensitive enough to find, to look for these small details and more differences.  Probably the pneumoperitoneum itself can induce adhesions.  But in our model, we failed to demonstrate that.” 

Daniel Kruschinski, MD:  “Because this is what I believe, that we get adhesions in every other site of the abdominal cavity even if we are not working there, because the patients, that are coming every second and third year and getting adhesion formation or adhesion surgery and they form adhesions somewhere completely else.  For example, they have surgery on the pelvis and they get adhesions on the small bowel in the upper abdominal quadrant.  So I think this is not only a co-factor, but also directly induces adhesion formation by carbon dioxide, by pressure.” 

Roger Molinas, MD: “Certainly, it is completely possible, and what I would like to stress is that knowing the pathogenesis of adhesion formation after the effect of the pneumoperitoneum, we can develop new adjuvants for the prevention of adhesions that could be not necessarily the same as those that we are using for open surgery, because we have to differentiate. 

The environment is completely different when you do open surgery to when you do laparoscopic surgery. The pathogenesis is basically the same but in some particular stage, can be different, and it is important to determine exactly in which respect they are different.  This is clinically significant because you cannot just extrapolate the adhesion prevention adjuvants that have been proven to be effective during open surgery to laparoscopic surgery. 

It is very important to clearly understand what is happening during the pneumoperitoneum and after the pneumoperitoneum in terms of adhesion formation.  What we strongly believe is that this process of hypoxia following the process of hyperoxia, trigger the expression of some factors with, until now, unknown role in adhesion formation as well as in endometriosis.” 

Daniel Kruschinski, MD:  “So, as we know, laparoscopy is like the best tool to do adhesion surgery.  What should we do or what can we do to prevent this kind of effect with CO₂ because we need to use it or we have to switch to another thing?” 

Roger Molinas, MD: “There are several alternatives, one of them is a gasless-laparoscopy, certainly.  Our main concern as a, let’s say, user of the classical laparoscopy, if you use gasless laparoscopy, it could be that you have more direct surgical trauma.  It is possible.  We have to prove that. But obviously you would have less indirect surgical trauma because you do not have the CO₂  pneumoperitoneum and it is highly dependent of the technique, highly dependent of the surgeon, but certainly this is one alternative. 

The other alternative is to modulate the CO₂ pneumoperitoneum in a way that you reduce the adverse effects.  You have to warm and to humidify the insufflation gas, and maybe to add some oxygen, because we strongly believe that the hypoxia is a main co-factor. We have some preliminary data that demonstrates that if we add oxygen to the CO₂ pneumoperitoneum, this is beneficial in preventing adhesions.” 

Daniel Kruschinski, MD:  “And what do you think about the theory of Douglas Ott, who says that not all this stuff with hypoxia or whatever causes the adhesion formation or is damaging the peritoneum?  He says that the over-pressure or the pressure itself in the abdominal cavity is causing all these problems.  Do you agree with that?” 

Roger Molinas, MD: “I partially agree because we have to differentiate between the chemical effect and the physical effects of the CO₂ pneumoperitoneum.  Certainly, when we use CO₂ for the pneumoperitoneum, we have to talk about the specific chemical effect of the CO_2. 

But, in addition to that, there are some physical effects that are gas independent.  Certainly the pressure and the duration are some of those effects.  What we believe is that by having a high pressure, you compress the capillary flow, the cells become hypoxic, but if you add oxygen from their apical surface the cells are able to pick up oxygen, even if you are inducing ischemia, because we have to remember that hypoxia is not only caused by ischemia. 

Ischemia is just one of the different factors causing hypoxia.  Certainly, even if you have oxygen in the pneumoperitoneum, we still have ischemia, because we are still compressing by the pressure the peritoneal circulation, the capillaries in the peritoneum, but the mesothelial cells are able to take the oxygen from the apical surface and, for that reason, although there is ischemia, they do not become hypoxic.” 

Daniel Kruschinski, MD:  “Very nice.  It’s very, very impressing work and I think it’s very necessary to evaluate all the effects of pneumoperitoneum and carbon dioxide because we need to move forward with laparoscopic surgery. 

We never want to go back to laparotomy because we have so many advantages for the patients and the community and for everyone so we need to continue advancing but we need to know what kind of effects can we cause when we use laparoscopic surgery with carbon dioxide and what can we do to prevent that.  So I think it’s a very, very important topic.  Very nice.” 

Roger Molinas, MD: “And I would like to say that, finally, people all over the world, they realise that the CO₂, although you do not see any evident effect, the CO₂ definitely is causing a lot of adverse effects for the patients, such as adhesion formation.” 

Daniel Kruschinski, MD:  “Like an instrument that we are using, but you don’t see it.  It’s an agent, an agent that is completely in the abdominal cavity but you don’t see the instrument.  This is why it’s dangerous not to know what can happen when you are using it for a long time in the body.  Very good, thank you very much.” 

Roger Molinas, MD: “Thank you.”

Feedback/Questions:

Question:

Invisible instrument used routinely, but indirectly may be a co-factor in adhesion formation. However, to my mind, this idea about the efect of the CO₂ is uncorrect! Why, the pressure inside the peritoneal cavity could be low enough to prevent the undue pressure over the peritoneal mesothelial circulation. Also, the release of the factors that cause adhesions formation is not proved yet, if any the perfusion after release of the pressure could wash these toxic factors. I would like to ask why in a such a study the possibilty of infection is not considered as a co-factor in adhesion formation after surgical trauma to any organ, and also may cause adhesions away from the site of interest. Also, the apical absorption of oxygen by the peritoneal cells is a concept which needs revison on sound physiological basis. Thank you.

Dr. Khaled Aly Zahran, MD

Answer:

Thank you for this interesting question.

1. The concept that CO₂ pneumoperitoneum is a cofactor in adhesion formation is only fully valid when high insufflation pressures and long procedures are used, suggesting a major role for the physical and not for the chemical properties of the CO₂ as insufflation gas. Nevertheless, there are a series of publications by other groups reporting detrimental systemic and local effects of CO₂ pnumoperitoneum even at low insufflation pressures. 
2. The most important factor in the development of adhesions is the direct surgical trauma. In our animal models, i.e. rabbits and mice, we failed to demonstrate adhesions at non-operative sites. We do recognise, however, that the models may not be sensitive enough to demonstrate this very likely effect. 
3. We do demonstrate in wild type and transgenic animals that the CO₂ pneumoperitoneum is associated with the release of several factors involved in adhesion formation. Furthermore, in some cases we demonstrate a causal relationship. We would like to invite those interested to read a series of three articles addressing these issues in Fertil Steril (July and September 2003), where a more comprehensive discussion can be found. 
4. In addition to the limited perfussion during the pneumoperitoneum, abdominal defflation leads to reperfusion which also could be an additional factor in the development of adhesions since ischemia-reperfusion is well known to induce Reactive Oxygen Species (ROS) expression. Moreover, ROS have been proven to play an important role in adhesion formation. Several groups have already addressed this issue and we are also performing some studies to evaluate the role of ROS during/after pneumoperitoneum in adhesion formation. 
5. Concerning the role of infection, in a series of more than 4,000 subjects (rabbits and mice) we did not observe any indication of infection till now. Anyway, this is a very important subject to consider and we thank you for the suggestion.
6. Certainly, we agree that the apical absorption of oxygen needs to be proven and we recognise that this is only a probable explanation for the observed beneficial effects of oxygen in adhesion prevention. Moreover, this assumption is based on the well known absorption of CO₂ from the apical surface, leading to hypercarbia and acidosis if not appropiately corrected by ventilation.

Roger Molinas, MD, MSc