US20020032464A1 - Adhesion prevention and an endoscopic insufflation system therefor - Google Patents
Adhesion prevention and an endoscopic insufflation system therefor Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
- A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M13/00—Insufflators for therapeutic or disinfectant purposes, i.e. devices for blowing a gas, powder or vapour into the body
- A61M13/003—Blowing gases other than for carrying powders, e.g. for inflating, dilating or rinsing
Definitions
- the present invention relates to adhesion prevention in general and to compounds, an endoscopic insufflation system and to a method for preventing adhesion formation in particular.
- Adhesion formation is a major problem following surgical procedures and is a frequent cause of postopera- tive pain and of infertility. Adhesions are the major cause of intestinal obstruction and it is estimated that following an intra-abdominal procedure, adhesions occur in some 50 to 80 percent of patients.
- the mechanism of adhesion formation can be summarized as follows: a trauma of the peritoneal lining is rapidly followed by an inflammatory reaction; exudation of plasma, and deposition of a fibrin matrix. Subsequently the lesion is healed by the degradation of the fibrin deposition, and by proliferation of the mesenchymal lining of the peritoneum. If the repair process is not completed within a few days, fibroblast proliferation starts which ultimately will end in collagen deposition and adhesion formation. Key players in this process are in particular fibrin and fibrinolysis, macrophages and their secretion products such as growth hormones and cytokines, and obviously the epithelial repair process.
- the invention relates in particular to the use of an anoxemia preventing compound for the manufacture of a medicament for preventing adhesion formation
- the damage caused by ischemia and/or anoxemia has been investigated to occur during the period of ischemia and/or anoxemia itself, and during the reperfusion period.
- the mechanisms which are recognized to be involved are Ca channels, kalium efflux, free oxygen radicals, expression of a series of proteins such as VEGF (a potent angiogenic factor), other cytokines which are leucocyte attractants and heat shock proteins.
- These drugs can be applied either systemically, or by local instillation during surgery, or by the prolonged administration intraperitoneally postoperatively, preferably locally e.g. by miniosmotic pumps. Experiments have shown, that this is feasible, that the local administration has the advantage that much higher concentrations of active drugs can be obtained, and that the administration for 24 to 36 hours postoperatively is sufficient.
- drugs to prevent anoxemia or the consequences thereof can also be administered, continuously or intermittently in the insufflation gas or mixture as an aerosol.
- all drugs as mentioned later can be used,
- indomethacin which can inhibit the membrane lipid peroxidation products following anoxemia
- prostaglandin El was shown to reduce the consequences of ischemia and/or anoxemia in the liver;
- calcium channel blockers [0022] calcium channel blockers, free radical scavengers, lipid peroxysomes, and pregnatrienes;
- acidosis can prevent reperfusion damage
- the amount of these active ingredients of the present invention may vary depending on the formulation, but it is usually from 0.1 to 50% by weight irrespective of the manner of administration.
- the dose is determined taken into consideration the age, sex, and syptom of disease of the subject, the desired therapeutic effect, the period of administration, etc.
- a daily dose of the active ingredient is from 0.05 to 100 mg for an adult.
- the invention relates also to a novel endoscopic insufflation system with supplying means for O 2 .
- Endoscopy also called minimal access surgery has become widely used over the last years because of clearcut advantages of a decreased postoperative morbidity, less pain and a shorter hospitalization. These procedures require by means of an insufflation system or an irrigation system a distension to permit visualization.
- Endoscopic surgery uses, at present, almost exclusively pure carbon dioxide gas (CO 2 ).
- CO 2 carbon dioxide gas
- All existing insufflation systems are designed to control gas flow for pure carbon dioxide gas. Since CO 2 is highly soluble in water, this gas has almost uniformly been used to induce the pneumoperitoneum, for safety reasons. In cases of accidental gas embolism the solubility in water and the exchange capacity in the lungs is estimated to be possibly of crucial life saving importance.
- CO 2 irritates the peritoneum, as evidenced by the pain when insufflated without anaesthesia, and by the shoulder pain following endoscopic procedures. This can be explained by the pH changes caused by CO 2 .
- the endoscopic insufflation system comprises gas supplying means for a insufflation line, wherein the supplying means are designed to supply gas mixtures comprising O 2 and in particular gas mixtures of O 2 /CO 2 .
- O 2 comprising gas mixtures reduce adhesion formation during or by pneumoperitoneum.
- the gas mixture is a CO 2 /O 2 gas mixture in which gasmixture O 2 is preferably present in a volume ratio from 1 to 20% and more preferably from 5 to 20% and most preferably from 5 to 10%.
- Parameters relevant to the upper limit of the mixing ratio are, among others, the explosiveness and the solubility of oxygen in blood.
- O 2 gas mixtures for example with N 2 O or Helium can also be used as insufflation gases with preventing adhesion formation characteristics according to the invention.
- the distension medium is generally a gas whereas for organs such as a uterus, both gases and fluids can be used.
- An endoscopic insufflation system according to the invention is preferably provided with means for moistening the insufflation gas, for example by means of a sprinkler device.
- FIGS. 1 and 2 are extensively schematised drawings of control means of a prefered embodiment of an insufflator system according to the invention.
