INSTRUCTIONS FOR USE. COR-MAN IN / EN Issue D, Rev S/W version INNOVISION ApS Skovvænget 2 DK-5620 Glamsbjerg Denmark

INSTRUCTIONS FOR USE COR-MAN-0000-001-IN / EN Issue D, Rev. 2 2016-02-10 S/W version 8.00 INNOVISION ApS Skovvænget 2 DK-5620 Glamsbjerg Denmark Tel.: +45 65 95 91 00 Fax: +45 65 95 78 00 info@innovision.dk www.innovision.dk

TABLE OF CONTENTS ABOUT THIS MANUAL...1 1. INTRODUCTION TO INNOCOR...1 1.1 INTENDED USE... 1 1.2 INTENDED APPLICATIONS AND PATIENT POPULATION... 3 1.3 INTENDED OPERATORS AND ENVIRONMENT... 3 1.4 DISCLAIMER... 3 2. PRODUCT OVERVIEW AND INSTALLATION...4 3. SYMBOLS...11 4. ATTENTION...15 5. WARNINGS...19 5.1 GENERAL... 19 5.2 SAFETY CLASSIFICATION... 19 5.3 ELECTRICAL... 19 5.4 ENVIRONMENTAL... 20 5.5 PROCEDURAL... 20 6. OPERATING ENVIRONMENT...21 7. SHORT INSTRUCTIONS...22 7.1 MAIN SCREEN... 22 7.2 CALIBRATION... 22 7.3 MEASUREMENT (CO BY REBREATHING / CPET PROGRAM)... 25 7.3.1 Operating Principle... 25 7.3.2 Start of Rebreathing / CPET Program... 25 7.3.3 Patient Database... 26 7.3.4 Test Preparation... 26 7.3.5 Test Execution... 26 7.3.6 Option: Breath-by-Breath... 27 7.3.7 Rebreathing Test... 27 7.3.8 Results... 28 7.3.9 After a Test... 35 7.3.10 Setup... 36 7.3.11 Data Exchange... 36 7.3.12 Blood Pressure Test (Stand-Alone)... 36 7.3.13 Recommended Settings... 37 7.3.14 Termination of Program... 37 7.4 MEASUREMENT (LCI BY MULTIPLE-BREATH WASH-OUT)... 38 7.4.1 Operating Principle... 38 7.4.2 Start of LCI Program... 38 7.4.3 Patient Selection... 38 7.4.4 General Screen Layout... 39 7.4.5 Test Preparation... 40 7.4.6 Test Execution... 41 7.4.7 Results... 45 February 2016 COR-MAN-0000-001-IN /EN, D/2 i

7.4.8 After a Test... 48 7.4.9 Setup... 48 7.4.10 Calibration... 49 7.4.11 Data Exchange... 49 7.4.12 Recommended Settings... 49 7.4.13 Termination of Program... 50 8. RVU DESCRIPTION...51 8.1 OPERATING PRINCIPLE... 51 8.2 VALVE INSERT... 52 8.3 FLOW RESTRICTOR... 53 8.4 RVU TEST... 54 8.5 SPIROMETRY MODE... 54 8.6 LCI MODE / DISPOSABLE SCRUBBER (CO 2 ABSORBER)... 55 9. PULSE OXIMETRY...56 9.1 OPERATING PRINCIPLE... 56 9.2 ATTACHING THE SENSOR... 56 9.3 ACCURACY... 57 9.4 PRECAUTIONS FOR USE... 57 9.5 CONTRAINDICATIONS... 57 10. BLOOD PRESSURE...58 10.1 OPERATING PRINCIPLE... 58 10.2 PERFORMANCE... 58 10.3 POSITIONING THE CUFF... 58 10.4 PRECAUTIONS FOR USE... 59 11. CLEANING AND MAINTENANCE...60 11.1 REPLACEMENT OF GAS ANALYSER FILTERS... 60 11.2 REPLACEMENT OF GAS ANALYSER SAMPLING TUBE... 60 11.3 REPLACEMENT OF RESPIRATORY PARTS... 60 11.4 CLEANING AND REPLACEMENT OF DUST FILTER FOR COOLING FAN... 60 11.5 CALIBRATIONS... 61 11.5.1 Gas Analyser Calibration... 61 11.5.2 Oxygen Sensor Calibration... 61 11.5.3 Airway Pressure Sensor Calibration... 61 11.5.4 Rebreathing Gas Filling Flow Calibrations... 61 11.5.5 Gas Cylinder Pressure Sensor Calibration... 61 11.5.6 Pulse Oximeter Calibration... 61 11.5.7 Non-Invasive Blood Pressure Calibration... 61 11.5.8 Flowmeter Sensor Calibration... 62 11.5.9 Flow-gas delay Calibration... 62 11.6 CLEANING... 62 11.6.1 General... 62 11.6.2 Casing... 62 11.6.3 LCD / Touch Screen Display... 62 February 2016 COR-MAN-0000-001-IN /EN, D/2 ii

11.6.4 Cleaning and Maintenance of RVU... 62 11.6.5 Cleaning of Respiratory Parts... 63 11.6.6 Cleaning of Gas Analyser Sampling Tube... 63 11.6.7 Cleaning of Pulse Oximetry Sensor... 64 11.6.8 Cleaning of NIBP Cuff (Option)... 64 11.6.9 External Computer... 64 12. PERIODICAL CHECKS...65 12.1 INSPECTION... 65 12.2 PERFORMANCE CHECK... 65 12.3 SAFETY CHECK... 65 13. DISASSEMBLY AND DISPOSAL...66 13.1 DISASSEMBLY PROCEDURE... 66 13.2 DISPOSAL OF DEVICE AND ACCESSORIES... 67 14. SPECIFICATIONS...68 15. ACCESSORIES...73 Annex A Guidance and manufacturer s declaration February 2016 COR-MAN-0000-001-IN /EN, D/2 iii

