WO1999020177A1

WO1999020177A1 - A sample collection and detection system used for breath analysis

Info

Publication number: WO1999020177A1
Application number: PCT/US1998/022091
Authority: WO
Inventors: Izabella T. Rybak; Govindanunny Thekkadath; Lawrence V. Haley
Original assignee: Ids Intelligent Detection Systems, Inc.
Priority date: 1997-10-22
Filing date: 1998-10-20
Publication date: 1999-04-29
Also published as: EP1024745A4; CA2306760A1; EP1024745A1; JP2001520068A

Abstract

A breath analyzer system for detecting target compounds comprises a mask device (12) for placement over a person's mouth having passageways (22, 25, 30, 35) enabling breath inhalation and exhalations. An electronic sensor (40) provided at a valve (102) located at an entrance of a first outlet passageway (25) initiates detection of a first breath exhalation and generates a control signal.

Description

A SAMPLE COLLECTION AND DETECTION SYSTEM USED FOR BREATH ANALYSIS

CROSS-REFERENCE TO RELATED APPLICATIONS

The following patent application is based on and claims the benefit of U.S. Provisional Patent Application Serial No. 60/062,683 filed October 22, 1997.

FIELD OF THE INVENTION

The present invention relates generally to breath analyzer systems, and more particularly, to a novel breath analyzer system optimized for the detecting target compounds, e.g., related to specific bodily disorder.

BACKGROUND OF THE INVENTION

In recent years, the cost of medical testing has increased at a very high rate. This increase is due to several factors, including very expensive instrumentation (i.e., MRI and CAT scanners), high labor costs for specialized personnel, more sophisticated test procedures and increased number of tests. During the diagnostic phase, a doctor must explore several possible conclusions and can only validate which of the possibilities is correct through a series of tests. Recent literature suggests that other non- invasive techniques would be useful to assist the physician in reducing the number of possible choices and, hence, the cost to the patient and the health care system.

Furthermore, a non- invasive technique could be used right in the doctor's office.

As the human breath contains a vast amount of information about metabolic processes occurring in the body, one technique is breath analysis. The analysis of human breath however, is a difficult and challenging task and is complicated by the presence of high concentrations of water as well as large amounts of organic compounds in a wide concentration range. More specifically, Human breath is not a homogenous gas as nearly 400 volatile organic compounds have been isolated in normal breath (Phillips 1992) . Nitrogen and oxygen together constitute more than 90% of the breath, but there is also a high concentration of water, up to 40 mg/L at 37°C. Carbon dioxide makes up approximately 5% of the breath. Most of the other volatile compounds in the breath are present in parts per million or less. It is this low concentration, volatile group of compounds that may contain target compounds related to specific disorders.

The reference entitled "Breath Tests in Medicine", Scientific American, July 1992, pp. 74-79, by Michael Phillips, describes conventional breath analysis techniques and describes a system requiring the prior ingestion of tracers or markers, e.g., radioactive carbon dioxide ¹⁴C0₂, to aid in detection of disorders in the stomach, intestine and pancreas. Particularly, such systems include breath exhalation collecting apparatuses which are largely stationary, bulky devices and require several meters of plastic tubing. These systems employ a series of water traps in addition to adsorptive binding agents for collecting the compounds which may be subsequently analyzed using gas chromatography (GO and/or ion mobility spectrometry (IMS) techniques. It would be highly desirable to provide a breath analysis system comprising a mask component having intelligence for enabling collection and detection of certain volatile group of compounds contained in breath exhalations that may contain target compounds related to specific bodily disorders.

SUMMARY OF THE INVENTION It is an object of the present invention to provide a portable and compact breath analysis instrument and methodology for detecting target compounds included in breath exhalations by measuring a total volume of breath samples received, while simultaneously collecting the breath sample in an adsorbing media.

