In-vivo measurement of end-tidal carbon monoxide concentration
Contents
1. NI Sheet 5 of 10 5 293 875 Mar 15 1994 U S Patent 131100 m SKY ANIN EN 09 JAYO INIT 09 1Y 31VY3d0 S LIH YINI lviu3S c zsu Y IAIN UNIS S00H21VM uJAIIC QU VOBA 3N 13538 NO 3804 SINJA3 0 1 t 01 3181 x t n 1 1N3A3 YSHOLYdSIO UIUVNVH INGA J 0 SIN3A3 GIWIL 035031519384 S1N3A 3 031 JILLON oor SIN3AJ q3I31LON S1N3 3 0313l10N SIN3A3 SIN3A3 Q3410N i NOLLVZIVLLINI SIN3AI 31310N SLN3A3 311 W SINIA 0t 1209 Q3i310N en 0 WOUd33 NI BIVA p ana 2 5 235 Sb i 1V 235 Sb sva go m 3314V 209 ONY 209 39V1d u3L4V 202 ONY 09 39v Id jio 09 3ufiSV3H 2 viva ANYI 0 3uf5V3H 0 viva 8l 1v 5 203 135 1V LNVIS 09 dfil 15 09 dfi13S 2 1 LIMNI Mm 0l 13282 giv 09 135 Mas 26 9 4 06 45 1 ON Sheet 6 of 10 5 293 875 Mar 15 1994 U S Patent ALluvd ON 4015 1 1188 Qnva0096 2 258 Qc 4 l 5138 NNIH 3H 00 WIS 26298 09 m TOVI T EOM Ves UJANA Su ui qu og 90QH21VAM SIN3A3 0 1 M3H21VdSIO u39VNVH 1N3A3 NOLVZ LII 001 51N3A3 GJM 383191938 S51N3A3 314110N S1N3A3 51N3 3 51N3A3 3I 31 10N QINI L SINJA3 011410 QAWL bed E 1 1 0341 LON SONJ SNOILISNVUL NOLIV ZUWILLINI N YIS 1020108d INN N02 P 31012. CO detector 30 are acquired The relative changes in CO concentration over time are then used to calculate the duty cycle dc of the patient s end tidal breath Prefera bly the signal corresponding to the carbon dioxide concentration is periodically sampled e g the analog signal is digitized at a first sampling rate e g 30 Hz during the second time period These samples are stored in a data buffer for post data acquisition processing and analysis Also the signals corresponding to the CO concentra tions obtained from detector 70 are acquired during the second time period Preferably the carbon monoxide concentration is periodically sampled e g the analog signal is digitized at a sampling rate of 1 0 Hz during the second time period These samples also are stored in the data buffer for analysis FIGS 3a and 3b illustrate representative sampled waveforms of the signals vco and vco provided by the CO and CO detectors 70 and 30 respectively during a second time period The waveforms thus display the concentration levels sensed corresponding to the cali brated CO and CO levels In these representative drawings the calibration functions were CO ppm 12 11 vco 0 95 and CO 211 96 veg 4 0 The calculated duty cycle dc was 42 30 the was 2 10 ppm the COroom was 2 01 ppm the vco_o was 0 78 v and the vco 1 was 0 088 v The vco min was 0 05 v and the vco max was 0 17 v correspond ing also to the start
3. for a first time period and a second means for indicating that the flow path inlet is to be placed to sample patient breath and second means for actuating the switch to pass a sample of patient breath to the carbon monoxide and carbon dioxide gas analyzers for a second time period wherein the calculating means calculates the end tidal carbon monoxide concentration following the end of the second time period 50 The apparatus of claim 45 wherein the calculating means calculates the end tidal carbon monoxide concen tration as equal to the quantity of the average carbon monoxide concentration minus the background carbon monoxide concentration divided by the duty cycle wherein the duty cycle corresponds to the end tidal portion of the patient breath flow gas sample _ UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENTNO 5 293 875 DATED March 15 1994 INVENTOR S Robert T Stone It is certified that error appears in the above indentified patent and that said Letters Patent is hereby corrected as shown below Column 9 line 24 delete respective and insert respectively Column 11 line 55 delete CO and insert CO Column 18 line 55 delete clam and insert claim Column 19 line 36 after comprising insert Column 20 line 13 after coupling insert to Column 20 line 26 delete the and insert a Column 20 line 34 after wherein delete the Si
4. gases of known concentrations inputting the known concentration val ues into the system during set up sequence 131 for CO and set up sequence 133 for CO operating the pump 60 to draw the known gas into the system and determining the signal level produced by the detector 30 or 70 depending on the gas only one detector is calibrated at a time in response to the known gas concentration during measurement sequence 132 for CO and measure ment sequence 134 for CO2 In a preferred embodiment the display 90 is used to provide a sequence of instructions for the operator to input data such as which gas detector is to be calibrated and the concentration of the test gas that is to be used sequences 131 and 133 This is followed by providing a sample of that test gas which is then sampled and measured sequences 132 and 134 Preferably at least two gas samples at different known concentrations are used for each of CO and CO From these two samples the foregoing gas calibration equations 2 and 3 for converting a provided voltage to a gas concentration are determined The calibration equations are reason ably accurate over the concentration ranges of interest e g accurate within 10 5 293 875 17 In one embodiment in sequences 131 and 133 a key board associated with display 90 may be used to input the test gas type and concentration data directly by pressing alphanumeric characters In accordance with a preferred embodiment
5. of the breath flow sample and calculating means for receiving the background car bon monoxide concentration the average carbon monoxide concentration and the determined duty cycle and calculating therefrom the end tidal car bon monoxide concentration 46 The apparatus of claim 45 wherein the analyzing means further comprises a first means for comparing the signal output CO2 to a first threshold and determining the duty cycle of the relative portion of said signal CO2 above the threshold for the given time period 47 The apparatus of claim 45 wherein the first and second providing means further comprise a flow path connecting the gas inputs of the carbon monoxide and carbon dioxide gas analyzers the flow path having a gas inlet for receiving a gas sample a pump connected to the flow path a switch for operating the pump to cause the gas sample at the gas inlet to flow along the flow path to the carbon monoxide and carbon dioxide gas analyzers 48 The apparatus of claim 47 further comprising a flow regulator interposed in the flow path for regulat ing the flow of the gas sample 49 The apparatus of claim 47 wherein the first and second providing means further comprise a display means for displaying information a first means for indicating on the display means that the flow path inlet is to be placed to sample room air and first means for actuating the switch to pass a sample of room air to the carbon monoxide gas analyzer
6. of the onset of jaundice and the resolution of those conditions over time Importantly with respect to newborn and premature newborns it provides for en 10 25 18 hanced detection of potential problems before the new borns are discharged from the hospital One skilled in the art will appreciate that the present invention can be practiced by other than the described embodiments which are presented for purposes of illus tration and not of limitation 1 claim 1 Apparatus for monitoring a patient s end tidal gas flow during breathing comprising a first gas detector for monitoring the concentration of a first selected gas in a gas sample and having an output corresponding to the monitored first se lected gas concentration a first means for monitoring a parameter correspond ing to the patient s breathing and determining the ratio of said parameter corresponding to the pa tient s end tidal breath portion to said parameter corresponding to inspired air as a duty cycle and having an output corresponding to the determined duty cycle first means for providing a sample of room air to the first gas detector for measuring a background con centration of the first gas second means for providing a sample of the patient s breath to the first gas detector for measuring a breath sample concentration of the first gas in the patient s breath and first means for receiving the output of the first gas detector and the first monitorin
7. sampled breath during the first time period 31 The method of claim 30 wherein step d further comprises i detecting the end tidal portion of a second gas in the sampled breath other than the first gas and ii determining the duty cycle as the ratio of the end tidal portion to the sampled breath portion of the second gas during the first time period 32 The method of claim 31 wherein the second gas is carbon dioxide 33 The method of claim 32 wherein step e further comprises subtracting the measured CO o54 from the measured CO and dividing the difference by the deter mined duty cycle 34 The method of claim 33 wherein step a further comprises passing a stream of room air through a car bon monoxide detector during a second time period and 5 293 875 21 measuring the COrom corresponding to the room car bon monoxide level 35 The method of claim 34 wherein step c further comprises measuring the CO as an average of a first number of discrete average samples obtained at the end of the first time period 36 The method of claim 32 wherein step a further comprises measuring an average carbon monoxide con centration in ambient room air over a second period of time 37 The method of claim 32 wherein step d ii fur ther comprises periodically sampling the sensed con centration of carbon dioxide at a first rate during the first time period wherein step c further comprises periodically sampling the sensed con