ABOUT THIS MANUAL NOTE: Before using Innocor please read this manual thoroughly. Pay special attention to WARNING! and CAUTION statements appearing throughout the manual and to the ATTENTION section. A warning (indicated with the word WARNING!) alerts about a situation which, if not avoided, could result in death or serious injury to the user or the patient. It also describes potential serious adverse reactions and safety hazards. A precaution statement (indicated with the word CAUTION) is used for a hazard alert that warns of a potentially hazardous situation which, if not avoided, may result in minor or moderate injury to the user or patient or damage to the equipment or other property. It is also used to alert against unsafe practices. This includes the special care necessary for the safe and effective use of the device and the care necessary to avoid damage to a device that may occur as a result of use or misuse. In the following all functions and options of Innocor are described. Some of the functions described or shown may not be available on the device you are using. 1. INTRODUCTION TO INNOCOR 1.1 INTENDED USE Innocor is a compact point-of-care device intended to be used for non-invasive measurement of cardiac output and related cardiopulmonary parameters. Cardiac output (CO) is defined as the volume of blood pumped by the heart per unit of time (blood flow in litre per minute). The measurement is noninvasive (i.e. does not necessitate catheterisation or any other penetration through a body orifice or the body surface) in that it is based on a pulmonary gas exchange method called inert gas rebreathing (IGR). The operating principle of Innocor is to let the patient breathe minute quantities of a blood soluble and an insoluble gas in a closed breathing assembly for a short period. The blood flowing through the lungs (effective pulmonary blood flow, PBF) absorbs the blood soluble gas and therefore the disappearance rate is proportional to the blood flow. Other factors affecting the distribution of the blood soluble gas are accounted for by also measuring the blood insoluble gas. The spontaneously breathing patient puts on a nose clip and breathes into a respiratory valve via a mouthpiece and bacterial filter. At the end of expiration the valve is activated so that the patient will breathe in and out (rebreathe) from a rubber bag for a period of 10-20 seconds. The patient is asked to empty the bag during each inspiration and breathe with a slightly increased respiration rate. After this period the patient is switched back to ambient air and the test is terminated. The bag is prefilled with an oxygen (O 2 ) enriched mixture containing two foreign gases; typically 0.5% nitrous oxide (N 2 O) and 0.1% sulphur hexafluoride (SF 6 ). These gases and CO 2 are measured continuously and simultaneously at the mouthpiece by a photoacoustic gas analyser inside Innocor. N 2 O is soluble in blood and is therefore absorbed during the blood s passage of the lungs at a rate, which is proportional to the blood flow. So, the higher the cardiac output the higher the disappearance rate (slope of measured gas curve). SF 6 is insoluble in blood and therefore stays in the gas phase and is used to determine the lung volume from which the soluble gas is removed. The rebreathing test can be performed as a single test at rest or at a given exercise level using e.g. a bicycle ergometer or a treadmill in a stand-alone configuration. Alternatively it can be performed as a part of an exercise protocol where the rebreathing manoeuvres are done at pre-programmed intervals/workloads. February 2016 COR-MAN-0000-001-IN /EN, D/2 1

By using a pulse oximeter the heart rate (HR) can be measured during the test and used to derive the stroke volume (SV) etc. The arterial oxygen saturation (SpO 2 ) indicates whether the oxygenation is normal and thus if there is a significant intrapulmonary shunt (SpO 2 < 95%). An oscillometric non-invasive blood pressure (BP) measuring system is also included as an option. It is designed to take blood pressure measurements including systolic (SYS), diastolic (DIA) and mean arterial pressures (MAP). By combining CO and MAP the systemic vascular resistance (SVR) can be determined. The BBB (Breath-by-Breath) option provides measurements of gas exchange parameters including oxygen uptake, carbon dioxide excretion, ventilation and end-tidal concentrations plus a number of derived parameters. These parameters are determined by simultaneous measurements of the respiratory flow and gas concentrations when breathing ambient air. The respiratory flow is measured by means of a differential pressure type flowmeter (pneumotachometer) placed between the respiratory valve unit and the patient. The gas exchange calculations are carried out online for each breath between the rebreathing tests. This gives the opportunity to perform an incremental exercise test on a bicycle ergometer or treadmill and measure the progress of cardiac function, pulmonary function and gas exchange at the same time. The Spirometry option provides measurements of the lung function with respect to dynamic lung volumes during forced expiration. This includes FEV 1 (forced expiratory volume in 1 second), FVC (forced vital capacity), FEV 1 %, PEF (peak expiratory flow), MEF 75 (Maximal instantaneous forced expiratory flow where 75% of the FVC remains to be expired), MEF 50, MEF 25, FET (Forced expiratory time) and MVV (Maximum voluntary ventilation). These parameters are determined by measurements of the respiratory flow when breathing ambient air during a spirometry manoeuvre (tidal breathing followed by first a full inspiration then a maximal forced expiration). The respiratory flow is measured by means of a differential pressure type flowmeter (pneumotachometer) placed in a standalone position to minimise the flow resistance. This gives the opportunity to perform a diagnosis after an exercise test: Is the patient s exercise intolerance caused by ventilatory limitation or is the abnormality caused by a limitation in the cardiovascular system? The LCI Option provides assessment of the ventilation distribution in a patient s lungs by recording of an inert gas multiple-breath washout (MBW) curve. The primary parameter measured is the Lung Clearance Index (LCI), which is the cumulative expired volume required to clear the inert gas from the lungs during normal breathing divided by the Functional Residual Capacity (FRC). The manoeuvre performed is similar to inert gas rebreathing (IGR) described above. The manoeuvre is only extended to monitor the breathing in the washout period (breathing normal air) after the rebreathing period. FRC and LCI are determined by combining the rebreathing test with the multiple-breath inert gas washout in open-circuit mode. During these combined tests the respiratory flow and SF 6 concentration are measured during tidal breathing. The respiratory flow is measured by means of a differential pressure type flowmeter (pneumotachometer). The SF 6 concentration is measured by means of a photoacoustic infrared analyzer. An oxygen enriched rebreathing gas mixture for wash-in of SF 6 is automatically filled into a rubber bag prior to testing by adding a bolus of mixture to air. When the SF 6 is adequately equilibrated in the lungs during rebreathing the test continues by letting the patient breathe ambient air in the multiple-breath wash-out period until the end-tidal SF 6 concentration has fallen below 1/40 of the starting concentration. Innocor runs under the Windows XP Embedded operating system on an integrated single-board computer or under Windows on an external computer/tablet. However, knowledge of Windows is not required to operate the device. The device is operated via a simple touch screen interface. February 2016 COR-MAN-0000-001-IN /EN, D/2 2