- the abdominal cavity generally is or can intentionally be irrigated with a solution such as Ringers lactate or any other physiologic solution.
- a solution such as Ringers lactate or any other physiologic solution.
- the invention that anoxemia or the consequences thereof should be prevented, will use medicated irrigation fluids.
- any of the substances as described can be used, in order to reduce that anoxemia or the consequences thereof, already during surgery.
- the peritoneal surfaces can be coated with a biodegradable gel, which will prevent the direct contact of CO 2 with the peritoneal surface and thus changes in pH and/or anoxemia.
- [0041] means for controlling the ratio of carbon dioxide-oxygen, which ratio is preferably controlled independently from the gas flow;
- [0042] means for adjusting the ratio of carbon dioxide-oxygen during the endoscopical surgery (e.g. start the operation with pure carbon dioxide and after a while switch only temporarily to a 50% oxygen mixture);
- the initiation of the pneumopericoneum should preferably be done at insufflation pressures below 15 mm Hg and at a flow rate of less than 1L/min. Once the pneumoperitoneum established, the most important factor is the intra-abdominal pressure which should not exceed 30 mm of Hg. The flow rate becomes relatively unimportant.
- a first embodiment of an insufflation system makes use of fixed gas mixtures.
- Flow control can be obtained using existing equipment.
- This embodiment has the advantage of its simplicity. The only extra equipment needed are some containers with mixtures of carbon dioxide gas and oxygen with different CO 2 -O 2 ratios and a valve to switch from one mixture to another.
- This valve can be placed before the gas inlet of existing equipment, or it can be integrated into an apparatus for gas flow control.
- the valve can be pure mechanical, or electromechanical.
- FIG. 1 gives a schematic overview of an open loop control system for mixing carbon dioxide and oxygen in a predefined ratio.
- the proposed solution consists of a buffer volume 6 and a controller unit 7 .
- the two (one for oxygen, one for carbon dioxide) gas inlets are equipped with electromechanical valves 4 and 5 .
- a periodically opening of the valves 4 and 5 makes it possible to mix the two gases in the buffer volume 6 . If one makes sure that the opening times of the valves are rather small, or the incoming gas flow is rather small or the buffer volume 6 is rather large, then the pressure in the buffer volume 6 will remain rather constant during one period.
- the increase in pressure in the buffer volume 6 during one period can be neglected for small periods, large buffer volumes or small incoming gas flows.
- the gas flow in the two gas inlets can be considered equal and the ratio of the two gases in the buffer volume 6 will be the same as the ratio of the opening times of the two valves.
- This embodiment has the advantage of flexibility over the previous one. By varying the ratio of opening times of the valves 4 and 5 any carbon dioxide-oxygen ratio can be achieved. Response will not be immediate, since the buffer volume 6 will introduce a delay,
- This embodiment can be placed before the gas inlet of existing equipment for flow control, or integrated in new equipment for flow control.
- This embodiment tries to overcome the problem of delayed response to different mixture ratios, as discussed above.
- FIG. 2 shows a schematic overview of a third embodiment of the invention with a closed loop control system.
- the control unit 14 measures via the sensor 13 the composition of the gas mixture. It compensates for deviations of a predefined composition by means of the proportional valves 11 and 12 at the gas inlets. This embodiment guarantees a quasi immediate response to a request to alter the mixing ratio. Pressure sensors at the inlets, to guard against a “no pressure”, situation at the inlet are no longer necessary, since this must be the case if the controller is no longer able to obtain the requested gas composition. They may be, however, useful in order to build a more efficient controller unit.
- this embodiment can be placed before existing equipment for flow control or integrated into new equipment for flow control. It offers the advantages of improved reaction speed and size (no buffer volume needed) to the open loop control system.
- a lower temperature obviously decreases metabolism and oxygen consumption and has been used to prevent ischemia and/or anoxemia e.g. for the mammary artery transplantation.
- a cooled CO 2 /oxygen mixture will be used to prevent adhesion prevention.
- the originality of the concept is illustrated by the recent introduction of 2 insufflators with warmed CO 2 up to 370°.
- the invention further relates to methods for preventing adhesion by controlling anoxemia.
- the present invention shows that the presence of O 2 diminished the adhesion formation. This was experimentally proven by the administration of 1,2.5,5;10 and 20%; of oxygen together with the CO 2 . In these experiments, exposure of 60 min of pure CO 2 increased the adhesion scores 4 fold in comparison with an exposure of 10 min. From a final concentration of 5% oxygen onwards, this adhesiogenic effect of CO 2 was completely abolished. Also visually the appearance of the lesions following pure CO 2 and following a CO 2 /oxygen mixture was obviously different, the latter looking much healthier.
- the invention further relates to a method according to the claims 11 - 14 .
- CO 2 in pneumoperitoneum is generally used because of safety. Indeed the solubility and high exchange rate in the lungs make it the..safest gas available with respect to gas embolism.
- CO 2 pneumoperitoneum has complex systemic and local effects depending on the duration of the application and intraabdominal pressure. Systematic effects of CO 2 pneumoperiteum have been described, such as changes in acid-base balance (Moten, M., et al, 1973, Volz, J., et al., 1996), cardiopulmonary system (Barnett, R. B., et al., 1992; Ho, H. S., et al., 1993; Liu, SD.