8. t2 and stop t3 measurement volt ages The maximum 2 was about 0 42 volts The 30 Hz sampling rate of CO was selected because it corresponds to the anatomical waveform of respira tion from which the ratio of the end tidal portion to the total air can be derived The CO sensor time response of 120 ms gives adequate resolution without acquiring excessive data The sampling rate of 1 Hz for the CO detector voltage Vco was selected because the CO detector has a much slower response time the half time of the CO response is about ten seconds which cannot discriminate the end tidal portions and room air Sam pling at a higher rate would not significantly improve the data resolution The selected rates were selected as compromises between collecting sufficient data with adequate resolution in view of the sensor response time and may be changed according to the sensors used and the particular conditions of use Following acquisition of the data the data is pro cessed by the microprocessor Z180 of microcontroller 80 to derive the duty cycle and the end tidal CO con centration COz The digitized samples of the voltage vco are passed through a low pass digital filter imple mented in the software which takes an average of the last five samples This filter is used to suppress noise It also advantageously permits use of the output of the digital filter without further averaging or storage of 5 293 875 15 separate values The cor
9. the gas detectors to remove moisture from the sample of breath In particular filter 15 is used so that moisture does not interfere with de tecting carbon dioxide Filter 15 is illustrated in FIG 1 as inserted between tube 14a which includes cannula 10 and a connector 16a which is secured to the base 5 which supports and preferably encloses the gas detec tors 30 and 70 pump 60 and flow regulator 50 One suitable hydrophobic filter 15 is part number 51190 available from Filtertek Inc Cannula 10 is one segment of tubing 14a which has one end 11 that is adapted for insertion into the nostril posterior nasal pharynx of a normally breathing pa tient e g an infant End 11 has at least one aperture 12 for extracting a sample of the exhaled breath as de scribed below Preferably end 11 has a length and an inner and outer diameter appropriate for insertion into the patient s nostril e g a 3 0 cm length of tubing hav ing an inner diameter on the order of 1 0 to 1 5 mm and an outer diameter of 2 3 mm and a sufficient number of holes 12 perforating the tube circumference for receiv ing a sample of breath The dimensions may be adjusted for the size of the patient The length of cannula 10 is sufficient to extend from the base 5 to the patient and is typically on the order of 75 to 100 cm Segments of tubing 14a 140 14c 14d 14e 14 and 14g are used to form the flow path between the various elements of the apparatus as shown in
10. virtual ground sup ply model TLE2425 available from Texas Instruments Dallas Tex Its output splits the five volt input into a 2 5 volt supply with a virtual ground at 2 5 volts DC real potential Amplifier BU1 of circuit 83 includes two type 1458 dual operational amplifiers BULA and BU1B available from National Semiconductor Santa Clara Calif Am plifier BU1B is configured as a differential amplifier with gain of 1 and has inputs of the virtual ground from the CO amplifier circuit 82 and the CO amplifier circuit 82 output Resistors BR3 120 kQ and capacitor BC3 10 pf provide further low pass filtering with a 1 2 second time constant Amplifier BUIA is configured as a voltage foliower with a low output impedance for driving the analog input on the Little Giant microcom puter board 80 Referring to FIG 2 the Little Giant LG X mi crocontroller 80 is programmable using Z World s Dy namic C language It uses about 200 mA contains a microprocessor Z180 having a 9 216 MHz clock fre quency and sufficient memory including read only memory ROM random access memory RAM and erasable programmable read only memory EPROM which collectively contain the software data and mem ory address locations for operating the apparatus pro cessing the acquired data and performing the data ma nipulation and post acquisition processing functions in accordance with the present invention as described herein The device also contains coun
11. 3 SINJA3 3141 ION 812 03 3LLINSNVUT HGOHX 31 EZ 3MDSY3H 8vo DWO ol NV SV 1 140 111 NOLVB8I V Of VIVO HIV 148 14 YOSN3S 1 35 fd OET HONIG cwonisnvur ONS ONS 121 9 8 1uVIS 101 c09 11 1090L04d WIGOWX NOLIV2INDHNO2 VIVO 2Nn1uN308 aava ELI 13Wi 0 MW0SN3S 3iVH8I1V2 03 a AQv3y Vc 9 3 Wwidsia 197 Sheet 4 of 10 5 293 875 Mar 15 1994 U S Patent Gl 13100 9433 ANNIN 1128V2 3 80 INIT 09 11 4340 WIS 26258 ru 83AIMQ a uo QuvOGA 3X 318V1 INIM u3u21VdSI 839vNVH 1N3A3 S1NJA3 0 1 die iV IH 8111 JOGHILVA S1N3 3 311110 S31fINIH G u314V 1603HlL 00 SJN3A3 51N3A3 Q313110N E e WW v 00 zx 00 48V8 ONY 31212 SONI H2N38 AING 31NdN09 235 Cb X03 209 3UNSV3M 7890203 78103 1 4 2515 24 IN dhid 19 WSYN 32V ld 3ufisv3N HW EI uu HONVO 103 NIN YO TION 0 00 VINA TWSWN 30914 vas 03 Q V NO dHfld 440 ONNOYIAWE SIN3A3 3H 0381191338 S1N3A3 314110 43 14 SSVd MOT 1 1 31H ION SON3 S31dHvS G 40 M 19235 Sb U31 JV 09 N008 3uflSV3H 01 4 18VIS 9 9 V8 Iu 0H 139NV 18 13538 NO 83M0d 001 NOI IV 21 TVILINI Oll
12. FIG 1 The tube segments may be made of for example medical grade catheter tubing polyethylene polypropylene or vinyl The ends of the segments are typically frictionally fitted over bosses of connectors 16 and the various compo nents as shown in FIG 1 and may be clamped for a 5 293 875 5 more secure interconnection Connectors 16a 165 and 16c are preferably mounted in the same region of base 5 to allow for easy access for replacement of the cannula and filters Cannula 10 is connected at its other end in series with filter 15 connector 162 a second length of tubing 145 and the input port 20 of a carbon dioxide detector 30 Detector 30 has a gas sample cell and is used to provide a signal corresponding to the sensed concentration of carbon dioxide in the gas The detector 30 has a re sponse time that is sufficiently fast to distinguish the concentration level of the end tidal portion from the other portions of the breath Thus the signal changes in response to changes in the concentration of carbon dioxide in the breath as the patient breathes The resul tant signal waveform is used as described below to determine the ratio of the end tidal portion of the breath to the entire inspired air This ratio referred to as the duty cycle dc is used to convert the detected carbon monoxide concentration CO to the end tidal carbon monoxide concentration COzr as described below One suitable carbon dioxide gas analyzer
13. United States Patent Stone UTRUM RDUM US005293875A 11 Patent Number 45 Date of Patent 5 293 875 Mar 15 1994 54 IN VIVO MEASUREMENT OF END TIDAL CARBON MONOXIDE CONCENTRATION APPARATUS AND METHODS Robert T Stone Sunnyvale Calif Natus Medical Incorporated San Carlos Calif 21 Appl 899 261 75 Inventor 73 Assignee 22 Filed Jun 16 1992 51 Int CL5 teet A61B 5 00 52 US 128 719 128 204 22 128 205 23 58 Field of Search 128 716 719 204 22 128 204 23 205 22 56 References Cited U S PATENT DOCUMENTS 3 977 394 8 1976 Jones et al 128 2 07 4 423 739 1 1984 Passaro et al 128 719 4 831 024 5 1989 Vreman et al 514 185 4 968 887 11 1990 Wong sseereeeten 250 343 5 003 985 4 1991 White et al 364 413 08 OTHER PUBLICATIONS Yeung et al Automatic End Expiratory Air Sampling Device for Breath Hydrogen Test in Infants The Lan cet vol 337 pp 90 93 Jan 1991 Product Literature Z World Engineering Little Giant Mina ture Microcontroller One page Product Literature Servomex Mode 1505 Co Infra 15 RENE Fam 2 DETECTOR red Transducer borchure 2 pages and technical note 9 pages Product literature KNF Diaphragm Micro Pump Type NMP 02 2 pages Primary Examiner Lee S C
14. V NI c E meds a z 0l Db cl abl Jj T a INO J1dHVS 43114 Gb 90 dd VA JINV2u0 AQT fpi 9 7 0 1 80123130 L Sheet 2 of 10 5 293 875 Mar 15 1994 U S Patent WOILYSA JU311V8 1v311U3A 1VNOZINOH Quvog uoss3 0udOu2IH 150484 1 ROHIN cop Aove 3404 1931 1 8 WAIHI INVIO 111111 QUOR 2 UL nace Wwe MI pA Ef L Xu 145 9 fo op LL wen wa te 9 set c 4 L 310H 9 T 7 0812 114419 13804 ef wow3 SNIHOLIMS SuadHAr ANALNO YOLONONI 8111 3901 dvd GOS X3H0AU35 JWIYIINI 834118 3V0 ue QUA been 9h 64 dO SIN 91 140d 9f 1a Wud IAY ZAY ALT er ier ou32 Nes YIM 810 9 SAU qul nn paran 0 0 193 09 es 1 9 9NIJIM 0111 INANI 90 syny S8v5U zezsy OL Sheet 3 of 10 5 293 875 Mar 15 1994 U S Patent 61 140d W0 94 13100 JNN A3AIIQ INIT 0 WiN3S 25258 dWiid 3189 1N3 3 2H S433 ANI 2480 91V 31V8340 WONV 1V 83H11 y UHI Lavis 900H21VM YAYO QuvOBA 3 5IN3A3 O I 13534 NO 83M0d YJHILVASIO 9 INIA NOI LV Z WILIM S1N3A3 QIWI 034931519389 S1N3A3 0311 L0N 001 o SIN3A3 SINJA3 SINAJ H HION 3131408 N0L23130 T MM n 19 9 7 1N3A
15. Y 3413238 NIHOVW 31V1S 249 LIVM INIT WO3 tin ian 3101 INN W09 oll WKISY 3H u3L LINSNVUI W 3Q0HX JYO W15323H W300NX T 31 314 HIVINE gg AW1dSI0 097 AQVIY Sheet 7 of 10 5 293 875 Mar 15 1994 U S Patent 10 11 3 109 00 AG 2 AG 2 AS 1 338 09 110 Svig JNINUOM 09 Sheet 8 of 10 5 293 875 Mar 15 1994 U S Patent j da ap 42 9 4 DOM 20 T R 4 Mi Dig cu F0 pete Ezra cado Mer eme Porra er inea Cn d proc REN E M6 AG 2 dn yovea AN9 TWALUIA AG 2 Ee Hoe ey es o MENU NUT EIE e C E AC i aNd 4 3 9 2 0 U S Patent Mar 15 1994 Sheet 9 of 10 5 293 875 1 25 0 50 vco 0 00 0 25 t FIG 3A TIME B 1 25 0 50 Vc02 7 TIHE 13 FIG 3B 002 CONCENTRATION OR C02 MEAN EQUIVALENT 002 SensoR RESPonse PC 7 DUTY CYCLE ETCO2 E1602 ETCO2 3 jane FIG 4A CO CONCENTRATION OR IDEAL CO SENSOR RESPONSE ETCO3 U S Patent Mar 15 1994 Sheet 10 of 10 5 293 875 NN i AV ul CC SPRER END TIDAL CO MONITOR IMPEDANCE PNEUMOGRAPH FIG 5 5 293 875 1 IN VIVO MEASUREMENT OF END TIDAL CARBON MONOXIDE CONCENTRATION APPARATUS AND METHODS A portion of