1.2 INTENDED APPLICATIONS AND PATIENT POPULATION Innocor can be used in a variety of medical fields where knowledge of cardiac output and gas exchange is important, e.g. cardiac exercise stress testing, heart failure, cardiac surgery, hypertension, pulmonary hypertension, hemodialysis and pacemaker programming. It can be used both in rest and exercise e.g. with patients who have no symptoms in rest or light exercise. The method involves no risk or pain to the patient. The only requirement is that the patient is capable of understanding the instructions from the operator and performing the manoeuvre well. 1.3 INTENDED OPERATORS AND ENVIRONMENT The Innocor should be used only by professional health care providers who have received training in the use of the equipment. Equipment specific training is required for the primary operating functions of Innocor. Two to four hours of on-site training is typically offered by the manufacturer or its representative during installation. 1.4 DISCLAIMER INNOVISION (the manufacturer) considers itself responsible for effects on safety, reliability and performance of this equipment only if: Persons authorised by the manufacturer carry out assembly, extensions, readjustments, modifications or repairs. The parts and components used for repairs, modifications, extensions or local applications are of a type approved by the manufacturer. The electrical installation to which the equipment is connected complies with appropriate requirements. Accessories listed in the Instructions for Use are used. The equipment is used in accordance with the Instructions for Use. The device contains no internal user-serviceable components. In the event of failure or defect, contact the manufacturer or his representative. February 2016 COR-MAN-0000-001-IN /EN, D/2 3

2. PRODUCT OVERVIEW AND INSTALLATION Do not connect anything or turn anything on before you have become fully familiar with the contents of this chapter on installation. Innocor is shown in figure 1a and 1b. Depending on the configuration of the device it may look different from what is shown in this and the following figures. 1 1 2 2 3 3 4 5 1) Colour LCD / Touch Screen* 2) Patient Interface Panel 3) Cooling Air Inlet * For devices with external computer, see figure 1b. 1) Lifting Slot 2) Cooling Air Outlet 3) Gas Cylinder Connection 4) Power Interface Panel 5) Data Interface Panel FIGURE 1a. Left) Right side view, Right) Rear view. The rear panel to the left is the power interface panel (figure 2) for the mains AC power input. February 2016 COR-MAN-0000-001-IN /EN, D/2 4

FIGURE 1b. Innocor version with external computer (tablet). FIGURE 2. Power interface panel for the mains AC power input. Connect an earthed mains power cord to the 230 V / 110 V input. The rear panel to the right is the data interface panel (figure 3). February 2016 COR-MAN-0000-001-IN /EN, D/2 5

FIGURE 3. Data interface panel. Upper: Innocor version with integrated computer and network connection. Lower: Innocor version with external computer (tablet) equipped with a USB type B connector and earth terminal screw (with cable connected to the right). For versions using an external computer, connect the computer using the USB type B connector to the right on the Data interface panel. Also, connect the earth wire to the earth terminal and tighten using a tool. Connect the USB type A end of the cable to the computer. WARNING! If using a version with external computer, the computer must be certified according to the European standard EN 60950. The computer should only be used on battery power. Otherwise, it is required to use a safety isolating transformer. The computer must be placed outside of the patient zone. Make sure not to block the gas outlet/inlet connector when installing the device. Remove protective plugs from the gas outlet/inlet connectors if mounted. Before connecting the gas cylinder to the fitting in the lower middle of the rear part (figure 1), ensure that an intact o-ring is in place (figure 4). Connect the gas cylinder to the fitting (figure 5) by hand tightening. NOTE: When the valve opens automatically extra torque is required to screw the cylinder onto the device (an additional approx. 2 turns). February 2016 COR-MAN-0000-001-IN /EN, D/2 6

FIGURE 4. Gas cylinder connection, position (left) and cross sectional view (right). Note correct positioning of O-ring seal (right). FIGURE 5. Innocor with gas cylinder mounted and RVU in storage position. The right side panel is the patient interface panel (figure 6). February 2016 COR-MAN-0000-001-IN /EN, D/2 7

FIGURE 6. Patient interface panel. Left) Shown without connections Right) Shown with connections. Connect the six-tube quick connector to the rebreathing valve unit hose connection on the side panel (it clicks on). Connect the gas analyser sampling tube to the gas inlet connection. Make sure to use a particle filter between the gas inlet connection (analyser) and the sampling tube. The filter has a male slip luer adapter on the analyser side and a female locking luer connector on the sampling tube side. Make sure the filter (membrane) is not contaminated (grey or black) inside. Guide the gas analyser sampling tube along the flexible tubing to the rebreathing valve unit, making sure not to kink or damage the sampling tube. Connect the pulse oximeter finger probe to the D-sub connector marked SpO 2 on the side panel. Connect the NIBP arm cuff to the NIBP quick connector on the side panel using the air hose (optional). The rebreathing valve unit is shown with connections in figure 7. February 2016 COR-MAN-0000-001-IN /EN, D/2 8

1 3 4 6 7 5 1 2 3 4 6 7 5 FIGURE 7. Rebreathing valve unit with connections (upper: standard RVU, lower: RVU with BBB option). 1) Gas sampling tube, 2) flowmeter, 3) respiratory bacterial/viral filter 4) mouthpiece 5) rebreathing bag 6) BBB port 7) RB port. February 2016 COR-MAN-0000-001-IN /EN, D/2 9

FIGURE 7 (continued). Rebreathing valve unit with connections (RVU with optional Disposable Scrubber (CO 2 absorber) for LCI option). Connect the gas sampling tube to the luer-lock on the rebreathing valve unit. Make sure a small tube is connected to the insert at the RB port. Connect a rebreathing bag to the rebreathing valve unit s RB port. Standard Innocor Connect a respiratory bacterial/viral filter with mouthpiece to the mouthpiece port of the rebreathing valve unit. Innocor with BBB option Connect the flowmeter to the mouthpiece port of the rebreathing valve unit. Connect a respiratory bacterial/viral filter with mouthpiece to the flowmeter. Connect a flow restrictor on the BBB port if the patient is unable to trigger / start a rebreathing test (only for measurements at rest). Innocor with LCI option Connect an optional Disposable Scrubber (CO 2 absorber) to the rebreathing port of the rebreathing valve unit via a black adapter before connecting the rebreathing bag. Make sure a small tube is connected to the insert at the RB port and guided through the centre hole of the scrubber material in case a scrubber with hole is used. February 2016 COR-MAN-0000-001-IN /EN, D/2 10

3. SYMBOLS The following symbols are used on the equipment, accessories and packaging: Symbol Description CAUTION Caution, consult accompanying documents Attention, see instructions for use i Consult instructions for use On (power) Off (power) Mains power inlet; Input voltage ranges and fuse rating ~ Alternating current Fuse Universal serial bus (USB) connections Network connection February 2016 COR-MAN-0000-001-IN /EN, D/2 11