According to the principles of the invention there is provided a breath analyzer system comprising a mask device for placement over a person's mouth for receiving that person's breath exhalations. An electronic sensor provided at a valve located at an entrance of a first outlet passageway initiates detection of breath exhalation and generates a control signal. Upon receipt of the control signal, a control device initiates a breath volume measurement and collection cycle including directing a pre -determined volume of breath exhalation through the first passageway in a first part of the measurement cycle, and, directing the remaining portion of breath exhalation to a second passageway for receipt by a breath adsorbing media located in the second passageway during a second part of the measurement cycle. The first and second measurement cycles are repeated until a desired volume of exhaled breath has been sampled. Subsequently, the contents of the breath collected by the adsorbing media is analyzed by an ion mobility spectrometer or combination gas chromatographic GC/IMS device. BRIEF DESCRIPTION OF THE DRAWINGS

Further features and advantages of the invention will become more readily apparent from a consideration of the following detailed description set forth with reference to the accompanying drawing, which specifies a preferred embodiment of the invention, in which:

Figure 1 is a diagram illustrating the breath analyzer system of the invention.

DETAILED DESCRIPTION OF THE INVENTION

The breath analyzer instrument of the instant invention implements the following basic methodology: 1) sample collection, 2) sample preparation, and 3) sample analysis. For sample collection, the device samples the breath of the patient and traps the organic compounds that are to be analyzed. Preferably, the instrument 10 is designed to take into account the mechanics of breathing. For example, a standard 70 -kg adult at rest breathes about 7.5L/min. The cycle that is responsible for this process consists of four stages: (rest, during inspiration) , end inspiration (equilibrium) , (during expiration) , and (expiration) . For getting air into the lungs, an amount of air that is moved in and out with each breath is called the tidal volume which is usually about 500 ml. Using 7.5 L/min, this relates to approximately 15 breaths/min. Additionally, the first 150 ml of every expiration consists of "dead space" air from upper airways, where no gas exchange has occurred. This volume is wasted since it does not participate in gas exchange in the lungs, consequently, is does not contain target compounds. This means that of every breath only about 350 ml of air is suitable for collection and analysis. Thus, for example, to determine how much of a sample to collect in order to detect a target compound with a concentration of 100 ppt, the total volume of usable air that must be collected has to be determined.

Since 150 ml of each breath is wasted, then only 350 ml of each breath is usable. With 15 breaths/min, a total volume of 5250 ml of usable air is expired in minute. At 100 ppt concentration, a calculated estimate of the volume of the target compound (with a molecular weight of 150 and a mass of 6 nanograms, for example) is 7750 ml. Using 5250 ml/min and 7750 ml total volume, the time of collection would be about 1.5 min. Based on these calculations, an estimated breath sampling time would be between 1-2 minutes. Using the above information and the results of the calculations, the breath analysis device of the invention automatically collects the correct amount of usable air from the patient. Figure 1 is schematic diagram depicting the the breath analyzer system 10 of the invention, including the mask component 12. As shown in Figure 1, the mask component 12 includes all the elements and on-board electronics 15 to carry out a pre-programmed sequence to efficiently collect the usable air as the patient breaths normally. Particularly, as will be described in greater detail, the invention supports the following modes of operation: 1) Stand-by and 2) Collect Sample. During the "Stand-by Mode" the mask is either placed over the patient's face to receive breath exhalations, a sample "trap" is removed from the mask, or, the mask is removed from the patient's face. During a collect sample mode of operation, the specified volume of usable air as the patient breaths normally, is collected.

As shown in Figure 1, the sample mask is provided with a first intake passageway 22, and outlet passageways 25, 30 and 35. The outlet passageway 30 includes a sample collection chamber 45 having media for collecting constituents of said exhaled breath. Three valves 101, 102 and 103 corresponding to respective passage ways 22, 25 and 30 which actuate in sequence with the in and out breathing of the patient are provided. For instance, during patient inhalation: valve 101 opens enabling the person to inhale via passageway 22, but valves 102-103 remain closed; during exhalation: valves 101 and 103 are closed, and valve 102 is open.

The operational sequence is as follows: first, a start button 20 is selected to initiate an operation sequence that is executed by the on-board control microprocessor 50. The microprocessor specifically waits for a signal from an electronics sensor 40 attached to valve 102. As the patient exhales, valve 101 closes and the shunt valve 103 opens. A signal from the electronics sensor 40 is received by the microprocessor 50 to start the measuring sequence.