- CO 2 pneumoperitoneum produces disturbances of the peritoneal surface. It was clinically demonstrated chat CO 2 pneumoperitoneum produces intense intraperitoneal acidosis (Volz, J., et al., 1997). Moreover, CO 2 exposure may have adverse effects on peritoneal microcirculation and cell-protective systems (Buhur, A., et al., 1997).
- Adhesions were evaluated by laparoscopy after one week. All second look laparoscopies were videotaped, and subsequently scored blindly by two investigators, taking into account extent (0 to 4 points), type (0 to 3 points), tenacity (0 to 3 points) and inflammatory reaction (0 to 3 points) at the injury and at de-novo siteds.
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Abstract
Description
- The present invention relates to adhesion prevention in general and to compounds, an endoscopic insufflation system and to a method for preventing adhesion formation in particular.
- Adhesion formation is a major problem following surgical procedures and is a frequent cause of postopera- tive pain and of infertility. Adhesions are the major cause of intestinal obstruction and it is estimated that following an intra-abdominal procedure, adhesions occur in some 50 to 80 percent of patients.
- The mechanism of adhesion formation can be summarized as follows: a trauma of the peritoneal lining is rapidly followed by an inflammatory reaction; exudation of plasma, and deposition of a fibrin matrix. Subsequently the lesion is healed by the degradation of the fibrin deposition, and by proliferation of the mesenchymal lining of the peritoneum. If the repair process is not completed within a few days, fibroblast proliferation starts which ultimately will end in collagen deposition and adhesion formation. Key players in this process are in particular fibrin and fibrinolysis, macrophages and their secretion products such as growth hormones and cytokines, and obviously the epithelial repair process.
- From this repair process it results that. adhesion formation is largely independent from the extent of the trauma.
- Prevention of adhesion formation has been attempted mechanically and by modulating the inflammatory reaction. Mechanical adhesion prevention has been attempted by barrier methods and by the instillation of viscous fluids at the end of surgery keeping the surfaces separated, or recently by coating the surfaces by biodegradable gels.
- These known approaches have been only moderately successful.
- It is the aim of the present invention to provide a use of a medicament, an endoscopic system, and a method for more effectively preventing adhesion.
- Surprisingly, it was found that anoxemia is a major cause and/or cofactor of adhesion formation. The invention relates in particular to the use of an anoxemia preventing compound for the manufacture of a medicament for preventing adhesion formation
- These local or systemic administered medicaments according to the invention reduce adhesion formation by decreasing anoxemia in particular of the peritonial lining or the consequences of peritoneal anoxemia.
- Hereunder mechanisms and drugs are highlighted which are proven to be relevant to reduce/prevent adhesion formation. These drugs have hitherto not been used in adhesion prevention, at least not in the concept of prevention of ischemia and/or anoxemia and/or of the consequences of ischemia and/or anoxemia, and in particular by or during CO2 pneumoperitoneum.
- The damage caused by ischemia and/or anoxemia has been investigated to occur during the period of ischemia and/or anoxemia itself, and during the reperfusion period. The mechanisms which are recognized to be involved are Ca channels, kalium efflux, free oxygen radicals, expression of a series of proteins such as VEGF (a potent angiogenic factor), other cytokines which are leucocyte attractants and heat shock proteins.
- These drugs can be applied either systemically, or by local instillation during surgery, or by the prolonged administration intraperitoneally postoperatively, preferably locally e.g. by miniosmotic pumps. Experiments have shown, that this is feasible, that the local administration has the advantage that much higher concentrations of active drugs can be obtained, and that the administration for 24 to 36 hours postoperatively is sufficient.
- Considering the knowledge of prevention of ischemia and/or anoxemia and/or of the consequences of ischemia and/or anoxemia the time course of administration of these drugs to prevent adhesions will obviously be different from those actually used.
- Together with the hereunder explained oxygen/CO2 pneumoperitoneum or independently at least the following mechanisms and/or drugs/mechanisms can be used for the prevention of adhesions:
- drugs to prevent anoxemia or the consequences thereof can also be administered, continuously or intermittently in the insufflation gas or mixture as an aerosol. For this purpose all drugs as mentioned later can be used,
- activation of potassium channels;
- modulation of macrophage activation and leucocyte attraction through cytokines, or their inhibitors e.g. IL8, IL6, IL1;
- the effect of VEGF expression, a direct consequence of anoxemia, will be blocked by antibodies or other inhibitors;
- indomethacin, which can inhibit the membrane lipid peroxidation products following anoxemia;
- prostaglandin El was shown to reduce the consequences of ischemia and/or anoxemia in the liver;
- allopurinol was shown to reduce the consequences of ischemia and/or anoxemia in the kuppfer cells of the liver through an effect on xanthine-oxidase;
- calcium channel blockers, free radical scavengers, lipid peroxysomes, and pregnatrienes;
- calcium antagonists;
- prevention of hypoxia associated stress proteins;
- acidosis can prevent reperfusion damage;
- MP, dopamine and ATP-MgCl2 administered following the anoxemia as demonstrated for the liver.