Symbol Description Gas outlet / inlet Gas inlet to gas analyser Rebreathing valve unit hose connection Non-invasive blood pressure hose connection Pulse oximeter probe connection Type BF Applied Part (EN 60601-1) (protection against electrical shock) Do not use oil or grease CE Marking indicating conformance to EC Directive No. 93/42/EEC concerning medical devices, with identification number of notified body LOT Lot number (batch code) SN Serial number February 2016 COR-MAN-0000-001-IN /EN, D/2 12

Symbol Description REF Catalogue/Reference number Date of manufacture (yyyy-mm / yyyy-mm-dd) Manufacturer Use by (yyyy-mm / yyyy-mmdd) Temperature limitation Keep dry 180 Contains gas under pressure, may explode if heated. May cause or intensify fire; oxidiser. February 2016 COR-MAN-0000-001-IN /EN, D/2 13

Symbol Description Dangerous goods label. CLASS 2 HAZARD - Gases (No. 2.2) Non-flammable, non-toxic gas. Black or white on green background. Dangerous goods label. Class 5.1 HAZARD - Oxidizing substances (No. 5.1) Black on yellow background. COMPRESSED GAS OXIDIZING, N.O.S. (OXYGEN MIXTURE) UN 3156, 5.1 Dangerous goods label. February 2016 COR-MAN-0000-001-IN /EN, D/2 14

4. ATTENTION When the ATTENTION symbol is shown on the device it means that the following safety guidelines should be followed. Additional warning and precaution statements appear in context throughout this manual: WARNING! Electrical shock hazard. Mains power inlet Do not open the cover. Refer servicing to qualified personnel. There are no user-serviceable parts inside. The power cord should be connected only to a properly grounded AC electrical outlet. Fuse WARNING! For continued protection against fire hazard, replace only with same type and rating of fuse. Data interfaces Universal serial bus (USB) connections and Network connection WARNING! The electrical interfaces on the data interface panel (USB and Network) shall not be used under normal clinical conditions within the patient zone but only during service and occasionally for data exchange. Peripheral equipment connected to these interfaces must be certified according to the respective European standards (e.g. EN 60950 for data processing equipment and EN 60601-1 for medical equipment). Furthermore, all configurations shall comply with the system standard EN 60601-1-1. Everybody who connects additional equipment to the signal input part configures a medical system, and is therefore responsible that the system complies with the requirements of the system standard EN 60601-1-1. If using a version with external computer, the computer must be certified according to the European standard EN 60950. The computer should only be used on battery power. Otherwise, it is required to use a safety isolating transformer. The computer must be placed outside of the patient zone. February 2016 COR-MAN-0000-001-IN /EN, D/2 15

Excessive EMI (electromagnetic interference) may to some extent interfere with the measurements. To avoid this interference, it may be necessary to move the interfering equipment or switch to another installation group. Gas outlet / inlet CAUTION. Do not block or connect anything to these connectors. CAUTION. Make sure no protective caps or plugs are fitted before bringing into use. WARNING! Fire hazard: Avoid open flames and smoking in the areas where the device is being used. WARNING! Explosion hazard: Gas cylinder and cylinder connection Improper use, filling, storage or disposal of gas cylinder may result in personal injury, death or property damage. Gas mixture vigorously accelerates combustion. Avoid open flames and smoking in the areas where the device and gas cylinders are being used or stored. Store and use at room temperature (10-40ºC). Make sure that both the male and female gas connections are kept clean and free from oil, grease and hydrocarbons before screwing the cylinder onto the device. Use no lubricant. Use only cleaning agents that do not leave organic residues. NOTE: To reduce friction gas cylinders are supplied with a small amount of a special lubricant for oxygen service on the threaded part. Do not remove this lubricant. Aluminium high pressure gas cylinder. WARNING! Do not alter or modify the cylinder or the valve in any way. Do not use any caustic or corrosive paint or cleaners on the gas cylinder. Do not remove the product label from the gas cylinder. Use only gas cylinders provided by the manufacturer or his representative. CAUTION. Make sure the o-ring is in place and not damaged before screwing the cylinder onto the device. To avoid damage of the o-ring seal, unscrew the cylinder in the following way: February 2016 COR-MAN-0000-001-IN /EN, D/2 16

1. Unscrew the cylinder slowly 1½ turns counter clockwise. 2. Vent the lines in the instrument to eliminate the pressure by following the steps shown on the screen during shut-down of the application program [Exit] (or by disconnecting and eventually re-connecting the rebreathing valve unit quick connector with the application program running). 3. Then unscrew the cylinder completely. NOTE: During routine use it is recommended not to unscrew the cylinder completely and vent the gas lines when powering off (e.g. overnight). Just unscrew the cylinder 1½ turns to close the cylinder valve. To open again just turn the cylinder back on 1½ turns clockwise. Non-invasive blood pressure hose connection Ensure that the air hose from Innocor to the cuff is not compressed, crimped or damaged. Ensure that the o-ring is not damaged. To connect, push on the connector until it clicks on. To disconnect, press the metal pushbutton to release the locking mechanism and pull. Pulse oximeter probe connection WARNING! Use only pulse oximeter sensors specified by the manufacturer (see Accessories). Using other sensors may cause improper performance. CAUTION. Inspect the sensor application site frequently to ensure correct sensor alignment and skin integrity. Patient sensitivity to sensors may vary depending on their medical status or the condition of their skin. CAUTION. Do not use a damaged sensor. If the sensor is damaged in any way, discontinue use immediately and replace the sensor. Gas inlet to gas analyser CAUTION. Always use a particle filter provided by the manufacturer or his representative between the gas inlet connector (analyser) and the sampling tube. The filter has a male slip luer adapter on the analyser side and a female locking luer connector on the sampling tube side. Make sure the filter (membrane) is not contaminated (grey or black) inside. February 2016 COR-MAN-0000-001-IN /EN, D/2 17

Use only the Nafion dryer type of sampling tube provided by the manufacturer or his representative. Filter and tubing must be properly screwed together. CAUTION. Make sure not to kink or otherwise damage the sampling tube. Never pull the tube. Ensure that the six o-rings are not damaged. Rebreathing valve unit hose connection To connect, push on the connector until it clicks on (note the position of the key). To disconnect, press the coloured pushbutton to release the locking mechanism and pull. CAUTION. Never pull the hose. For use only with Innocor. Disposable Scrubber (CO 2 absorber) Do not use if packaging or product is damaged or has been tampered with. Do not attempt to disassemble the product. WARNING! The CO 2 absorbent contains caustic compounds; direct contact with unprotected skin can produce severe burns. In case of contact with skin or eyes, rinse immediately with plenty of fresh water. WARNING! CO 2 absorbent is harmful if swallowed. Keep out of reach of children. Minimize time from opening packaging to use. Do not use after expiration date. Storage temperature: -20 C to +50 C. The Calcium Hydroxide CO 2 absorbent is classified as irritant only and can be handled, transported and disposed off as non-hazardous material. February 2016 COR-MAN-0000-001-IN /EN, D/2 18

