|Publication number||WO1998041153 A1|
|Publication date||24 Sep 1998|
|Filing date||16 Mar 1998|
|Priority date||16 Mar 1997|
|Publication number||PCT/1998/480, PCT/SE/1998/000480, PCT/SE/1998/00480, PCT/SE/98/000480, PCT/SE/98/00480, PCT/SE1998/000480, PCT/SE1998/00480, PCT/SE1998000480, PCT/SE199800480, PCT/SE98/000480, PCT/SE98/00480, PCT/SE98000480, PCT/SE9800480, WO 1998/041153 A1, WO 1998041153 A1, WO 1998041153A1, WO 9841153 A1, WO 9841153A1, WO-A1-1998041153, WO-A1-9841153, WO1998/041153A1, WO1998041153 A1, WO1998041153A1, WO9841153 A1, WO9841153A1|
|Inventors||Anders Pettersson, Lars Fändriks, Anders ÅNEMAN|
|Applicant||A+ Science Invest Ab|
|Export Citation||BiBTeX, EndNote, RefMan|
|Patent Citations (3), Referenced by (4), Classifications (9), Legal Events (8)|
|External Links: Patentscope, Espacenet|
DEVICE AND METHOD TO OBTAIN REGIONALLY
REPRESENTATIVE GASEOUS SAMPLES FROM THE HUMAN
GASTROINTESTINAL TRACT USED IN THE DIAGNOSIS OF
Field of the invention The invention relates to an endoluminal sampling catheter device and to a method for obtaining a gaseous NO sample from a hollow internal organ of a mammal.
Background of the invention The gastrointestinal epithelium represents an area of approximately 170 square meters that constitutes a protective barrier to prevent the entry of noxious sub- stances into the interior of the organism and yet must permit the selective uptake of ingested nutrients. The function of this epithelial barrier is affected in several pathophysiological conditions including cardiovascular, inflammatory and degenerative diseases. Nitric oxide (NO) as a modulator and regulator of biological processes has received increasing attention since its recognition as an endothelial derived relaxing factor (see e.g. Moncada, S., Higgs, A., The L-arginine - nitric oxide pathway, N. Eng. J. Med., 1993, 329:2002- 2012) . In particular, several additional important roles for NO in physiologic as well as pathophysiologic conditions have been discovered. With respect to the gastrointestinal epithelium, NO has been demonstrated to affect epithelial permeability, intestinal blood flow, infla ma- tory processes and secretory/absorptive capabilities (see e.g. Salzman, A. L., Nitric oxide in the gut, New Horizons, 1995, 3:38-45) .
Critical reduction of gastrointestinal blood flow and oxygenation are thought to be major contributing fac- tors to the development of multiple organ dysfunction syndrome (MODS) . MODS is the leading cause of death in
CONFIRMATION COPY modem intensive care units, largely due to our present inability to detect its early symptoms and institute prompt therapeutic measures. The intraluminal occurrence of NO may be used as a marker of gastrointestinal oxygen consumption, with decreased NO levels being characteristic of decreased oxygen utilization (see e.g. Aneman, A., Reduced NO-synthesis in the gut by endogenous NO-synthase inhibition during cardiac tamponade in pigs, Shock, 1995, suppl. vol. 3:29). In addition, by endoluminal sampling of NO, the concentration of this biologically very active compound may be directly assessed. This simple, atrau- matic technique makes other investigative approaches superfluous, including vessel catheterization (e.g. the use of heptic venous catheters to monitor splanchnic oxygen consumption) and endoluminal endoscopy, which often only provides relevant information in late stages of developing gastrointestinal ischemia.