- The amount of these active ingredients of the present invention may vary depending on the formulation, but it is usually from 0.1 to 50% by weight irrespective of the manner of administration. The dose is determined taken into consideration the age, sex, and syptom of disease of the subject, the desired therapeutic effect, the period of administration, etc. However preferably a daily dose of the active ingredient is from 0.05 to 100 mg for an adult.
- The invention relates also to a novel endoscopic insufflation system with supplying means for O2.
- Endoscopy also called minimal access surgery has become widely used over the last years because of clearcut advantages of a decreased postoperative morbidity, less pain and a shorter hospitalization. These procedures require by means of an insufflation system or an irrigation system a distension to permit visualization.
- Endoscopic surgery uses, at present, almost exclusively pure carbon dioxide gas (CO2). A standard lesion induced either by CO2 laser (superficial lesion) or by monopolar, or bipolar coagulation, (deeper lesion) cause more adhesions when the duration of the pneumoperitoneum is longer. The amount of adhesions increase with time, at least up to 2 hours. All existing insufflation systems are designed to control gas flow for pure carbon dioxide gas. Since CO2 is highly soluble in water, this gas has almost uniformly been used to induce the pneumoperitoneum, for safety reasons. In cases of accidental gas embolism the solubility in water and the exchange capacity in the lungs is estimated to be possibly of crucial life saving importance.
- CO2 irritates the peritoneum, as evidenced by the pain when insufflated without anaesthesia, and by the shoulder pain following endoscopic procedures. This can be explained by the pH changes caused by CO2.
- The endoscopic insufflation system according to the invention comprises gas supplying means for a insufflation line, wherein the supplying means are designed to supply gas mixtures comprising O2 and in particular gas mixtures of O2/CO2. Surprisingly it was found that O2 comprising gas mixtures reduce adhesion formation during or by pneumoperitoneum. Preferably the gas mixture is a CO2/O2 gas mixture in which gasmixture O2 is preferably present in a volume ratio from 1 to 20% and more preferably from 5 to 20% and most preferably from 5 to 10%. Parameters relevant to the upper limit of the mixing ratio are, among others, the explosiveness and the solubility of oxygen in blood.
- Other O2 gas mixtures, for example with N2O or Helium can also be used as insufflation gases with preventing adhesion formation characteristics according to the invention.
- For intra-abdominal endoscopy, the distension medium is generally a gas whereas for organs such as a uterus, both gases and fluids can be used.
- An endoscopic insufflation system according to the invention is preferably provided with means for moistening the insufflation gas, for example by means of a sprinkler device.
- Drying of peritoneal surfaces has been considered a cofactor in adhesion formation. For this reason as a single measure or together with the prevention of anoxemia using oxygen in the insufflation gas or using drugs to prevent anoxemia or the consequences thereof, it is important that the insufflated gas is moistened in order to prevent dehydration of the peritoneal surfaces Instead of moistening the insufflated gas, a sprinkler system has been devised which intermittently sprays the abdominal cavity. This sprinkler device can be attached to any canula, or preferably to the endoscope: under high pressure a small volume of irrigating fluid is intermit- tently and automatically sprayed in all directions of the abdominal cavity.
- The insufflation system according to the invention will be further illustrated hereunder, on the basis of a number of non limitative embodiments, and with reference to the annexed drawing, wherein FIGS. 1 and 2 are extensively schematised drawings of control means of a prefered embodiment of an insufflator system according to the invention.
- During endoscopy or endoscopic surgery, the abdominal cavity generally is or can intentionally be irrigated with a solution such as Ringers lactate or any other physiologic solution. The invention that anoxemia or the consequences thereof should be prevented, will use medicated irrigation fluids. For this purpose any of the substances as described can be used, in order to reduce that anoxemia or the consequences thereof, already during surgery. Alternatively, at the beginning of the surgery, the peritoneal surfaces can be coated with a biodegradable gel, which will prevent the direct contact of CO2 with the peritoneal surface and thus changes in pH and/or anoxemia.
- First an overview is given of possible technical solutions to the problem of applying carbon dioxide-oxygen (CO2/O2) gas mixtures during endoscopical surgery.
- The requirements of such an insufflation system according to the invention are those of a pure CO2 insufflator with additionally:
- means for controlling the ratio of carbon dioxide-oxygen, which ratio is preferably controlled independently from the gas flow;
- means for adjusting the ratio of carbon dioxide-oxygen during the endoscopical surgery (e.g. start the operation with pure carbon dioxide and after a while switch only temporarily to a 50% oxygen mixture);
- flow control means for the carbon dioxide-oxygen gas mixture;
- all materials in contact with oxygen or the gas mixture shall withstand the chemical effects of O2;
- if, at least in a part of the system and temporarily, a high O2 concentration may occur, explosion protection is required.
- These modifications required by the handling of O2 are known, per se, from respiration systems.
- The initiation of the pneumopericoneum should preferably be done at insufflation pressures below 15 mm Hg and at a flow rate of less than 1L/min. Once the pneumoperitoneum established, the most important factor is the intra-abdominal pressure which should not exceed 30 mm of Hg. The flow rate becomes relatively unimportant.