5. WARNINGS 5.1 GENERAL In case the device fails, disconnect it from the patient. Stop using the device until the problem has been solved. Contact the manufacturer or his representative if necessary. 5.2 SAFETY CLASSIFICATION The Innocor device is classified as CLASS I Type BF equipment according to the type and degree of protection against electrical shock in accordance with EN 60601-1. 5.3 ELECTRICAL WARNING! Electrical shock hazard. Do not open the cover. Refer servicing to qualified personnel. There are no user-serviceable parts inside. The power cord should be connected only to a properly grounded AC electrical outlet. WARNING! For continued protection against fire hazard, replace only with same type and rating of fuse. WARNING! The electrical interfaces on the data interface panel (USB and Network) shall not be used under normal clinical conditions within the patient zone but only during service and occasionally for data exchange. Peripheral equipment connected to these interfaces must be certified according to the respective European standards (e.g. EN 60950 for data processing equipment and EN 60601-1 for medical equipment). Furthermore, all configurations shall comply with the system standard EN 60601-1-1. Everybody who connects additional equipment to the signal input part configures a medical system, and is therefore responsible that the system complies with the requirements of the system standard EN 60601-1-1. If using a version with external computer, the computer must be certified according to the European standard EN 60950. The computer should only be used on battery power. Otherwise, it is required to use a safety isolating transformer. The computer must be placed outside of the patient zone. Excessive EMI (electromagnetic interference) may to some extent interfere with the measurements. To avoid this interference, it may be necessary to move the interfering equipment or switch to another installation group. WARNING! Medical electrical equipment needs special precautions regarding electromagnetic compatibility (EMC) and needs to be installed and put into service according to the EMC information provided in this instruction for use (see guidance and manufactures declaration attached in annex). Portable and mobile radio frequency (RF) communications equipment can affect medical electrical equipment. February 2016 COR-MAN-0000-001-IN /EN, D/2 19

WARNING! The use of electrical accessories with Innocor other than those specified may result in increased EMISSION (risk of disturbance of other devices) or decreased IMMUNITY (risk of disturbance of the Innocor). 5.4 ENVIRONMENTAL WARNING! Fire hazard: Avoid open flames and smoking in the areas where the device is being used. WARNING! Explosion hazard: In order to avoid an explosion risk, do not use the equipment in areas in which flammable anesthetics are applied. WARNING! Explosion hazard: Improper use, filling, storage or disposal of gas cylinder may result in personal injury, death or property damage. Gas mixture vigorously accelerates combustion. Avoid open flames and smoking in the areas where the device and gas cylinders are being used or stored. Store and use at room temperature (10-40ºC). Make sure that both the male and female gas connections are kept clean and free from oil, grease and hydrocarbons before screwing the cylinder onto the device. Use no lubricant. Use only cleaning agents that do not leave organic residues. WARNING! Do not alter or modify the cylinder or the valve in any way. Do not use any caustic or corrosive paint or cleaners on the gas cylinder. Do not remove the product label from the gas cylinder. Use only gas cylinders provided by the manufacturer or his representative. WARNING! The CO 2 absorbent contains caustic compounds; direct contact with unprotected skin can produce severe burns. In case of contact with skin or eyes, rinse immediately with plenty of fresh water. WARNING! CO 2 absorbent is harmful if swallowed. Keep out of reach of children. 5.5 PROCEDURAL WARNING! Never use the device without a new disposable single patient use bacterial/viral filter in the patient connection to minimise the risk of cross-contamination. WARNING! Use only pulse oximeter sensors specified by the manufacturer (see Accessories). Using other sensors may cause improper performance. February 2016 COR-MAN-0000-001-IN /EN, D/2 20

6. OPERATING ENVIRONMENT Safe ambient operating temperatures range from 10-40 C. Humidity should not exceed 90% RH non-condensing at 30 C. If the device has been exposed to temperatures significantly below the operating environment temperature, an acclimatisation period is necessary. Avoid excessive heat, dust and direct sunlight. For optimum performance the device must be used in a reasonably vibration-free environment because of the photoacoustic gas measurement principle. Place on a flat, horizontal and solid surface. WARNING! Fire hazard: Avoid open flames and smoking in the areas where the device is being used. WARNING! Explosion hazard: In order to avoid an explosion risk, do not use the equipment in areas in which flammable anesthetics are applied. February 2016 COR-MAN-0000-001-IN /EN, D/2 21

7. SHORT INSTRUCTIONS When all electrical and pneumatic connections are made you can switch the power on ( I ). The device is ready after a couple of minutes after being powered up. 7.1 MAIN SCREEN The Innocor application program's main screen appears (figure 8): FIGURE 8. Innocor main screen. Select Measurement to perform tests or to examine data from previous tests. Select Setup to change test, calculation or graphic settings and to perform service and calibration procedures. Select Data Management for data exchange functions. Select Blood Pressure to make a blood pressure measurement without rebreathing (option). 7.2 CALIBRATION It is recommended to perform all calibrations below once a day before starting the tests. It is also recommended to make a new flow calibration every time the flowmeter screen is replaced and a new flow-gas delay calibration every time the gas sample line is replaced. Select Configuration Press Measurement on Screen. Select the configuration: E.g. StdRVU_Ser_Scr (adults,+25kg). Press Prepare to calibrate Innocor (only once a day). February 2016 COR-MAN-0000-001-IN /EN, D/2 22

FIGURE 9. Selection of configuration (example). FIGURE 10. Calibration status menu. Ambient Data Press Change ambient data and enter actual values. Flowmeter Calibration If the Innocor contains the Breath-by-Breath or LCI Option, it is recommended to perform a gain calibration of the flowmeter once a day. It is also recommended to make a new calibration every time the flowmeter screen is replaced. Press Calibrate flowmeter. Connect a 1 litre or 3 litre calibrated syringe to the RVU, and set the program switch accordingly. Empty the syringe Press Calibrate Fill the syringe at a relatively low rate without bumping at the end. When the program is ready empty the syringe again at a low rate. Repeat the filling and emptying until 2x5 strokes have been applied, and the OK button is highlighted. Increase the flow rate at each of the 2x5 strokes in order to try to cover the physiological test range. February 2016 COR-MAN-0000-001-IN /EN, D/2 23