16. al value based on the determined ratio of end tidal to inspired breath Preferably the most common interfering substances from a sampled breath are removed from the sample by a consumable filtration medium so that these substances do not affect the measurement The present invention also applies to gas components of exhaled breath other than carbon monoxide which gas components cannot be directly monitored because of the slow response time of avail able gas detectors One aspect of the present invention concerns using a second gas component of the breath other than the first gas component whose concentration is being moni tored to determine the ratio of the end tidal breath to inspired air The relative concentration level of the second gas during respiration is monitored and the ratio or duty cycle of the end tidal portion of the sensed concentration waveform relative to the inspired air is determined A sensor for detecting the level or concen tration of the second gas having a time response that is fast enough to distinguish the end tidal breath concen tration from the inspired air is preferably used One suitable gas component is carbon dioxide which has a large distinctive change in concentration with breath ing Other gases may be used e g hydrogen oxygen or some combination of gases e g carbon dioxide and hydrogen The determined end tidal carbon monoxide concen tration may be used by a physician or other suitable he
17. alth care provider to evaluate the rate or relative level of hemolysis occurring in the infant The evalua tion is typically made by comparing the determined end tidal carbon monoxide concentration to known or preselected standards For example when measured soon after birth the end tidal carbon monoxide range 0 6 1 9 is considered normal and the range above about 2 l l is considered at risk Premature infants have both a higher risk of neonatal jaundice and a higher normal range of end tidal carbon monoxide The present invention provides a tool for predicting the likelihood that the determined level of hemolysis will lead to adverse consequences such as jaundice and hyperbilirubinemia which might not appear for several days Thus the apparatus and methods of the present invention provide for reliable detection and early treat ment of the condition by an appropriate remedy and for monitoring the efficacy of the treatment BRIEF DESCRIPTION OF THE DRAWINGS The above and other objects and advantages of the invention will be apparent upon consideration of the following detailed description taken in conjunction with the accompanying drawings in which like refer ence characters refer to like parts throughout and in which 35 45 50 55 4 FIG 1 is a schematic block diagram of an apparatus for determining end tidal carbon monoxide concentra tion in accordance with the present invention FIG 2 is a diagram of a mul
18. blood The concentration of carbon monoxide in the end tidal breath i e the gas that is last expelled each breath is presumed to be at equilibrium with the concentration in the blood This is because the end tidal breath con tains predominantly if not exclusively the gas expelled from the alveoli in the lungs which gas was within the alveoli for a time generally sufficient to equilibrate with the blood It is known that hemolysis and the resulting by products and consequences of hemolysis can be esti mated or predicted from a measure of the concentration of carbon monoxide in the end tidal breath See Smith D W et al Neonatal Bilirubin Production Estimated from End Tidal Carbon Monoxide Concentration Journal of Pediatric Gastroenterology and Nutrition 3 77 80 1984 One method of analysis previously reported includes incrementally acquiring a sample of end tidal breath and analyzing the acquired sample by mass spectros copy or gas chromatography to determine the end tidal carbon monoxide concentration The sample is obtained by extracting from each of several successive breaths a portion of the apparent end tidal breath using a syringe The end tidal portion of breath is determined by observ ing the chest movements of the infant See e g Vreman et al U S Pat No 4 831 024 One problem With this technique is that it requires a skilled trained user to obtain the end tidal sample in successive increments based on wa
19. centration of car bon monoxide at a second rate during the first time period 38 The method of claim 37 wherein the first rate is on the order of 30 Hz and the second rate is on the order of 1 0 Hz 39 The method of claim 37 wherein the number of average samples is on the order of 5 40 The method of claim 37 wherein step c further comprises low pass filtering the samples of carbon mon oxide sensed during the first time period 41 The method of claim 25 further comprising con trolling a device having a first gas analyzer for perform ing step a prior to performing step b and providing a first delay period between the performance of steps a and b 42 The method of claim 41 further comprising pro viding a second delay period following step b each time it is performed and before step a is next per formed 43 The method of claim 42 wherein the second delay is on the order of from 1 to 3 minutes 44 The method of claim 42 wherein the first delay period is on the order of from 1 to 3 minutes 45 Apparatus for determining the carbon monoxide concentration in the end tidal portion of the exhaled breath flow of a patient comprising a carbon monoxide gas analyzer having a gas input for receiving a gas sample and a signal output CO representative of the measured concentration of carbon monoxide in the gas sample said carbon monoxide gas analyzer having a response time that is not sufficiently fast to distinguish th
20. centration of room air is approximately 0 and that the end tidal CO concentration is related to the duty cycle of the breath waveform and the mean value of the CO concentration namely CO z7 dc CO2 mean 5 Thus based on these assumptions the CO and CO2 ratios are COET CO2room CO2rmean de COET COroom CO2 mean ix CO room CO mean CO mean NE COroom and thus CO CO 6 dee et room 6 COmean ae COroom and the total end tidal COgris COmean COroam 0 COET de COroom 10 15 20 25 30 35 45 50 55 65 16 Therefore to obtain the patient s actual end tidal CO level produced the portion of the patient s breath from the CO oom concentration i e the CO level that was inhaled by the patient must be subtracted from the total which yields the equation 1 above The determined values are then displayed on display 90 and any desired printouts of the acquired data may be made or stored to a memory device or medium for subsequent analysis as desired The routine then exits the measuring sequence 120 and returns to the idle state at 110 The display preferably include the determined COe r e g in ppm and also may provide the duty cycle of the carbon dioxide waveform corresponding to the end tidal portion and or various voltages from the detectors 30 and 70 such as minimum and maximum voltages corresponding to CO and CO and initial and final vol
21. e dual operational amplifiers avail able from Precision Monolithics Inc Santa Clara Calif Amplifier U2B is configured as a current to volt age converter having a 0 1 uf capacitor C3 in parallel with a 50 resistor R1 in the feedback loop The gain is determined by resistor R1 Amplifier U1B is a second order lowpass filter with approximately a 0 5 second time constant using two 470 kQ resistors R2 and R3 and two pf capacitors C2 and C3 configured as shown The filter is used to attenuate electrical noise Amplifier U3B is configured as a simple amplifier with gain adjustment potentiometer R8 100 KQ in series with a 10 resistor R7 both of which are in parallel with a 0 1 uf capacitor C4 in the feedback loop and a 10 kQ input resistor R4 at the inverting amplifier input Potentiometer R8 is used to allow initial calibra tion to compensate for sensitivity variations in gas de tectors Amplifier U3B also has a secondary input from amplifier U1A which is configured as an adjustable voltage source that may be used to compensate for a zero gas output of detector 70 i Amplifier U3A is configured as a unity gain buffer designed to isolate the previous stages from any load effects that may imposed by following circuitry Amplifier U2A is configured as shown as an adjust able bias source for the counter electrode of detector 70 5 293 875 9 as determined by the setting of resistor R21 a 500 kN potentiometer A 10 0 r
22. e carbon monoxide concentration of the end tidal portion from other portions of a gas sample that is a patient breath flow a carbon dioxide gas analyzer having an input for receiving a gas sample and a signal output CO2 representative of the measured concentration of carbon dioxide in the gas sample said carbon diox ide gas analyzer having a response time that is sufficiently fast to distinguish the carbon dioxide concentration of the end tidal portion form other portions of a gas sample that is a patient breath flow means for analyzing the signal output CO2 over a given time period and determining a duty cycle for said signal output relative to a preselected signal parameter 10 20 25 30 40 45 50 55 22 first means for providing a room air gas sample flow to the carbon monoxide gas analyzer for a first duration so that the carbon monoxide gas analyzer signal output CO corresponds to a background carbon monoxide concentration second means for providing a patient breath flow gas sample flow of a second duration to the carbon monoxide gas analyzer and to the carbon dioxide gas analyzer wherein the carbon monoxide gas analyzer signal output CO corresponds to an aver age carbon monoxide concentration near the end of the second duration the preselected signal parame ter corresponds to the patient s end tidal carbon dioxide concentration and the analyzing means determines the duty cycle of the end tidal portion