Specifically, after about 150 ml of air has been measured by flow sensor 42 through the shunt valve 102, the microprocessor directs valve 102 to close, and simultaneously, directs valve 103 to open to allow the remaining exhaled breath to pass through a sample trap 60. In the preferred embodiment, the trap 60 contains a suitable high surface area adsorbant material, e.g., hydrophobic adsorbent such as Tenax-polymeric. Flow sensor 70 then measures the usable air volume. As the patient breaths in and out without any special instructions, the microprocessor keeps an account of the total volume of usable air that passes through valve 103. When the appropriate volume has been expired (5000-10,000 ml), the microprocessor 50 closes valve 103 and signals that the process is finished. Valves 101 and 102 are now in the standby configuration.

Finally, the sample collector 60 including the adsorbed breath sample is removed, for example, by a robotic interface device, and is placed in an analyzer.

To decrease the time that is required to obtain a result and maintain chemical accuracy, the breath analyzer system 10 includes a modified GC/IMS based instrument 80 with a robotic interface to prepare sample traps for processing in a GC/IMS analytical device, which may comprise for example, a modified version of an ORION explosive detection system (manufactured by Intelligent Detection Systems, Inc., the assignee of the present invention), similar to the system described in U.S. Patent Nos. 5,189,301, 5,465,607 and 5,585,575, the contents and disclosure of each of which are incorporated by reference as if fully set forth herein. The modifications would include optimized analytical components to accommodate the various target compounds, a list of which may be found in Appendix A. Preferably, the analysis time should not exceed 15 to 20 seconds. The foregoing merely illustrates the principles of the present invention. Those skilled in the art will be able to devise various modifications, which although not explicitly described or shown herein, embody the principles of the invention and are thus within its spirit and scope.

APPEN&IX A

DISORDER/FUNCORGΛN/PΛRT OF CHEMICAL SOURCE OF INFO TION TEST THE BODY SUBSTΛNCE(S) IN THE BREATH peptic ulcer stomach 14C or 13C see chapter and chronic 14C-urea test below, gastri tis/ Helicobacter Heli cobacter pylori pylori infection

Fat digestion in 13C- trioctanoin Medical maldigestion early life Research Councel Dunn Nutrition Unit, Cambridge, UK, 1993

Ox.i dative stress Genox Corp.1996

Oxidat i ve Genox Corp.1996 Stress State

Malabsorption an intestinal hydrogen from Phillips, M.1992 syndrome oral dose of xylose or other speci f i c carbohydrate

Deficiency of small bowel lactose lactase in the dose/hydrogen small bowel

Bacterial intestine Phillip, M.1992 overgrowth

Pancreas pancreas hydrogen after Perman,J.A. of damage/cys ic a dose of rice the John f ibrosis s rch Hopkins University School of Medicine (in Phillips 1992) other diseases pancreas IOC in 14C02 Phillips 1992 causi ng from a dose of pancreas radiol abeled dysfunction trig! yceride

also pancreatic pancreas 13C - trioctanoin Dept. of function after test Surgery II, pancrea oduo- Natoya denectomy University School of Medicine, Japan 1993

Liver damage in liver dimethyl sul - the early fide and comstages pounds labeled cirrhosis and with radiohepatitis active tracer

F «ork\ 751 \minc\ J O<)J 6 . l B t Cystic fibrosis measurement of 13C rich maize Medical starch Research digestion Council Dunn Nutrition Unit, Cambridge UK 1992 hepatic liver 13C- Hospital E. steatosis ketoi ocaproic Herriot, Lyon aci d France

Atopic liver 1 C-methacetin Dept. of dermatitis Allergy, National Children' s Hospital , Tokyo Japan, 1994

Function test- liver 13C-Aminopyrine Uni versi ty assessment of Hospital Basel lidocaine Switzerland metaboli te 1993 formation

Liver cirrhosis 1 i ver gl yci ne- 1 C Shindo K. et 1 abel ed al . , Am J glycocholate Gastroen erol 12/8R/1993

Function test mi tochondri a 13C- University of

Ketoi socaproate Bern act d Switzerland 1994, 1995

Lung cancer lungs a higher than normal concentrations of acetone, methyl - ethylketone n- propanol , tolualdehyde and oxepanone