Press OK if the new gain values are in the range 0.9 to 1.1, otherwise replace the flowmeter screen and repeat the calibration. NOTE: The flowmeter is automatically offset adjusted prior to each stroke. A gas cylinder must be connected in order to close the RB port of the RB valve during the flow calibration. Flow-gas Delay Calibration If the Innocor contains the Breath-by-Breath or LCI Option, it is recommended to perform a calibration of the flow-gas delay once a day. It is also recommended to make a new calibration every time the gas sample line is replaced. If only the Spirometry Option is used the flow-gas delay calibration can be skipped. Press Calibrate flow-gas delay. Wait 1 minute for warming up. The operator (not the subject) starts breathing in and out of the RVU. When ready the Calibration button is pressed. Then the operator must make some slow expirations followed by very fast inspirations until the OK button is highlighted. The inspirations have to be fast in order to get a precise determination of the flow-gas delay. If one or two breaths fail the software will automatically filter these results. The delays should not vary more than 20-40 ms from day to day if the same gas sample inlet is used. NOTE: A gas cylinder must be connected in order to close the RB valve during the delay calibration The BBB port on the RVU must not be connected to other devices during the delay calibration The calibration of the flow-gas delay is critical an error of 25 ms can give a 5% error on the Vo 2, Vco 2, FRC and LCI results! Oxygen Calibration If an oxygen sensor is included in the system it is recommended to perform a calibration of the baseline of the oxygen sensor once a day. Press Calibrate Oxygen. Expose gas sample line to air by removing it from breathing assembly. Press Start to perform a one point calibration of the Oxygen. Press OK (to Exit Prepare). Press OK (to select configuration). February 2016 COR-MAN-0000-001-IN /EN, D/2 24

7.3 MEASUREMENT (CO BY REBREATHING / CPET PROGRAM) 7.3.1 Operating Principle The operating principle of Inert Gas Rebreathing by Innocor is to let the patient breathe minute quantities of a blood soluble and an insoluble gas in a closed breathing assembly for a short period. The blood flowing through the lungs (effective pulmonary blood flow, PBF) absorbs the blood soluble gas. Therefore, its disappearance rate is proportional to the blood flow. Other factors affecting the distribution of the blood soluble gas are accounted for by measuring the levels of the blood insoluble gas. 7.3.2 Start of Rebreathing / CPET Program The procedure described in the following sections will under normal conditions be adequate to perform a rebreathing measurement or cardiopulmonary exercise test: Start the program from the Innocor menu by selecting Measurement. The screen layout is as shown in figure 11. 1 2 3 5 4 FIGURE 11. General screen layout. 1) Patient identification field 2) date and time field 3) push button panel 4) status bar and numerical display* 5) data field for numerical results, graphics and database information etc. * Abnormal operation of pulse oximeter or probe faults is indicated by --- in the HR and SpO2 fields. February 2016 COR-MAN-0000-001-IN /EN, D/2 25

7.3.3 Patient Database Choose Patient to enter the patient database section of the program. Press New Pt. to enter data for a new patient. Enter relevant data for the patient or test subject by pointing at the appropriate entry field and using the alphanumeric keyboard shown on the screen. Select Male or Female from the selection list or type M or F on the keyboard to select the patient s sex. Press Clear to clear all fields. Instead of entering new data it is also possible to search a patient already appearing in the database. Use the Search button for this feature. Enter one or more search criteria and press Filter to start the search process. Press All to disable all search criteria and display all patients. Press Edit to change patient data if necessary. After having entered or chosen the patient data, press the Select button. Results from the latest previous test are shown on the screen if available. 7.3.4 Test Preparation Check that the bottle pressure displayed in the status bar at the bottom of the screen is adequate (i.e. > 10 bar). Attach the articulated pulse oximeter (SpO 2 ) finger clip sensor. Avoid using the same arm for BP and SpO 2 measurements. See also section Pulse Oximetry. Option: Attach the BP cuff. See section Blood Pressure. Connect to the mouthpiece and attach a nose clip, or use a face mask. WARNING! Never use the device without a new disposable single patient use bacterial/viral filter in the patient connection to minimise the risk of cross-contamination. 7.3.5 Test Execution Press Test to prepare a new measurement. Enter or verify the height and weight of the patient and enter the haemoglobin (Hb) concentration to allow calculation of derived parameters (optional). Option: If the Innocor software is an exercise or Breath-by-Breath version, the user can select an exercise protocol, which controls the progress of the exercise level and controls a series of predefined rebreathing tests in respect to bag volume and bolus concentration. Option: If the Innocor software contains the Spirometry version, the user can select a Spirometry test, where the user performs up to 8 forced expiration manoeuvres in order to determine the basic spirometry parameters of the subject. If the Innocor software is a standard version without exercise or Breath-by-Breath, the Test button will start a Rebreathing test immediately. OPTION: Spirometry Press Test and select Spirometry. The spirometry manoeuvre starts with normal tidal breathing February 2016 COR-MAN-0000-001-IN /EN, D/2 26

followed by a rapid and complete inspiration. Then immediately after the subject makes a maximal forced expiration until no more air can be expelled. Finally the subject performs a fast inspiration. It is recommended to make more than one spirometry manoeuvre in order to be sure that the measurement is representative for the subject. ATS requires at least 3 well performed spirometry manoeuvres. The best performed manoeuvre is automatically selected and saved together with the other Innocor results. 7.3.6 Option: Breath-by-Breath The breath-by-breath calculation of gas exchange parameters starts when the exercise protocol is selected and continues until the protocol is finished - only interrupted by the rebreathings. The results of the breath-by-breath calculation are displayed on-line in a table to the left and as graphics to the right. The content of the table can be modified using the Table Setup, and similar with the graphics, which can be configured in 1, 2 or 3 plots using the Graph Setup. The default display is the breath-by-breath display, but the user can select other displays using the Show results button. The Show protocol displays the progress of the exercise test, and gives the possibility to change settings of the next steps to come if necessary. The Show results displays the results of the previous rebreathing test, and the Show online data displays the raw flow and gas data. A protocol can be temporary interrupted using the Hold protocol / Stop protocol. The Innocor switches to 5 minutes cool down period, when the protocol finishes, or when the protocol is manually terminated using the Stop protocol. 7.3.7 Rebreathing Test The device automatically prepares the rebreathing bag by emptying (using automatic detection of when the bag is empty) and filling it with the desired volume of gas. A mixture of ambient air and gas from the cylinder is filled into the bag. When the bag is ready the screen shows end-tidal gas concentrations, gas curves and the airway pressure curve. Press Start to start the rebreathing test. Start can be pressed during any phase of the breathing cycle. The device will open to the rebreathing bag at the end of the actual expiration or at the end of the subsequent expiration following the actual inspiration. When the valve shifts the patient should hold the breath until the valve has switched completely (approx. half a second). When breathing, try to follow the speed indicator. Breathe faster if the indicator is to the right of OK ( Faster ). Breathe slower if the indicator is to the left of OK ( Slower ). It is essential that the rebreathing bag is being emptied completely during the first and the subsequent inspirations. The test stops automatically with empty bag when an adequate number of breaths are acquired typical 4 or 5 breaths. Option blood pressure (BP) measurement It is a good idea to start a BP measurement during the bag filling (the Start NIBP button). See also section Blood Pressure. The current cuff pressure is shown in the status bar in the lower right corner of the main test window. The BP measurement can be stopped / aborted (the Stop NIBP button) and restarted again during the rebreathing test. Only the last measured values are saved in the database. February 2016 COR-MAN-0000-001-IN /EN, D/2 27