Celiac disease (non-tropical sprue, gluten enteropa- thy) is clinically suspected by symptoms of diarrhea, weight loss, steatorrhea and malabsorption (anemia, edema and even tetany) , all of which may be features of other inflammatory bowel diseases. Hypersensitvity towards the gliadin fraction of wheat or rye gluten is considered the pathogenetic mechanism, although the exact cause of the disease is imperfectly understood. The diagnostic tools applicable to celiac disease include endoscopy and collection of biopsies for histological examination which in the typical case reveals marked atrophy of the intestinal villi and microvilli, increased depth of the intervillous cryps and a pronounced inflammatory response in the lamina propria. In addition, techniques to demonstrate malabsorption has been applied, including failure to absorb D-xylose. Biopsy procedures can potentially cause the patient considerable discomfort and are associated with risk of intestinal perforation. Moreover, the his- tologic diagnosis is only possible when severe epithelial damage is already established. Approximately 50% of adults diagnosed with celiac disease recall symptoms dating back to childhood, reflecting the difficulties in reaching an early, correct diagnosis.
Recent studies have indicated that the gastrointes- tinal epithelium contains NO synthase, the enzyme respon¬ sible for the production of NO while converting L- arginine to L-citrulline. Furthermore, several cellular elements of the ucosa may contribute to the production of NO such as monocytes, granulocytes, neurons, myocytes, enterocytes, endothelial cells and mast cells (see e.g. Salzman, A. L., Nitric oxide in the gut, New Horizons, 1995, 3:38-45). The luminal occurrence of NO may also re¬ flect acidified reduction of luminal nitrate and bacterial denitrification. Quantitative measurements of NO are made difficult by the high chemical reactivity of NO with other biological compounds, inherent with the radical properties of the NO molecule. However, NO may be detected with high specificity in a gaseous phase by chemiluminescence . There is no reliable technique described in the literature or in clinical use to quantitatively measure NO , in the human gastrointestinal tract. Previous reports on gastrointestinal NO principally rely on indirect measurements, for example citrulline from NO synthesis (see e.g. Middleton, S. J. , Shorthouse, M. , Hunter, J. 0., Increased nitric oxide synthesis in ulcerative colitis, The Lancet, 1993, 341:465-466) or met-hemoglobin from NO reacting with hemoglobin (see e.g. Wennmalm, A., Benthin, G., Petersson, A., Dependence of the metabolism of nitric oxide (NO) in healthy human whole blood on the oxygena- tion of its red cell haemoglobin, Br. J. Pharmacol., 1992, 106:507-508). A few investigations have measured NO in regurgitated air from the stomach, which may be contaminated by NO from the airways in an unknown proportion (see e.g. Lundberg, J. , Weitzberg, E., Lundberg, J. M. ,
Alving, K., Intragastric nitric oxide in humans: measurements in expelled air, Gut, 1994, 35:1543-1546). The hallmark of celiac disease is atrophy of the villous structure in the gut and a concomitant profound inflammatory reaction. As a result of these early changes, the intraluminal occurrence of NO is increased. The increase of NO cannot be discerned in regurgitated air samples due to the many confounding sources of NO in the stomach and airways .
Summary of the invention There is a need for a regional technique to sample the intraluminal atmosphere for detection of NO. Such a technique should be simple, minimally invasive, well tolerated by the patient and allow a specific and rapid analysis of NO. Moreover, in inflammatory bowel diseases such as ulcerative colitis and regional ileitis, the endoluminal levels of NO may be used to monitor the inflammatory activity in the gut, and may consequently be used for rapid and sensitive therapeutic guidance with minimal discomfort for the patient. Endoluminal NO levels may be used to detect dysoxia and to indicate whether cardiovascular supportive actions are beneficial for the situation in the gut during critical illness with reduced gastrointestinal oxygen delivery leading to an ischemic inflammatory response. The present invention provided a method and a device for obtaining regional samples of the intraluminal intestinal atmosphere for analysis of the gaseous content of NO without contamination by other endogenous sources of NO. Thus, the present invention related to a device for collection of a gaseous NO sample from a hollow internal organ of a mammal, said device comprising a catheter tube, the wall of which is made of a gas impermeable material, and, arranged at one end of the tube and in com- munication with the tube, a sampling chamber, the wall of which is made of a gas permeable but substantially liquid impermeable material. The present invention also relates to use of the above device for sampling of gaseous NO from an organ selected from the group consisting of the gut, the colon, the small intestine, and the stomach. Finally, the present invention relates to a method for detection of inflammatory conditions or conditions of dysoxia in a hollow internal organ which comprises providing a catheter having a catheter tube, the wall of said tube comprising a material which is impermeable to nitric oxide; and walled sampling chamber on the tube in communication with the interior of the tube; the wall of said walled sampling chamber comprising a material which is freely permeable to nitric oxide gas in solution but poorly permeable to liquid fluid, introducing the cathe- ter to the organ of interest so that the chamber is disposed at a desired sampling site and leaving the sampling chamber disposed at the sampling site for a length of time sufficient to allow any nitric oxide gas present at the sampling site to diffuse across the wall of the sam- pling chamber into aspirating gas contained within the sampling chamber, withdrawing at least a portion of the said aspirating gas containing any diffused nitric oxide gas via the catheter tube, analyzing the sample thus withdrawn for nitric oxide, and determining whether coeliac disease, ulcerative colitis, Crohn' s disease or dysoxia is present on the basis of nitric oxide determination.