23. e to acquire the appropriate gas samples Further display device 90 is preferably user interactive and includes both a keyboard for operator input and a visual display for prompting the operator to act Also the display device 90 may include a paper printer or have an associated printer not shown for providing a printed copy of the parameters determined and or measured in character text or graphic form Alternately or in addition audible sounds visual indi cators or lights may be used to prompt the operator to perform the appropriate act One suitable display device is a model LG LCD keypad liquid crystal display device available from Z World Engineering This device has definable function keys on a keyboard and a visual character display The visual display includes a 2 line by 16 character LCD The keyboard has a 4 x 4 keypad and a beeper for key pad feedback It is compatible with and directly inter faces with the Little Giant LG X miniature microcon troller l Referring to FIG 2 a printed circuit board layout of the Z World Little Giant microcontroller circuit board is illustrated and the interconnection of elements is de scribed using the manufacture s conventional pin con nections unless otherwise stated Referring to terminal board one or more AC DC regulated power supplies not shown are used to provide the following signals to the four numbered input pins of terminal TB1 12 volts to pin 1 ground poten
24. erating routine to step 120 Also during the idle state 110 the operator may press button 3 to select a sequence from a menu displayed on the display unit 90 and button 4 to display various operation sequences One such sequence is a calibration routine for calibrating the carbon monoxide detector 70 and carbon dioxide detector 30 at step 130 The opera tor also may press button 2 at any time to exit what ever routine it is executing reset the apparatus and return the routine to step 100 Referring to FIGS 2A and 2B in response to press ing button 1 in the idle state 110 the routine moves from the idle step 110 to step 120 for the sequence for determining end tidal carbon monoxide concentration COgr There are three phases to this determination a sequence at step 121 for measuring the background carbon monoxide CO during a first time period a pause or delay period at step 122 and a sequence at step 123 for measuring breath carbon dioxide CO and car bon monoxide CO during a second time period In the present invention before each sample is ob tained pump 60 is off for a delay time period This allows the CO detector to return to a zero state so that effectively no CO is in the sample cell When desired a supply of inert gas may be provided and pump 60 acti vated for a time to clear the sample cell of any CO and CO gas A three way valve and an actuator may be included not shown to achieve this cell clearing func
25. esistor R22 provides a means of r ading the bias voltage without making direct contact with the gas detector connections The CO detector amplifier circuit 82 operates as a low power supply voltage to prevent excess leakage currents from impos ing undesirable bias currents on the detector 70 and to allow low power continuous biasing of the detector 70 to allow for stable operation Preferably amplifiers U2A and U3A also are type OP 290 amplifiers In the circuits illustrated in FIGS 2E and 2F all ground con nections are to a virtual ground which is provided by a CO amplifier power supply circuit 83 Referring to FIG 2F the CO amplifier power supply and interface circuit 83 is shown The power supply consists of a normal supply B1 and a backup supply B2 Normal supply B1 may be any nominal 12 volt DC power supply In one preferred embodiment nor mal supply B1 is a regulated power supply derived from AC mains Alternately two 12 volt batteries e g re chargable batteries could be used Devices Q3 and Q4 are integrated circuit regulators types LM78L05 and LM79L05 with provide 5 volts respective for powering the interface amplifier BUI1A Diodes D1 and D2 IN4148 type diodes auto matically switch to supply to the CO amplifier BU1A the greater of the normal 12 volt DC supply Bia and the backup battery B2 an alkaline 9 volt battery Device Q1 regulates the supply voltage to 5 volts Device Q2 is an integrated circuit
26. ferring to FIG 1 the macro flow diagrams of FIGS 2A to 2D and the software appendix attached hereto a preferred embodiment of the operation of the present invention is now described In this embodiment display device 90 is configured to use four buttons which are used for controlling the operation of the 20 25 30 45 50 55 65 12 apparatus Button 1 is a start button to initiate some action by the apparatus to reset the apparatus operation button 2 is a reset button button 3 is a select button to select some option from a menu and button 4 is a menu button to display one or more instruction and or operation menu Each button is activated by pressing in and then releasing the button Other alternatives for providing user input in an interactive device may of course be used Referring to FIG 2A the device becomes activated on power on or reset pressing button 2 and enters an initialization sequence at step 100 During initialization the operating code of microcontroller 80 is booted and various system checks and device initializations are performed Following initialization the routine passes to an idle state at step 110 where it waits for user input During the idle state the system preferably generates a suitable message on display 90 e g Ready press 1 to start Thus during the idle step 110 the user may provide an input by pressing button 1 to start a mea suring sequence This passes the op
27. g means for deter mining a end tidal concentration of the first gas in response to the determined duty cycle the deter mined background concentration of the first gas in room air and the determined breath sample con centration of the first gas in the patient s breath 2 The apparatus of claim 1 wherein the first gas is carbon monoxide the first gas detector detects the con centration of carbon monoxide and the first receiving and determining means determines the end tidal con 40 centration of carbon monoxide 60 65 3 The apparatus of claim 1 wherein the first monitor ing and determining means further comprises a second gas detector for monitoring an concentra tion of a second selected gas in the patient s breath other than the first selected gas and having an out put corresponding to the second selected gas con centration and second means for receiving the output of the second gas detector and for determining the duty cycle as the ratio of the end tidal portion of the second gas in the patient s breath to the patient s breath based on monitored relative changes in the sensed con centration of the second gas 4 The apparatus of clam 3 wherein the second gas detector further comprises a carbon dioxide gas analy zer 5 The apparatus of claim 3 wherein the second pro viding means further comprises means for passing the sample of the patient s breath to the first and second gas detectors wherein the second gas detec
28. gned and Sealed this Second Day of September 1997 Attest VS nce lehwu BRUCE LEHMAN Attesting Officer Commissioner of Patents and Trademarks
29. he display 90 interface pins J10 are connected as follows Pin J10 10 are the common front pane buttons pin J10 12 is for button 1 pin J10 14 is for button 2 pin J10 16 is for button 3 and pin J10 18 is for button 4 Regarding the Servomex model 1505 circuit board it is connected as follows For device Power pin PL1 1 is connected to TB1 1 12 v pin PL1 2 is not con nected pin PL1 3 is connected to TB1 2 ground pin PL1 4 is connected to TB1 3 5 v For device Thermistor Status pins PL2 are not connected For device Nitrous Oxide Compensation pins PL3 1 and PL3 2 are jumpered and no other pins are connected For device Signal Output pins PL4 1 is connected to Little Giant pin J4 3 and pin PL42 is connected to Little Giant board J4 4 For device Remote Calibration Adjustment there are no pin connections According to a preferred embodiment of the present invention the end tidal carbon monoxide concentration of the patient is measured in the following manner An initial value of carbon monoxide may be obtained for analysis purposes Pump 60 is then started and a sample of room air is drawn through the segments of tubing 14a 14g at the selected flow rate of e g 50 ml min past the carbon dioxide detector 30 and the carbon monoxide detector 70 At the end of a first time period e g 45 seconds the measures of the concentrations of the carbon dioxide and carbon monoxide in the sample celis of the carbon dioxide sens
30. in more preferably 50 ml min This provides for withdrawing continuously a gas sample either from room air or from the patient s posterior nasal pharynx depending on placement of the cannula 10 including expired and end tidal breath for patients having a breathing rate of from 10 to 90 breaths per minute The flow regulator 50 provides for limiting the flow rate of the analyte gas stream and the pump 60 provides for sampling the gas sample room air or breath such that pump 60 is driven against the flow rate limit set by flow regulator 50 This maintains a constant flow rate for the analyte stream and avoids any flow surges due to a patient s inhalation or expiration One suitable flow regulator is orifice needle valve model F 2822 41 B80 55 available from Air Logic Racine Wis which can be adjusted to obtain the desired gas flow rate in the range of 40 60 ml min One suitable pump is model NMP 02 diaphragm micro pump available from KNF Neu berger Inc Princeton N J which has a free flow ca pacity of 0 22 to 0 55 L min Pump 60 and flow regula tor 50 may be located anywhere in the flow stream preferably between the carbon dioxide detector 30 and carbon monoxide detector 70 inside the enclosure of base 5 Pump 60 also passes the analyte flow stream out exhaust 75 downstream of the gas detectors 30 and 70 of the apparatus Carbon monoxide detector 70 is preferably an elec trochemical sensor that produces an electrical current p