When the BP measurement is finished the resulting Systolic / Diastolic pressures are shown for 20 s in the status bar. If the BP measurement has not finished when the rebreathing test is finished, you get a message to wait for the BP measurement. If the BP measurement is stopped the rebreathing test results will still be saved in the patient database. 7.3.8 Results Data is being saved automatically and results are shown immediately on the screen. The display of results are organised in the following views: Tab \ Focus Exercise test Single rebreathing test Main results of the Main results of a Results rebreathing: Selected rebreathing: CO, CI, Vo 2 /kg, parameters at rest, AT and SV, A-V O 2 diff max exercise. Details Table display of BBB Detailed results of a Graphs Data Table Data View 1-4 Data View 5-8 parameters versus time Graphic display of BBB parameters in up to 3x3 plots rebreathing Rebreathing curves for evaluation of the quality of the test Main results of a spirometry test: FVC, FEV 1, FEV 1 %, PEF, MEF 75, MEF 50, MEF 25, FET & MVV Detailed results of the spirometry manoeuvres Graphic display of the best performed spirometry manoeuvre Table display of rebreathing and BBB results for one or more rebreathings / exercise tests Graphic display of rebreathing and BBB results for one or more rebreathings / exercise tests The results are displayed in different ways depending on where the focus is set in the Date/Time list: a complete exercise test, a spirometry test or a single rebreathing test. The focus is set on an exercise test by selecting a line in bold with name Ex.n. or BBB.n, see below. Selecting a line named n:1, n:2 etc. will set the focus on a single rebreathing test. A spirometry test is selected by selecting a line named Spi. FIGURE 12. Test selection panel. February 2016 COR-MAN-0000-001-IN /EN, D/2 28

Rebreathing Results: FIGURE 13. Main rebreathing results. FIGURE 14. Detailed rebreathing results. Pointing inside a rebreathing plot can expand each of the four plots. See the examples below in figure 15. February 2016 COR-MAN-0000-001-IN /EN, D/2 29

FIGURE 15a. Rebreathing curves. FIGURE 15b. Normalised soluble gas (N 2 O). FIGURE 15c. Insoluble gas (SF 6 ). February 2016 COR-MAN-0000-001-IN /EN, D/2 30

FIGURE 15d. Normalised oxygen. FIGURE 15e. Soluble (N 2 O) and insoluble gas (SF 6 ). See note (*). FIGURE 15f. Carbon dioxide (CO 2 ). See note (*). (*) The plot in the upper left corner of figure 15a can be configured to show one or more curves on a common y-axis. Curves are set on/off using the Graph Setup button. February 2016 COR-MAN-0000-001-IN /EN, D/2 31

Breath-by-Breath results With focus on an exercise test and the Results tab activated will display selected BBB parameters at Rest, AT (Anaerobic Threshold) and at Max exercise level: FIGURE 16. Main exercise results (example of setup). Pressing the Details tab will display selected BBB parameters in a table. The time step can be configured to 30, 60, 90, 120 seconds or every breath. FIGURE 17. Detailed exercise results (example of setup). Pointing on the Breath-by-Breath plots (Graphs) will expand the plots. A second press on a plot will expand the actual plot. February 2016 COR-MAN-0000-001-IN /EN, D/2 32

FIGURE 18. 3x3 plots of Breath-by-Breath results. Spirometry results With focus on a spirometry test and the Results tab activated gives a numerical display of the spirometry results: FIGURE 19. Spirometry main results. February 2016 COR-MAN-0000-001-IN /EN, D/2 33

Pressing the Details tab will display the results of the individual spirometry manoeuvres. FIGURE 20. Spirometry details results. Pressing the Graphs tab will display the graphic result of the best performed spirometry manoeuvre. FIGURE 21. Spirometry graphic results. Pointing on the spirometry plots (Graphs) will enter the detailed display of the individual spirometry manoeuvres. Common results Press the Data Table Tab to display the results in a tabular form for the selected tests. The Table Setup can be used to configure the contents of the table. The table can be printed directly using the Print Table. February 2016 COR-MAN-0000-001-IN /EN, D/2 34

FIGURE 22. Data Table. Pressing the Data View Tabs will display the results in XY plots for the selected tests. The data view can be configured via the Dataview Setup. Both the X-axis and the Y-axis can be defined with respect to what to display, grid and min/max on axes. Up to 5 parameters can be selected on the y-axis. Each parameter can be assigned to the left or right y-axis, and a 1st or 2nd order regression line can be fitted to the data. FIGURE 23. Data View. 7.3.9 After a Test Press one of the following buttons: Test to repeat a test on the same patient (allow sufficient time for washout of inert gases). Print Prev. to preview and print results. Patient to enter the patient database for entering or searching patient data. Pt. Data to change patient data (Hb, Height, Weight). Test Param. to change settings for the rebreathing manoeuvre. February 2016 COR-MAN-0000-001-IN /EN, D/2 35