- A first embodiment of an insufflation system according to the invention makes use of fixed gas mixtures. One can perform endoscopical surgery using carbon dioxide-oxygen gas mixtures using containers of premixed gases. It is obvious that this solution offers total independability of CO2-O2 ratio from gas flow. Flow control can be obtained using existing equipment. This embodiment has the advantage of its simplicity. The only extra equipment needed are some containers with mixtures of carbon dioxide gas and oxygen with different CO2-O2 ratios and a valve to switch from one mixture to another. This valve can be placed before the gas inlet of existing equipment, or it can be integrated into an apparatus for gas flow control. The valve can be pure mechanical, or electromechanical.
- An important limitation of this first embodiment is the fact that it is impossible to continuously vary the carbon-dioxide-oxygen ratio during an endoscopical operation. Only a number of fixed ratios can be used during an operation. Hereunder are two other embodiments proposed, which can overcome this limitation.
- FIG. 1 gives a schematic overview of an open loop control system for mixing carbon dioxide and oxygen in a predefined ratio.
- The proposed solution consists of a
buffer volume 6 and acontroller unit 7. The two (one for oxygen, one for carbon dioxide) gas inlets are equipped withelectromechanical valves 4 and 5. - A periodically opening of the
valves 4 and 5, makes it possible to mix the two gases in thebuffer volume 6. If one makes sure that the opening times of the valves are rather small, or the incoming gas flow is rather small or thebuffer volume 6 is rather large, then the pressure in thebuffer volume 6 will remain rather constant during one period. - In short, the increase in pressure in the
buffer volume 6 during one period, can be neglected for small periods, large buffer volumes or small incoming gas flows. By consequence, if these conditions are met, the gas flow in the two gas inlets can be considered equal and the ratio of the two gases in thebuffer volume 6 will be the same as the ratio of the opening times of the two valves. - Since no feedback is provided in this solution, some extra measures are necessary to make sure gas always flows in the
buffer volume 6 through thevalves 3. and 4. This can be achieved by providing thepressure sensors controller unit 7 may only periodically open valves if the pressure atsensor 3 is smaller than the pressure at thesensors buffer volume 6 and the incoming gas flows. - This embodiment has the advantage of flexibility over the previous one. By varying the ratio of opening times of the
valves 4 and 5 any carbon dioxide-oxygen ratio can be achieved. Response will not be immediate, since thebuffer volume 6 will introduce a delay, - This embodiment can be placed before the gas inlet of existing equipment for flow control, or integrated in new equipment for flow control.
- This embodiment tries to overcome the problem of delayed response to different mixture ratios, as discussed above.
- FIG. 2 shows a schematic overview of a third embodiment of the invention with a closed loop control system.
- The
control unit 14 measures via thesensor 13 the composition of the gas mixture. It compensates for deviations of a predefined composition by means of theproportional valves 11 and 12 at the gas inlets. This embodiment guarantees a quasi immediate response to a request to alter the mixing ratio. Pressure sensors at the inlets, to guard against a “no pressure”, situation at the inlet are no longer necessary, since this must be the case if the controller is no longer able to obtain the requested gas composition. They may be, however, useful in order to build a more efficient controller unit. - Again, this embodiment can be placed before existing equipment for flow control or integrated into new equipment for flow control. It offers the advantages of improved reaction speed and size (no buffer volume needed) to the open loop control system.
- It must be stated, however, the above given embodiments are extensively simplificated for reasons of clarity, and it is further possible to add some extra sensors for pressure measurement and flow measurement, and if the controller unit is well designed, this system can implement gas mixture and flow control all together, so no extra equipment for flow control will be necessary anymore.
- Prevention of anoxemia and of the consequences of anoxemia have been investigated mainly in obstetrics, in cardiology and in transplant surgery. In obstetrics it is obvious that prevention of anoxemia and/or of the consequences of anoxenia are important to prevent brain damage of the child. Also in cardiology prevention of anoxemia and/or of the consequences of anoxemia as a result of ischemia is important to minimize the consequences of an infarction. During transplant surgery (kidney, heart, lung, liver) prevention of ischemia and/or anoxemia and/of of the consequences of ischemia and/or anoxemia is essential to minimize damage of the donor organ.
- A lower temperature obviously decreases metabolism and oxygen consumption and has been used to prevent ischemia and/or anoxemia e.g. for the mammary artery transplantation.
- A cooled CO2/oxygen mixture will be used to prevent adhesion prevention. The originality of the concept is illustrated by the recent introduction of 2 insufflators with warmed CO2 up to 370°.
- The invention further relates to methods for preventing adhesion by controlling anoxemia.
- The present invention shows that the presence of O2 diminished the adhesion formation. This was experimentally proven by the administration of 1,2.5,5;10 and 20%; of oxygen together with the CO2. In these experiments, exposure of 60 min of pure CO2 increased the adhesion scores 4 fold in comparison with an exposure of 10 min. From a final concentration of 5% oxygen onwards, this adhesiogenic effect of CO2 was completely abolished. Also visually the appearance of the lesions following pure CO2 and following a CO2/oxygen mixture was obviously different, the latter looking much healthier.
- These above mentioned experiments demonstrate clearly that prevention of anoxemia reduces adhesion formation by or during CO2 pneumoperitoneum, which principle is used as a basis in developing an insufflation system which delivers a controlled O2/CO2 mixture.
- The invention further relates to a method according to the claims11-14.