31. ing methods and analysis tech niques for measuring the concentration of end tidal carbon monoxide in breath particularly in newborn and premature infants Broadly the invention concerns de termining the concentration of end tidal carbon monox ide based on a measure of the room air carbon monoxide concentration a measure of the average carbon monox ide concentration for a breath sample over a period of time and a determined ratio of the end tidal breath to inspired air for the sampled portion The present invention is based in part on the discov ery that accurate assessment of end tidal carbon monox ide concentration may be obtained based on knowledge of the fraction of the gas sample that is end tidal gas Thus the present invention is able to avoid selectively 5 293 815 3 sampling small samples of end tidal breath over succes sive respiratory cycles to obtain a sufficiently large end tidal breath sample which incremental sampling is problematic Further the invention advantageously uses a conventional carbon monoxide detector which has a response time that is not fast enough to distinguish carbon monoxide in end tidal breath from carbon mon oxide in inspired air to derive the end tidal carbon monoxide concentration in real time More particularly a conventional carbon monoxide detector can be used to obtain the average carbon monoxide concentration level during breathing which average value can be related to the end tid
32. ion COmom from detector 70 that is dis played also may be displayed for diagnostic purposes The CO and CO gas equations used to convert the sampled voltage signals corresponding to the detector signal outputs to gas concentrations are CO ppm m vco ci 2 CO296 m vcan 2 3 where m and c are the slope and intercept calibration constants relating the voltage vco derived from the CO detector 70 output in response to the concentration of carbon monoxide in a sample to ppm and m and c are the slope and intercept calibration constants relating the voltage vcoo derived from the CO detector 30 output in response to the carbon dioxide concentration in a sample in percent Thus at time to with CO 0 ppm using the above equation 02m vco c and Q 1 ci m vco o 2 2 where vco o corresponds to the signal produced by CO detector 70 at time to At time 11 COroomppm miVco 1 ci 2 3 myVco myWco o 2 4 m Vco 1 Vco o 2 5 where vco 1 corresponds to the signal produced by CO detector 70 at time tj When pump 60 is stopped at time t at the conclusion of the background step 121 the CO is measured and the routine enters pause step 122 During the pause step 122 the operator is prompted to place the nasal cannula 10 inside the patient s nostril and then to press button 1 to resume the measurement sequence The system prefera bly displays a suitable message on display 90 e g place na
33. is the com mercially available Servomex model 1505 fast response carbon dioxide infrared transducer which is available from Servomex Company 90 Kerry Place Norwood Mass 02062 This device is a temperature compensated sealed transducer that is based upon a single beam sin gle wavelength technique absorption for measuring carbon dioxide It has a complete optical bench and uses a fast infra red carrier which is attenuated by the infra red absorption of carbon dioxide in the gas The device has detection circuitry that will convert fast changes of attenuation into an electrical output signal The Servomex model 1505 transducer is used in ac cordance with the manufacturers directions and specifi cations It provides under constant conditions a linear output voltage of from 0 to 1 0 volts corresponding to from 0 to 10 carbon dioxide and is extendable up to 1 5 volts corresponding to 15 carbon dioxide The response time is on the order of 120 ms at a flow of 100 ml min and the flow rates may be in the range of from 50 200 ml min Other carbon dioxide measuring de vices also could be used It should be understood that any device that is capa ble of determining the duty cycle of end tidal breath to inspired air over a given period of time may be used in place of the carbon dioxide detector provided that the determined duty cycle is for the same period of time during which the sample on which the carbon monox ide concentration dete
34. l results in a relatively slow response time such that discrete samples of the end tidal breath must be obtained and analyzed to determine the end tidal carbon monoxide concentration SUMMARY OF THE INVENTION It is therefore an object of the present invention to provide improved non invasive apparatus and methods for measuring carbon monoxide concentration in the end tidal breath It is another object to provide appara tus and methods that operate in real time It is another object to provide apparatus and methods for use in determining the rate of hemolysis from the concentra tion of end tidal carbon monoxide It is another object of the present invention to pro vide apparatus and methods for measuring end tidal carbon monoxide that do not require a highly skilled trained individual to obtain and determine the measure It is another object to provide such apparatus and meth ods that do not require incrementally acquiring samples of end tidal breath during successive respiratory cycles It is another object of the invention to provide a portable easy to use apparatus that can be used in a nursery a physician s office a hospital a clinic and a mobile clinic for measuring end tidal carbon monoxide in real time for assessing the likelihood of elevated levels of hemolysis for immediate entry on the patient s record and prescription of an appropriate remedy In accordance with this invention there is provided an apparatus sampl
35. nd gas detector is a carbon dioxide gas analyzer 18 The apparatus of claim 5 wherein the first gas detector is a carbon monoxide gas analyzer and the second gas detector is a carbon dioxide gas analyzer 19 The apparatus of claim 2 wherein the first gas detector detects the room air carbon monoxide concen tration in response to the first providing means and an average concentration of carbon monoxide in the pa tients breath in response to the second providing means 20 The apparatus of claim 19 wherein the first receiv ing and determining means determines the end tidal carbon monoxide concentration based on the room air 25 30 35 45 50 55 a 65 20 concentration the average concentration and the duty cycle 21 The apparatus of claim 1 further comprising an interactive keyboard and display associated with the first and second providing means 22 The apparatus of claim 1 wherein the second providing means provides a sample of the patient s breath for a first time period so that the first gas detec tor provides a signal corresponding to an average con centration of the first gas 23 The apparatus of claim 1 wherein the first means for monitoring breathing further comprises an impe dance sensor for coupling the patient for sensing changes in impedance with the patient s respiratory activity 24 The apparatus of claim 1 wherein the first means for monitoring breathing further comprises a spirome te
36. ohen Assistant Examiner Robert L Nasser Attorney Agent or Firm David Hoxie Faithfull amp Hapgood 57 ABSTRACT A noninvasive device and methods for measuring the end tidal carbon monoxide concentration in a patient s breath particularly newborn and premature infants The patient s breath is monitored An average carbon monoxide concentration is determined based on an av erage of discrete samples in a given time period The ratio of the end tidal portion of the breath flow sample is separately determined preferably based on monitor ing the level of carbon dioxide in the gas sample and identifying the carbon dioxide concentration levels cor responding to the end tidal portion of the breath sam ple The sensed carbon monoxide level is converted to the end tidal carbon monoxide level by subtracting the ambient carbon monoxide level and dividing the re mainder by the ratio of end tidal breath to breath in the breath sample An easy to use microcontroller based device containing a carbon dioxide detector a carbon monoxide detect and a pump for use in a hospital home physician s office or clinic by persons not requiring high skill and training is described 50 Claims 10 Drawing Sheets ORGANIC VAPOR FILTER 14d INFANT BREATH i SAMPLING TUBE HYDROPHOBIC FILTER 12 5 293 875 Sheet 1 of 10 Mar 15 1994 US Patent 0 i N el 3 4 D NI D QISQHdOUGAH Y ny oz Jan INITAWYS a nuno 34g 1N
37. or 30 and carbon monox ide sensor 70 are obtained respectively The measures are obtained as analog signals from the detectors 70 and 30 e g sensed currents converted to conditioned volt ages vcoand vcq2 which are respectively digitized into n bit words n is preferably 8 at selected sampling rates and passed into a data buffer and or memory The val ues are stored as COpoom and COdzero Pump 60 is then turned off and the cannula 10 is placed in the patient s nostril preferably in the posterior nasal pharynx Then the pump 60 is turned on again and an analyte stream of breath is drawn past the respective gas detectors 70 and 30 The concentrations of carbon monoxide and carbon dioxide are respectively sensed and sampled during a second time period e g 45 sec onds The acquired measures of the carbon dioxide concen tration over the second time period are evaluated First the relative changes in the carbon dioxide concentration are evaluated to determine the duty cycle correspond ing to the end tidal portion of the patient s breath An average of the end tidal CO concentration CO gr to the average CO is obtained providing the duty cycle dc The end tidal CO concentration COr7 is then determined from the following relationship COgr CO meon COroon dc i where COmean is the average or mean carbon monoxide concentration at the end of the second period and dc is the duty cycle determined for Re