The characterising features of the invention will be evident from the following description and the appended claims.
The method according to the invention comprises placing a flexible, gas impermeable radiopaque tube fitted with a distal gas permeable, inflatable sampling chamber in the gut of the patient. The tube is positioned via the nasal route in the proximal jejunum taking advantage of the peristalsis of the gut. In critically ill patients, a flexible guide wire inserted into a central lu- men of the catheter may be used to manipulate the catheter into the desired position. Moreover, in this latter group of patients, after withdrawal of the guide wire, the central lumen may be used for supplementing or sam- pling fluid into the proximal jejunum, thus making the catheter an ideal device for administering parenteral nutrition. The position may be verified by fluoroscopy. A defined amount of room air or specified gas mixture is used to inflate the sampling chamber. Following a speci- fied time for equilibration, the atmosphere of the sampling chamber is emptied into a gas-tight syringe for subsequent analysis of the NO content. Alternatively, the gas chamber may be emptied directly into a chemilumines- cence detector for immediate recording of the NO content. The sampling chamber represents the only part of the tube comprising gas permeable walls. Particularly silastic is preferred for construction of the sampling chamber, but also other plastic or rubber membranes known to the skilled person, can be used. The inlet and outlet lines to and from the sampling chamber are made of gas impermeable material. Particularly PEEK is preferred for construction of the channels communicating with the sampling chamber, but also other gas tight plastic or rubber materials known to the skilled person, can be used. It is im- portant that the catheter tube is impermeable to gaseous NO, to prevent the passage of NO into the sample from other parts of the body than the region where the sampling chamber is placed. This feature makes it possible to obtain a regionally representative gas sample. The invention will be further illustrated in the description of a preferred embodiment and in the examples below, which in no way are intended to limit the invention. Reference will be made to the accompanying drawings on which: Fig. 1 shows a device according to the invention;
Fig. 2 is a longitudinal sectional view of the device from figure 1; Fig. 3 is a transverse sectional view of a catheter tube comprising several channels; Fig. 4 is a diagram showing that elevated intrajejunal NO concentrations found in celiac disease are re- gional specific due to the inflammatory reaction;
Fig. 5 a-d are graphs illustrating correlations between
NO levels measured by the device according to the inventions : Fig. 6 is a graph illustrating the relation between jeju- nal NO and gastrointestinal oxygen consumption during graded hemorrhage.
Description of a preferred embodiment To simplify the device according to the invention may be described as a chamber with a "ballooned" form passed over the end of a tube.
A preferred embodiment of the device according to the invention is shown in figure 1, and also in a longitudinal sectional view in figure 2. This preferred embodiment comprises a flexible catheter tube 1 and a sampling chamber 2. The wall 3 of the catheter tube 1 of the preferred device is impermeable to gases and radiopaque; the preferred material is PEEK. The sampling chamber 2 is arranged at one end of the catheter tube 1 and in communication with the interior of the catheter tube 1. The wall 4 of the sampling chamber 2 is permeable to gas but substantially impermeable to liquids. In the preferred embodiment the sampling chamber is inflatable, and the material constituting its wall 4 is preferably silastic.
The easiest way to establish communication between the sampling chamber 2 and the interior of the catheter tube 1 is to provide at least one opening 5 in the wall 3 of the catheter tube 1 surrounded by the sampling chamber 2.