- As an illustration of part of the method and of the effectiveness of the method according to
claim 13, as an example, in the following a series of experiments in rabbits is described that show that CO2 is an independent adhesiogenic factor. CO2 causes not only pH changes. Taking into account the relative pressures, it was found that the peritoneal lining was anoxic during the pneumoperitoneum, and that this was a direct cause of cell damage and adhesion formation. - CO2 in pneumoperitoneum is generally used because of safety. Indeed the solubility and high exchange rate in the lungs make it the..safest gas available with respect to gas embolism. CO2 pneumoperitoneum has complex systemic and local effects depending on the duration of the application and intraabdominal pressure. Systematic effects of CO2 pneumoperiteum have been described, such as changes in acid-base balance (Moten, M., et al, 1973, Volz, J., et al., 1996), cardiopulmonary system (Barnett, R. B., et al., 1992; Ho, H. S., et al., 1993; Liu, SD. Y., et al., 1991) inmunologic and endocrine systems (Volz, J., et al., 1996). For this reason, other gases have been investigated. Nitrous oxide or air have been used but they are potentially combustible or explosive in presence of cautery (Robinson, J. S., et al., 1975; Esposito, J. M., 1975; El-Minawi, M. F., et al., 1981). Helium is physiologically inert, nonexplosive but it is very expensive (Leighton, T. A., et al., 1992; Bongard, F. S., et al., 1993; Rademaker, B. M., et al., 1995). Locally, the CO2 pneumoperitoneum produces disturbances of the peritoneal surface. It was clinically demonstrated chat CO2 pneumoperitoneum produces intense intraperitoneal acidosis (Volz, J., et al., 1997). Moreover, CO2 exposure may have adverse effects on peritoneal microcirculation and cell-protective systems (Buhur, A., et al., 1997).
- Our observation that CO2 pneuoperitoneum increases adhesion formation, could be explained by acidosis or by local anoxemia. To test the latter hypothesis, experiments were carried out with variable O2 concentrations.
- Materials and methods
- Experimental design:
- All animals received two standard CO2 laser injuries. A non opposing lesion was inflicted in the retro-uterine space, i.e. on the posterior utero-vaginal wall, consisting of a 2 cm2 vaporization of the superficial layers with CO2 laser. In addition, an apposing lesion was performed in the oviduct and pelvic side wall, consisting of a 2 cm2 vaporization, on both sides. The time required to induce the lesions varied from 3 to 7 minutes.
- Animals were assigned randomly on a daily base, to one of the following seven experimental groups. First and second groups were considered control groups. In
group 1, using conventional CO2 pneumoperitoneum, the total duration of the procedure was restricted to 10 minutes. Ingroup 2, the pneumoperitoneum was maintained for 70 minutes, to demonstrate the effect of CO2 pneumoperitoneum. Ingroups groups - Adhesions were evaluated by laparoscopy after one week. All second look laparoscopies were videotaped, and subsequently scored blindly by two investigators, taking into account extent (0 to 4 points), type (0 to 3 points), tenacity (0 to 3 points) and inflammatory reaction (0 to 3 points) at the injury and at de-novo siteds.
- Animals and surgical procedures:
- Sixty five New Zealand white rabbits weighing between 2150 and 3000 grams were operated with a standard puncture laparoscopy. Standard surgical injuries were inflicted with CO2 laser (Sharplan 1060: Sharplan, Tel Aviv, Israel) with a spot diameter of 1 mm and a power setting of 10 watts in the continuous superpulse mode. Pneumoperitoneum was created and maintained with two Thermoflators™ (Karl Storz-Endoscope, Belgium), one for CO2 and one for O2. The output of both insufflators was mixed in a mixing chamber, humidified and warmed. The insufflation pressure was 10 cm of water and the
intraabdominal flow rate 20 1/min. It is obvious that all means in contact with O2 are adapted therefor. - Results
- Results are summarized in table 1 and FIG. 3. Adhesion score was higher in
group 2 than ingroup 1 confirming the effect of CO2. Using increasing concentrations of oxygen, the amount of adhesions decreased progressively.TABLE 1 Differences in total adhesion score between the groups 100% of CO2 (Group 2). Total adhesion score in the experimenial groups 10′ CO 260′ 1 % O 260′ 2.5 % O 260′ 5 % O 260′ 10 % O 260′ 20 % O 260′ CO2 P = 0.0002 P = NS P = 0.05 P = 0.0005 P = 0.007 P = 0.005 -
Groups groups control group 1, consisting in only 10 minutes procedure (4.5±3.7, P=NS). (FIG. 3). - This decrease in total adhesion score with the addition of O2 was not only observed at the lesion sites, i.e. opposing lesion in tube/side wall (P=0.0014) and non opposing lesion in the pouch of Douglas (P=0.0002), but also de novo adhesions around the opposite tube (P=0.0001) (FIG. 4).
- Moreover, this reduction in total score was obviously produced by a reduction in all items of the scoring system, such as inflammation, extent, tenacity and type (FIG. 5) .