38. r 25 A method of measuring end tidal carbon monox ide concentration in expired breath comprising the steps of a measuring a carbon monoxide concentration in ambient room air CO oom b sampling a patient s breath over a first period of time c measuring the carbon monoxide concentration CO in a sampled patient s breath during the first time period d determining a duty cycle of an end tidal portion of the patient s breath during the first time period and e determining an end tidal carbon monoxide level based on the determined duty cycle the measured COroom and the measured CO 26 The method of claim 25 wherein the step e fur ther comprises subtracting the measured CO oom from the measured CO and dividing the difference by the determined duty cycle 27 The method of claim 25 wherein step a further comprises passing a stream of room air through a car bon monoxide detector during a second time period and measuring the CO oom corresponding to the room car bon monoxide concentration 28 The method of claim 27 wherein step a further comprises measuring an average of the CO concentra tion in ambient room air over a second period of time 29 The method of claim 28 further comprising mea suring the CO as an average of a first number of discrete average samples obtained at the end of the first time period 30 The method of claim 25 wherein step d further comprises determining the duty cycle based on the
39. responding average or mean CO concentration at time t3 CO mean is thus COmean Mm Vg ci 4 where V is the average of the last five voltage samples VCO The duty cycle dc is calculated based on analysis of the sampled voltages vco between time 12 and t5 as follows the number of CO samples gt Vj dc total number of CO samples the number of CO samples gt 1 5 total number of CO samples where V is a selected threshold voltage corresponding to e g a 1 5 CO concentration and is obtained from the CO gas equation 3 as follows 1 5 m Vite V 1 5 c 2 m2 For an ideal CO detector 70 m2 10 and c2 0 such that V 0 15 volts Of course other values and thresh old voltages could be used as appropriate in the particu lar circumstances Then the patient s end tidal CO concentration COET is COET COmean COro0om de 1 This may be calculated in a straightforward manner from the acquired data The foregoing equations are based on the realization that the physical behavior of CO and CO are very similar with respect to for example diffusion flow rates and other behavior characteristics in the patient s cardiopulmonary system Accordingly it can be as sumed that ratio of the end tidal CO portion to the total CO portion is the same as the ratio of the end tidal CO portion to the total CO portion This is illustrated in FIGS 4a and 4B Further it can be assumed that the CO con
40. rmination is based was acquired Such a device may be a spirometer 600 for measuring flow velocity or flow volume a non breath flow device 500 for monitoring breathing e g an impedance pneu mograph a microphone sensor and the like See FIG 5 which shows the conventional locations of spirome ter 600 and an impedance pneumograph type non flow breath monitor 500 the latter of which surrounds the patient s body to produce a signal that varies as the patient s body varies with breathing Also a breath gas detector for monitoring a breath gas other than carbon dioxide may be used The carbon dioxide detector is preferred because changes in CO concentrations related to end tidal flow are relatively large and easily detectable using a thresh old level of carbon dioxide Further the same sample of breath can be used to determine the carbon monoxide and carbon dioxide concentrations without affecting the sample particularly when the sample stream is passed 5 20 25 40 45 55 60 6 through an infrared absorption type carbon dioxide detector prior to an electrochemical cell type carbon monoxide detector In addition the use of an exhaled gas carbon dioxide or another provides a non intrusive and non invasive technique for determining the duty cycle dc It does not require an additional or alternate sensor or transducer on or near the patient and it does not require additional patient cooperation or discom for
41. roportional to the concentration of reducing gases such as carbon monoxide which are present in the gas at the gas permeable membrane of detector 70 not shown The response time of the carbon monoxide detector 70 and the averaging function of the filter 45 preferably result in a signal output from the detector 70 that is proportional to the average concentration of the reducing gas at the membrane One suitable carbon monoxide sensor is model Drag erSensor CO available from Dragerwerke of Lubeck Germany It has a plastic gas permeable membrane a liquid electrolyte sensing reference and counter elec trodes in the electrolyte and a potentiostatic circuit that maintains a constant voltage between the sensing and 5 15 20 25 30 35 40 45 50 60 65 8 reference electrodes The carbon monoxide in the gas is electrochemically converted at the sensing electrode which produces a current proportional to the carbon monoxide partial pressure The device is temperature compensated It has a concentration sensitivity in the range up to 500 ppm and provides an output current of 0 13 0 4 LA ppm and requires about 20 seconds to equilibrate fully with the gas sample being monitored it has a reaction half life of ten seconds Microcontroller 80 is used to control the operation of the apparatus Microcontroller 80 receives signals re lated to the output signals from carbon dioxide detector 30 and carbon monoxide detec
42. s determines the duty cycle based on the sampled signals that are above and below the selected threshold 12 The apparatus of claim 11 wherein the second receiving and determining means determines the duty cycle based on the number of sampled signals above the selected threshold 13 The apparatus of claim 12 wherein the second receiving and determining means determines the duty cycle based on the ratio of the number of samples above the threshold and the number of samples 14 The apparatus of claim 11 further comprising second means for periodically sampling the output of the first gas detector corresponding to the sensed concentration of the first gas during the first se lected time period and means for providing a first signal corresponding to an average of a selected number of sampled second signals near the end of the first period 15 The apparatus of claim 14 wherein the first time period is on the order of 45 seconds the first sampling means samples the second gas detector output on the order of 30 Hz the second sampling means samples the first gas detector output on the order of 1 0 Hz and the selected number of sampled second signals is on the order of 5 16 The apparatus of claim 14 wherein the first gas detector is a carbon monoxide gas analyzer and the second gas detector is a carbon dioxide gas analyzer 17 The apparatus of claim 11 wherein the first gas detector is a carbon monoxide gas analyzer and the seco
43. sal cannula to prompt the user to place the cannula 10 The pause step 122 preferably includes a minimum delay period Timeout of about ten seconds and a maximum delay period Timeout of about five minutes Thus if the operator does not press the start button 1 within the Timeout period the system will return to the idle state 110 The Timeout period is used to provide for sampling the room air and patient carbon monoxide concentrations within a time period wherein it is not likely that the room air concentration level will change very much The Timeout period also is selected to permit the operator sufficient time to insert the nasal cannula 10 in a patient such as a newborn infant which may require some time to accomplish Once the cannula 10 is place the operator presses button 1 to resume the measurement sequence 123 At time t pump 60 is turned on for a second time period which is preferably the same as the first time period i e 45 seconds Initial CO and CO samples may be ob 15 30 35 45 60 65 14 tained for analytical purposes During this second time period the display 90 preferably displays a suitable message corresponding to the duration of the measuring test e g how much time remains to complete the test in seconds or in percent At time t3 at the end of the second time period pump 60 is turned off During the second time period the signals corre sponding to the CO concentration obtained from