The catheter tube 1 of the device according to the invention may comprise more than one channel, this is il- lustrated in the transverse sectional view in figure 3. Preferably, a central channel 6 is arranged to accommodate a guide wire during introduction of the device into the hollow organ. This guide wire facilitates the intro- duction of the device into the patient.
This central channel 6 may be surrounded by several, e.g. 1-5, other channels. One channel 7 is in communication with the sampling chamber 2. The other channel or channels 8 are working channels constituting means in- tended to facilitate introduction of different instruments, such as optic fibers, electrodes, connecting wires, and biopsy forceps, during or after introduction of the device into the hollow organ.
Finally, the preferred embodiment also comprises a gas tight stoplock 9, such as a luer lock.
In the preferred embodiment the length of the sampling chamber 2 is 3-5 cm, and its diameter when inflated is 1 cm or less.
Examples Example 1
In this example the device according to the invention was used to obtain samples of NO from the jejunal lumen from patients suffering from celiac disease as well as from patients having suffered from celiac disease and also having been treated for the disease, and from healthy individuals constituting a control group. It was found that the jejunal luminal NO concentrations in the patients with celiac disease were more than 20 times higher than in the individuals in the control group. The mean value of the concentrations in the patients with celiac disease was 740 ppb (range 215-1690 ppb) , and the mean value for the control group was 35 ppb range (0-77 ppb). There was no overlap between the two groups. The duodenal concentrations of NO did not differ between the patients suffering from the disease and the individuals in the control group, nor did concentrations in the stomach differ significantly. The results from the measure- ments are shown in figure 4. The result clearly indicate that the elevated intrajejunal NO concentrations found in celiac disease are regionally specific due to the inflammatory reaction and not the result of NO spill-over from the stomach, and thus that the device and the method according to the invention are suitable for detection of celiac disease.
Example 2 In order to further illustrate the accurate results obtained when using the device according to the invention, four different devices according to the invention was used to obtain sample from 12 or 13 different standard aqueous solutions of NO with NO concentrations is the range of 0-490 μM. The correlations between the NO concentrations measured in the samples obtained with the devices according to the invention and the exact concentrations in the solutions are shown in figures 5 a-d.
The explanation to the fact that the concentration measured by use of the device in the standard solution with the concentration 0 μM is not 0 ppb is due to background disturbances caused by NO contained in the air.
Example 3 In this example the device according to the invention was used to determine the jejunal intraluminal concentration of NO in patients suffering from graded hemorrhage. Also the gastrointestinal oxygen consumption, V02, was determined in a conventional way known to persons skilled in the art by determining the difference between the amount of oxygen supplied in arterial blood and the amount of oxygen. The relation between jejunal NO and gastrointestinal oxygen consumption during graded hemorrhage was highly significant, which is illustrated in figure 6. This which demonstrates the sensitivity of the method according to the invention in detection of gastrointestinal dysoxia.
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|WO1996017244A1 *||29 Nov 1995||6 Jun 1996||Kjell Alving||Diagnostic method for inflammatory conditions in the intestines|
|WO1997037587A1 *||11 Apr 1997||16 Oct 1997||Kjell Alving||Method and device for use in the diagnosis of inflammatory states in the urogenital tract|
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|Citing Patent||Filing date||Publication date||Applicant||Title|
|WO2001036969A1 *||16 Nov 2000||25 May 2001||Aerocrine Ab||Method for use in the diagnosis of food allergies and/or food intolerances|
|WO2002080775A1 *||2 Apr 2002||17 Oct 2002||Enterix Inc.||Method of collecting a gastrointestinal tract sample|
|US6511425||15 Nov 2000||28 Jan 2003||Aerocrine Ab||Method for the diagnosis of food intolerance|
|US7306953||14 Jan 2005||11 Dec 2007||The University Of The West Of England, Bristol||Detection of disease by analysis of emissions|
|International Classification||A61B10/00, A61M25/00, G01N33/497|
|Cooperative Classification||A61M25/0043, G01N33/497, A61B10/00, A61B2010/0083|
|European Classification||G01N33/497, A61B10/00|
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