- Laparoscopic surgery requires a pneumoperitoneum to provide adequate space to work. CO2 gas is the most common distending medium in laparoscopic surgery because its high solubility and exchange rate in the lungs. CO2 absorbed across the peritoneal surface can cause systematic effects such as respiratory acidosis, hypercarbia and arrhytmia. Locally, CO2 induces severe acidosis and some anoxemia in the periconeal surface. These disadvantages of CO2 pneumoperitoneum have led investigators to look for other gases. Nitrous oxide and air have been tested but they can be dangerous in presence of cautery. Gasless laparoscopy is another alternative. The disadvantage is a more difficult surgical procedure, since the visceras can interfere with a good visualization. Helium is nonexplosive, inert and nontoxic but is expensive. Our data suggest that the addition of oxygen is useful in the preventing of adhesion formation.
Claims (25)
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US10/170,704 US7073512B2 (en) | 1997-05-07 | 2002-06-14 | Adhesion prevention and an endoscopic insufflation system therefor |
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EP97201358.5 | 1997-05-07 | ||
EP97201358 | 1997-05-07 | ||
EP97201358A EP0887076A3 (en) | 1997-05-07 | 1997-05-07 | Adhesion prevention and an endoscopic insufflation system therefor |
PCT/EP1998/002829 WO1998050064A2 (en) | 1997-05-07 | 1998-05-07 | Adhesion prevention and an endoscopic insufflation system therefor |
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PCT/EP1998/002829 A-371-Of-International WO1998050064A2 (en) | 1997-05-07 | 1998-05-07 | Adhesion prevention and an endoscopic insufflation system therefor |
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US10/170,704 Continuation US7073512B2 (en) | 1997-05-07 | 2002-06-14 | Adhesion prevention and an endoscopic insufflation system therefor |
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US6428500B1 US6428500B1 (en) | 2002-08-06 |
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US09/423,192 Expired - Fee Related US6428500B1 (en) | 1997-05-07 | 1998-05-07 | Adhesion prevention and an endoscopic insufflation system therefor |
US10/170,704 Expired - Fee Related US7073512B2 (en) | 1997-05-07 | 2002-06-14 | Adhesion prevention and an endoscopic insufflation system therefor |
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US (2) | US6428500B1 (en) |
EP (2) | EP0887076A3 (en) |
AU (1) | AU7912298A (en) |
DE (1) | DE69827619T2 (en) |
WO (1) | WO1998050064A2 (en) |
Families Citing this family (16)
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EP0887076A3 (en) * | 1997-05-07 | 1999-03-31 | Saturnus A.G. | Adhesion prevention and an endoscopic insufflation system therefor |
ATE347908T1 (en) * | 2002-01-29 | 2007-01-15 | Vlaams Interuniv Inst Biotech | PREVENTION OF TISSUE ADHESION |
DE10233861A1 (en) * | 2002-07-19 | 2004-02-12 | Storz Endoskop Produktions Gmbh | Device, insufflation device, measuring device and method for insufflating a body cavity with an insufflation gas |
EP1556121B1 (en) | 2002-10-28 | 2016-06-01 | Northgate Technologies Incorporated | Insufflation system with a multi-capacity tube |
CA2552137A1 (en) * | 2003-01-29 | 2004-08-19 | Children's Medical Center Corporation | Prevention of surgical adhesions using selective cox-2 inhibitors |
US7654975B2 (en) * | 2003-04-24 | 2010-02-02 | Northgate Technologies, Inc. | Mixed-gas insufflation system |
DE202004021703U1 (en) * | 2003-10-07 | 2010-05-27 | Northgate Technologies Inc., Elgin | Device for dispensing a substance into a body cavity |
WO2005042079A1 (en) | 2003-10-31 | 2005-05-12 | Trudell Medical International | System and method for manipulating a catheter for delivering a substance to a body cavity |
JP4526313B2 (en) * | 2004-07-01 | 2010-08-18 | オリンパス株式会社 | Air supply system |
CA2660050A1 (en) * | 2006-08-04 | 2008-02-07 | Northgate Technologies Inc. | In-dwelling port for access into a body |
US20080269665A1 (en) * | 2007-04-24 | 2008-10-30 | Johan Petersen | Chemotherapy delivery device |
US8153695B2 (en) * | 2007-06-04 | 2012-04-10 | Boston Scientific Scimed, Inc. | Methods for inhibiting post-surgical adhesions |
US20100222371A1 (en) * | 2008-11-20 | 2010-09-02 | Children's Medical Center Corporation | Prevention of surgical adhesions |
GB2478356A (en) * | 2010-03-05 | 2011-09-07 | Esaturnus Nv | Nitrous oxide gas for use in preventing adhesion |
US9402863B2 (en) * | 2010-03-05 | 2016-08-02 | Endosat Nv | Methods and systems for conditioning in surgery |
US9572595B1 (en) | 2014-03-05 | 2017-02-21 | Northgate Technologies Inc. | In-dwelling port for access into a body |