Kidney and dimenthylamine liver di seases & volatile fatty acids

Λrthriti s increase level of pentane

Mul tipl e pentane sclerosis

Psychotic pentane schizophrenia

Acu e pentane myocardi al infarction

Def iciency of elevated level Vi tamin E of ethane trace metals as elevated level selenium and of ethane copper

common mo th Volatile sulfur halitosi s compounds (VSC) - hydrogen sul f i de, methyl mercaptan, other thiols, imethyl sul fide

Function - ethane and Conway, J.G. & lipid pentane J.Λ. Popp. 1995 peroxidat ion

Function 13C- Dept. of gastric gl yci ne/1 C - Medicine emptyi ng octanoi c acid University

Hospi tal

Gasthuisberg,

Leuven, Belgium

1994-1995

Function - 13C-acetate Div. of Gastro- gastric enterol ogy , emptying Uni versity Hospi tal , Basel , Swi tzerl and 1994 also Center of Internal Medicine, University Hospi al , Frankfur /Ma in, Germany 1995

occupat ionally benzene and Ljunαkvist health field sampling end- other hazardous G . M . ; exhaled air substances Nordl inder R.G. ,

University of Goetebor , Sweden 1995 also Polafoff PL. Integrated Health Management Associates, Albany, CA

F vorV\731\mlnc\10')a6 1st

Claims

WHAT IS CLAIMED IS:

1. A breath analyzer system comprising: ΓÇó a mask device for placement over a person's mouth for receiving that person's breath exhalations, said mask device comprising at least one passageway and valve for directing exhaled breath into said system; a breath sample collection chamber located in a first passageway for receiving a sample of breath; an electronic sensor provided at a valve located at an entrance of a second passageway, said sensor for initiating detection of breath exhalation and generating a first control signal; a control device for initiating a breath volume measurement and collection cycle in response to said first control signal, said measurement and collection cycle including directing pre-determined volume of breath exhalation through said second passageway in a first part of said measurement cycle, and, directing the remaining portion of breath exhalation to said first passageway for receipt by said breath sample collection chamber during a second part of said measurement cycle; and, analyzer device for determining contents of said exhaled breath in said sample collection chamber.

2. The breath analyzer system of Claim 1, further comprising: a first valve mechanism located at an entrance to said first passageway includes that opens under control of said control device for directing said breath exhalation through said first passageway during said second part of said measurement cycle; and, a flow sensor device for measuring volume of exhaled breath received during said second part of said measurement cycle.

_ 3. The breath analyzer system of Claim 1, wherein said sample collection chamber includes an adsorbant material for adsorbing constituents of said exhaled breath.

4. The breath analyzer system of Claim 1, wherein said analyzer device includes an ion mobility spectrometer.

5. The breath analyzer system of Claim 2, further comprising: a second valve mechanism located at an entrance of said second passageway that opens under control of said control device for directing said pre- determined volume of breath exhalation through said second passageway during said first part of said measurement cycle, and closes for said second part of said measurement cycle; and a flow sensor provided in said second passageway for measuring said predetermined volume of exhaled breath during said first part of said measurement cycle.

6. The breath analyzer system of Claim 5, wherein said flow sensor located at said second passageway generates a control signal for directing said control means to close said second valve mechanism at said second passageway after reaching said predetermined volume of exhaled breath determining and open said first valve at said first passageway.

7. A method for analyzing constituents of a person's breath comprising the steps of: a) placing a mask device over a person's mouth for receiving that person's breath exhalations, said mask device comprising at least one passageway and valve for directing exhaled breath into said system; b) detecting a beginning of the person's breath exhalation process and opening up a first valve to direct exhaled breath through a first passageway; c) measuring a pre-determined volume of exhaled breath through said first passageway; d) closing said first valve after receipt of said pre-determined volume of breath, and simultaneously opening a second valve to direct remaining exhaled breath through a second passageway; and, f) collecting said remaining exhaled breath by a breath adsorbing media located in said second passageway.

8. The method as claimed in Claim 7, wherein collecting step f) further includes the step of measuring said remaining exhaled volume of breath received through said second passageway.

9. The method as claimed in Claim 8, further including repeating steps b) through f) until a desired volume of a person's exhaled breath has been received, said desired volume useful in detecting a target component of specified molecular weight and mass in said breath.

10. The method as claimed in Claim 7, further including the step of analyzing said adsorbed sample of breath to determine constituent components of said person's breath.