44. t Furthermore using one time sample of breath to determine the duty cycle of end tidal breath is more accurate than visually monitoring chest wall movement or respiratory activity over a period of breathing cycles or relying on a predetermined breathing rate which are subject to change and attempting to obtain samples of exhaled breath only during end tidal portions Other gas sensors may be used e g oxygen which would have a relatively reduced concentration level during end tidal breath or hydrogen which would have a relatively increased concentration level during end tidal breath Two different gas detectors e g car bon dioxide and hydrogen could be used to identify the end tidal portion wherein carbon dioxide provides a fast response and hydrogen provides a slow response to changes in concentration Another advantage of the invention with respect to relying on changes in gas concentration levels is that the measurement decouples the breath gas concentrations from rhythmic respiratory activity In other words pump 60 may be used to provide a gas flow rate through cannula 10 and the flow path that is greater than the patient s respiratory flow This in turn provides an end tidal waveform stretching that enhances evalua tion of the gas concentrations and determination of the end tidal portion of the breath based on a breath gas It also provides for synchronization between the respira tory activity corresponding to the end
45. tages for COmean and or CO during the second time period It is noted that in connection with the second time period for monitoring the patient s breath ing the time references to and t may be used in place of time references t and 1 respectively Preferably the data from the measurement cycle just finished will remain displayed for a period of time to allow the operator to record manually the data The display 90 may be cleared by pressing button 1 or reset 2 Following measurement of a sample the aforementioned delay time period of about one minute or three minutes is provided to allow the CO and CO detectors 70 and 30 to decay to a zero state before the next background measurement cycle begins Preferably any attempt to obtain another measurement before the end of the delay period will be simply delayed until the expiration of that time and then automatically com mence Referring to FIGS 2A and 2C the CO and CO detectors 70 and 30 are periodically calibrated using conventional CO and CO gases having known concen trations To begin the calibration sequence 130 the system must be in the idle state 110 The operator then presses button 4 to call the menu up on display 90 The menu will display an appropriate message such as menu 1 Calibrate CO CO2 sensor Activate button 1 to start The operator then presses button 1 which begins the calibration sequence 130 The calibration sequence involves the selection of test
46. tching chest wall movements It also requires a trained skilled person to operate a complex piece of analytical laboratory equip 30 35 40 45 50 55 65 2 ment to analyze the acquired sample In addition this technique requires time and personnel to transport the sample from the patient to the laboratory or equip ment where the analysis is conducted and then to report back to the attending physician practitioner for a diagnosis and prescription if any Another problem with this technique is that accurate assessment of the concentration difference in carbon monoxide requires obtaining good samples of end tidal patient breath This essentially requires that the patient have a regular predictable breathing cycle Thus it can be difficult to obtain a good sample by watching chest wall movement particularly for a newborn and for patients having irregular breathing cycles Chemical electrochemical sensors capable of measur ing carbon monoxide concentrations in the range of interest 0 to 500 parts per million ppm are commer cially available e g model DragerSensor CO available from Dragerwerk Lubeck Germany However such sensors are sensitive to many other gases as well as carbon monoxide and are therefore susceptible to er ror Another problem with such sensors is that the mea surement dynamics of the sample gas transport through the gas permeable membrane and oxidation reduction in the electrochemical cel
47. tem failures Any terminal device such as a portable computer equipped with a suitable communication pro gram such as BITCOM or PROCOMM will automati cally be able to receive the data files at 9600 baud for the examination and evaluation Set forth as a software appendix hereto is a program code listing of software written in Z World Dynamic C language for operating the Little Giant multipurpose microcontroller and the Little Giant LG LCD display device and the above identified CO and CO detectors and pump Implementation of the present invention in alternate microprocessor controlled devices analog circuit controlled devices and finite state machines with appropriate controlling software integrated and or discrete circuit elements and logic circuits is be lieved to be within the ability of a person of ordinary skill in the art One advantage of the present invention that it pro vides a simple and easy to use device that accurately and relatively quickly obtains a measure of the end tidal carbon monoxide concentration of a patient The deter mination is made immediately following acquisition of the breath sample and is thus performed in real time It overcomes the above noted problems of the prior art techniques The present invention is particularly useful for detecting abnormal levels of hemolysis in newborn and premature infants as well as determining incipient hyperbilirubinemia elevated levels of bilirubin the likelihood
48. ter timers includ ing a 2 Hz watchdog timer for automatically resetting the microprocessor in the event of undefined operations or temporary power loss serial input output ports parallel input output ports time and date clocks multi channel analog to digital converter a digital to analog converter operational amplifiers for input signal condi tioning in single ended or double ended modes adjust able gain and input voltage ranges a high current driver output suitable for driving pump 60 and other particu oma 5 20 35 40 45 60 65 10 lar elements provided by the manufacturer which either are used in a conventional manner although not perti nent to the present invention or are not used The mi crocontroller is used in accordance with the manufac turer s directions and specifications except as otherwise noted and reference is made to the user manual for the device entitled Little Giant Single Board Computer Technical Manual Version E which is available from the manufacturer for information regarding configur ing and implementing use of the microcontroller The display device 90 is capable of providing a dis play corresponding to the determined carbon monoxide concentration level in the end tidal breath COzr Pref erably display 90 includes a display screen for alphanu meric text including the determined COzr concentra tion and preferably instructions to the operator for operating the devic
49. the disclosure of this patent document contains material which is subject to copyright protec tion The copyright owner has no objection to the fac simile reproduction by anyone of the patent disclosure as it appears in the Patent and Trademark Office patent files or records but otherwise reserves all copyright rights whatsoever FIELD OF THE INVENTION This invention relates to methods and apparatus for in vivo real time measurement of end tidal carbon monoxide concentration in the exhaled breath more particularly the determination of end tidal carbon mon oxide concentration in the breath of a newborn infant BACKGROUND OF THE INVENTION In most animal systems carbon monoxide is a waste product produced in the breakdown of free hemoglobin within the blood Ordinarily hemoglobin is contained 20 within red blood cells and is stable However aging of 25 red blood cells and certain disease processes produce hemolysis i e the breakdown of the cell wall This produces free hemoglobin which breaks down in the blood The carbon monoxide that is produced by the breakdown of free hemoglobin is normally excreted in the breath When the system is in equilibrium the carbon monox ide concentration in the breath is proportional to the difference in the concentration of carbon monoxide in the blood and the concentration of carbon monoxide in room air This difference in concentration is propor tional to the rate of hemolysis in the
50. tial to pin 2 5 volts to pin 3 and 12 volts to pin 4 The corresponding four output pins of terminal board TBI designated TB1 X wherein X refers to the output pin are respectively connected in series with the input pins of TB1 and the pins of the apparatus illustrated in FIG 1 as follows Regarding microcontroller 80 the high current out put wiring connectors J1 have pin J1 8 connected to the negative terminal of pump 60 for providing a current to drive pump 60 at the selected rate There are no other connections for wiring connectors J1 The power wir ing connectors J2 have pin J2 1 connected to J2 4 pin J2 2 connected to J2 3 pin J2 6 connected to FB1 2 ground pin J2 7 connected to TB1 4 12 v and no other J2 pin being connected The RS485 field wir ing connectors J3 are not used in this embodiment The analog input field wiring connectors J4 have pins J4 1 and J4 2 connected to amplifier interface board pins J2 1 and J2 2 respectively pin J4 3 connected to pin PL4 1 on the Servomex 1505 board and pin J4 4 connected to pin PL4 2 on the Servomex model 1505 board Analog input pins J5 RS232 port pins J7 and RS485 program pins J9 are not used The pins at key board interface J6 are used to connect a flat ribbon 5 293 875 11 cable to the back panel of the display 90 LCD display device model LG LCD The pins J8 for the RS232 port are connected on the back panel to a conventional nine pin D sub connector T