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US4464169A (en) * | 1981-10-15 | 1984-08-07 | Kurt Semm | Apparatus and method for insufflating fluid media into a cavity |
US4661092A (en) * | 1983-12-09 | 1987-04-28 | Popovich Robert P | Peritoneal artificial lung |
US5407426A (en) * | 1991-02-14 | 1995-04-18 | Wayne State University | Method and apparatus for delivering oxygen into blood |
DE3741149A1 (en) * | 1987-12-04 | 1989-06-15 | Thomae Gmbh Dr K | PREPARATION FORMS FOR PREVENTING ADHAESIONS OF ORGANS AND ORGAN PARTS |
US5023090A (en) * | 1989-08-16 | 1991-06-11 | Levin Robert H | Topical compositions containing LYCD and other topically active medicinal ingredients for the treatment of ACNE |
DE68909648T2 (en) * | 1988-03-21 | 1994-02-10 | Ethicon Inc | Intraperitoneal treatment with a chemotherapeutic agent and a non-steroidal anti-inflammatory drug. |
US4911926A (en) * | 1988-11-16 | 1990-03-27 | Mediventures Inc. | Method and composition for reducing postsurgical adhesions |
AU4543193A (en) * | 1992-06-22 | 1994-01-24 | Henry E. Young | Scar inhibitory factor and use thereof |
US5246419A (en) * | 1992-09-04 | 1993-09-21 | Omnivision, Inc. | Intra-abdominal insufflation apparatus |
US5411474A (en) * | 1993-07-14 | 1995-05-02 | Douglas E. Ott | Method and apparatus for conditioning insufflation gas for laparoscopic surgery |
US5411988A (en) * | 1993-10-27 | 1995-05-02 | Bockow; Barry I. | Compositions and methods for inhibiting inflammation and adhesion formation |
EP0712635B1 (en) | 1994-05-13 | 2003-05-02 | Kuraray Co., Ltd. | Medical polymer gel |
US5478837A (en) * | 1994-06-07 | 1995-12-26 | University Of Southern California | Use of quinacrine in preventing adhesion formation |
US5558668A (en) | 1994-10-11 | 1996-09-24 | Plc Medical Systems, Inc. | Medical laser treatment system and method |
DE4437207C1 (en) * | 1994-10-18 | 1996-01-04 | Draegerwerk Ag | Gas-flow ratio regulation of anaesthetic gases |
US5464867A (en) * | 1994-11-16 | 1995-11-07 | American Home Products Corporation | Diaminocyclobutene-3,4-diones |
US5534261A (en) * | 1995-01-17 | 1996-07-09 | University Of Southern California | Retinoid-based compositions and method for preventing adhesion formation using the same |
ATE306903T1 (en) * | 1995-03-24 | 2005-11-15 | Genzyme Corp | REDUCTION OF ADHESIONS THROUGH CONTROLLED ADMINISTRATION OF ACTIVE OXYGEN INHIBITORS |
CA2223590A1 (en) | 1995-06-07 | 1996-12-19 | The University Of Southern California | Method for reducing or preventing post-surgical adhesion formation using 5-lipoxygenase inhibitors |
WO1997000956A1 (en) * | 1995-06-20 | 1997-01-09 | Trustees Of Boston University | Hypoxia-responsive adhesion molecules, specific antibodies, and their uses |
DE69617719D1 (en) * | 1995-10-20 | 2002-01-17 | Air Liquide | PHARMACEUTICAL COMPOSITION OF NITROGEN MONOXIDE |
TW406215B (en) * | 1996-08-07 | 2000-09-21 | Fuji Photo Film Co Ltd | Composition for anti-reflective coating material in lithographic process, and process for forming resist pattern |
EP0887076A3 (en) * | 1997-05-07 | 1999-03-31 | Saturnus A.G. | Adhesion prevention and an endoscopic insufflation system therefor |
WO1999009982A1 (en) * | 1997-08-25 | 1999-03-04 | Harold Brem | Prevention of adhesions and excessive scar formation using angiogenesis inhibitors |
CA2316248A1 (en) * | 1997-12-23 | 1999-07-01 | Alliance Pharmaceutical Corp. | Methods and compositions for the delivery of pharmaceutical agents and/or the prevention of adhesions |
-
1997
- 1997-05-07 EP EP97201358A patent/EP0887076A3/en not_active Withdrawn
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1998
- 1998-05-07 EP EP98929308A patent/EP0980255B1/en not_active Expired - Lifetime
- 1998-05-07 AU AU79122/98A patent/AU7912298A/en not_active Abandoned
- 1998-05-07 US US09/423,192 patent/US6428500B1/en not_active Expired - Fee Related
- 1998-05-07 WO PCT/EP1998/002829 patent/WO1998050064A2/en active IP Right Grant
- 1998-05-07 DE DE69827619T patent/DE69827619T2/en not_active Expired - Lifetime
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2002
- 2002-06-14 US US10/170,704 patent/US7073512B2/en not_active Expired - Fee Related
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US6428500B1 (en) | 2002-08-06 |
US7073512B2 (en) | 2006-07-11 |
EP0887076A3 (en) | 1999-03-31 |
WO1998050064A2 (en) | 1998-11-12 |
DE69827619D1 (en) | 2004-12-23 |
EP0980255A2 (en) | 2000-02-23 |
EP0980255B1 (en) | 2004-11-17 |
EP0887076A2 (en) | 1998-12-30 |
WO1998050064A3 (en) | 1999-03-11 |
DE69827619T2 (en) | 2005-12-01 |
US20020183687A1 (en) | 2002-12-05 |
AU7912298A (en) | 1998-11-27 |
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