51. tidal portion based on carbon dioxide and the detection of carbon monoxide concentration in the same breath sample flow Consequently the carbon monoxide concentra tion may be calculated based on post data acquisition processing analysis of the last acquired sample As a result the end tidal carbon monoxide determination is effectively provided in real time and without the delay occasioned by the previously reported techniques In addition the present invention avoids reliance on a previously established breathing cycle or rate to predict when chest wall movement coincides with end tidal flow Instead the invention is completely responsive to changes in the patient s breathing rate and volume as the sample is acquired The prior known techniques are not The gas flow output 40 of detector 30 is in turn con nected to a piece of tubing 14 and passed through connector 160 into tube segment 14d Tube segment 14d contains an organic vapor filter 45 Filter 45 may con tain any medium that will absorb organic vapors and reducing gases that might interfere with detecting car bon monoxide levels in the carbon monoxide detector 10 Filter 45 preferably contains activated charcoal It is preferably constructed as a canister that either can be inserted interior to the flow path of tube 14d or is in serted between two segments of tubing such that the analyte gas stream passes through the canister Filter 45 illustrated in FIG 1 connected between
52. tion The delay time period is at least about one minute more preferably three minutes In the background measurement sequence step 121 the user is prompted to place the end 11 of cannula 10 somewhere in the vicinity of the patient but not inside the nostri and then to press button 1 In response to pressing button 1 pump 60 is activated at time to and the background room air is drawn through tubing 14 and during a first time period of approximately 45 sec onds During this time display 90 preferably displays a suitable message corresponding to the duration of the background measuring test e g how much time re mains to complete the test in seconds or in percent At time 11 at the end of the first time period pump 60 is turned off The carbon monoxide concentration in the sample cell of the carbon monoxide detector 70 is then determined and recorded in memory as noted the carbon monoxide gas detector has a time 5 293 875 13 response to the analyte flow that produces an average carbon monoxide concentration As set forth in the software appendix hereto the digitized samples corre sponding to the carbon monoxide concentration are processed so that the output signal is the average of the last five acquired samples Preferably the determined concentration value is displayed e g in parts per mil lion ppm The amplitude of the voltage signal vco corresponding to the averaged sensed carbon monoxide concentrat
53. tipurpose microcon troller board for controlling the device in FIG 1 FIGS 2A 2D are macro flow diagrams for the over all breath measurements calibration and data commu nication operations of the apparatus of FIG 1 FIGS 2E and 2F are circuit schematic diagrams for a signal conditioning amplifier and a power supply re spectively for interfacing the carbon monoxide sensor of FIG 1 and the microcontroller circuit board of FIG 2 FIGS 3A and 3B are graphical illustrations of mea surements of carbon monoxide carbon dioxide concen trations acquired using the device of FIG 1 and FIGS 4A and 4B are graphical illustrations of the carbon monoxide and carbon dioxide concentrations in a representative breath flow and FIG 5 is a schematic block diagram of an apparatus for determining end tidal carbon monoxide concentra tion in accordance with alternate embodiments of the present invention DETAILED DESCRIPTION OF THE INVENTION Referring to FIG 1 a preferred embodiment of the present invention relates to methods and apparatus for monitoring breath flow of a patient over a period of time and determining the end tidal concentration of carbon monoxide in the breath The apparatus includes a nasal cannula 10 a carbon dioxide detector 30 an organic vapor filter 45 a flow regulator 50 a pump 60 a carbon monoxide detector 70 and a microcontroller 80 Preferably a hydrophobic filter 15 is provided be tween the cannula 10 and
54. tor 70 corresponding to the sensed instantaneous carbon dioxide concentration and sensed average carbon monoxide concentration respectively These received signals are processed to compute a value corresponding to the end tidal carbon monoxide concentration in the patient s breath as de scribed below The computed value may then be dis played on a display 90 such as a liquid crystal display device Preferably a conventional digital microcontroller system is used having a suitable software controlled microprocessor memory analog to digital conversion and signal conditioning functions Of course as will be apparent to persons of ordinary skill in the art discrete analog circuit elements and solid state finite state ma chines also may be used to control the operation of the elements and obtain the concentration measurement One suitable digital microcontroller is the model Little Giant LG X miniature microcontroller available from Z World Engineering Davis Calif The mi crocontroller 80 is connected to carbon dioxide detec tor 30 carbon monoxide detector 70 pump 60 and flow regulator 50 if one is used to operate and or receive signals from those devices An amplifier interface cir cuit 82 is used to provide for current to voltage conver sion of the signals provided by carbon monoxide detec tor 70 Referring to FIG 2E interface circuit 82 includes three amplifiers U1B U2B and U3B which are prefera bly OP 290 low nois
55. tor monitors changes in the concentration of the second gas in the patient s breath over time 6 The apparatus of claim 5 wherein the passing means further comprises a pump and a flow path the flow path connecting the first and second gas detectors in gaseous communication and the pump passing a gas sample therethrough 5 293 875 19 7 The apparatus of claim 6 wherein the second pro viding means turns the pump on for a selected first time period 8 The apparatus of claim 6 wherein the first provid ing means turns the pump on for a first selected time period and the first gas detector detects the room air concentration of the first gas 9 The apparatus of claim 8 wherein the second pro viding means turns the pump on for a second selected time period following the end of a first time period 10 The apparatus of claim 8 wherein the first provid ing means turns the pump on for on the order of forty five seconds and wherein the second providing means turns the pump on for on the order of forty five sec onds 11 The apparatus of claim 7 wherein the second receiving and determining means further comprises first means for periodically sampling the output of the second gas detector corresponding to the sensed concentration of the second gas during the first selected time period and 15 20 comparator means for comparing the sampled signals to a selected threshold wherein the second receiving and determining mean
56. two connectors 165 and 16c so that it is external to base 5 This provides for simple and quick replacement of filter 45 when it is 5 293 875 7 substantially consumed Filter 45 may be an inexpensive disposable portion of the apparatus One advantage to using filter 45 is that it tends to average the concentrations of gas in the analyte stream by thoroughly mixing the stream within the volume of filter 45 A preferred construction of filter 45 is to use a 20 mm length of charcoal rod having a circumference of 24 4 mm which is sandwiched between 3 0 mm seg ments of white acetate having the same circumference The charcoal rod is preferably cut from Filtrona AAD Charcoal Filter Rods available from American Filtrona Corp Richmond Va Where desired more than one carbon rod segment may be used provided that pump 60 has sufficient power to pass the analyte gas stream therethrough Flow regulator 50 and pump 60 are inserted prefera bly in tandem as illustrated in FIG 1 into or between segments of tubing 14 to maintain a desired constant fiow velocity of the analyte stream Flow regulator 50 is interposed between tubing 14e which is connected to connector 16c and tubing 14 which is connected to pump 60 Pump 60 is in turn interposed between tubing 14f and tubing 14g which is connected to carbon mon oxide detector 70 Preferably pump 60 and flow regulator 50 are ad justed so that the flow is maintained at from 40 to 60 ml m
57. using the Little Giant LCD dis play device select button 3 is used to toggle a digit that is underscored on the display screen menu between values to display the known gas concentration value The menu button 4 is used to move the underscore along the displayed characters for selecting the charac ter to be changed Start button 1 is used to indicate that the character now displayed is the correct value which value is then stored for use in deriving the cali bration function for the gas detector being calibrated The calibration is thus conducted in a known manner and preferably produces a linearized calibration func tion Preferably two samples of each gas at known concen trations are used Thus two points are obtained v1 p1 and v2 p2 where v1 and v2 are the measured voltages and p1 and p2 are the corresponding known gas concen trations Using these two test points the calibration constants are conventionally obtained as follows m p2 pt v2 v1 8 c pl v1 p2 y1 v2 v1 9 Referring to FIG 2D a macro flow diagram of the data communication function of the apparatus is shown Initialization step 100 provides for initialization of the communications channel This channel establishes serial RS 232 communication under the industry standard x modem protocol with external devices such as porta ble computers It is used to monitor the operation of the gas analyzer and for development and diagnosis of sys
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