Demo to perform a trial rebreathing test using air (dry run). Exit Meas. to exit to the Innocor main screen (menu). 7.3.10 Setup From the Innocor main screen (menu), use the Setup button to change test settings (or press the Test Param. button from a test result screen). Change settings for the rebreathing test from the main Setup screen. It is recommended to use the factory default settings. As a guideline use a Bolus fraction on 10%. Choose Ambient from the Setup screen to change ambient data (pressure, temperature and humidity). Choose User Params to define up to 5 user defined parameters (numbers). The name of the user parameters are limited to standard characters [a..z,a..z,0..9,_]. A user parameter is deleted by deleting the name of the parameter. User parameters are manual entered before or after a test. Choose Language from the Setup screen to select the language. Option: Choose Protocol Setup to define one or more protocols. A protocol is defined as a series of rebreathing tests at different exercise levels on a bicycle ergometer or a treadmill. For each step the exercise level, time interval, bag volume, bolus and breathing frequency shall be defined as a fixed or auto value. An auto value calculates automatically the value during the execution of the protocol. Choose Gas Cylinder from the Setup screen to enter the Gas Cylinder identification menu. Use this menu to mount a new gas cylinder to the Innocor, or when changing gas cylinders. Calibration Choose Adjust O2 for calibration of the oxygen sensor (option). Follow the instructions on the screen. It is recommended to perform a one-point calibration using air (20.95% O 2 ) once every month. Option: Choose Adjust Flowmeter for a calibration of the flowmeter. It is recommended to perform the calibration every day. Option: Choose Calculate gas delay for a calibration of the delay between the gas signal and the flow signal. It is recommended to perform the calibration every day. Gas calibration will normally not be necessary because of the stability of the analyser and the fact that only relative changes are determined in the rebreathing method. Press Close from the Setup screen to go back to the Innocor main screen (menu). 7.3.11 Data Exchange For data exchange, press the Data management button in the Innocor main menu. 7.3.12 Blood Pressure Test (Stand-Alone) Option: For access to a stand-alone blood pressure program press Blood Pressure. Set the initial pressure and press start to initiate the measurement. See also section Blood Pressure. February 2016 COR-MAN-0000-001-IN /EN, D/2 36

7.3.13 Recommended Settings At rest it is recommended to use a rebreathing frequency of 20-30 /min. During exercise it is recommended to use a larger rebreathing bag volume of 2-2.5 litre and a rebreathing frequency of 30 /min, resulting in a ventilation of at least 60 l/min. Allow sufficient time for washout of inert gases between repeated tests on the same patient. At rest 5 minutes is generally adequate. During exercise 2 minutes is recommended. Select a bolus fraction of e.g. 10 % of the bag volume (can be set to 7.5-50 % of the bag volume). However, ensure that the bolus volume is big enough to prevent a situation with deficiency of oxygen in the inspired air, in particular when testing during exercise. 7.3.14 Termination of Program Remember to unscrew the gas cylinder (as a minimum 1½ turns) before you exit the Innocor application. When turning the gas cylinder 1½ turns counter-clockwise the main valve of the gas cylinder is closed. February 2016 COR-MAN-0000-001-IN /EN, D/2 37

7.4 MEASUREMENT (LCI BY MULTIPLE-BREATH WASH-OUT) 7.4.1 Operating Principle Innocor uses a combination of two techniques to determine the LCI, using SF 6 as the inert tracer gas: Inert gas rebreathing (IGR) is used for rapid wash-in of a very small amount of SF 6 until an even concentration is obtained in the lungs before the wash-out can start. During rebreathing the patient inhales an oxygen enriched mixture from a pre-filled rubber bag. This is followed by multiple-breath wash-out (MBW) for determination of the cumulative expired volume (V CE ) required to clear the SF 6 from the lungs. The wash-out phase is initiated by automatically disconnecting from the bag at the end of an inspiration where after the patient breathes room air until the end-tidal SF 6 concentration has fallen below the predetermined fraction of 1/40 th of the starting concentration. See figure 24. 0.10 SF6 conc. (%) 0.05 Quick equilibration and reliable FRC determination Washout to 1/40 of starting concentration 0.00 0 20 40 60 80 100 120 140 Time (s) FIGURE 24. The SF 6 concentration measured during wash-in by rebreathing followed by wash-out in open-circuit breath-by-breath mode. 7.4.2 Start of LCI Program After a successful calibration the following procedure (7.4.3 to 7.4.10) will under normal conditions be adequate to perform a measurement: Start a test from the Innocor menu by selecting Measurement. 7.4.3 Patient Selection Select a patient in the patient database or press New Pt. to enter data for a new patient. February 2016 COR-MAN-0000-001-IN /EN, D/2 38

Enter relevant data for the patient or test subject by pointing at the appropriate entry field and using the alphanumeric keyboard shown on the screen. Select Male or Female from the selection list or type M or F on the keyboard to select the patient s sex. Press Clear to clear all fields. It is possible to search a patient already appearing in the database. Use the Search button for this purpose. Enter one or more search criteria and press Search to start the search process. Press Show All to disable all search criteria and display all patients. Press Edit to change patient data if necessary. After having entered or chosen the patient data, press the Select button. 7.4.4 General Screen Layout The general screen layout is shown in figure 25. 4 1 2 3 6 5 8 7 FIGURE 25. General screen layout. 1) Patient identification field, 2) data field for numerical results, 3) date and time field, 4) list of performed tests, 5) push button panel, 6) data field for graphic results, 7) status field for Gas bottle pressure, heart rate and oxygen saturation*, and 8) test comments field. * Abnormal operation of pulse oximeter or probe faults is indicated by --- in the HR and SpO2 fields. Results from the most recent test are shown on the screen if available. February 2016 COR-MAN-0000-001-IN /EN, D/2 39

7.4.5 Test Preparation Check that the bottle pressure displayed in the status bar at the bottom of the screen is adequate (i.e. > 10 bar). Attach the articulated pulse oximeter (SpO 2 ) finger clip sensor. See also section Pulse Oximetry. Connect to the mouthpiece or face mask and attach a nose clip. WARNING! Never use the device without a new disposable single patient use bacterial/viral filter in the patient connection to minimise the risk of cross-contamination. Press Test Param. to edit the setup. FIGURE 26. Setup menu. It is recommended to use the factory default settings. February 2016 COR-MAN-0000-001-IN /EN, D/2 40

Parameter Default Comments O 2 limit 13% The wash-in is stopped if the O 2 gets lower than the O 2 limit. CO 2 limit 10% The wash-in is stopped if the CO 2 gets higher than the CO 2 limit. Bolus fraction 20% Fraction of the bag volume coming from the gas bottle. A higher bolus fraction gives a higher O 2 concentration in the bag. FRC mixing threshold 15% Threshold to find the location of the breaths used for the FRC calculation. LCI mixing threshold 2% Threshold to determine the stop of the wash-in. Bag volume VT ratio 1.5 Ratio to determine the bag volume based on the VT. FRC breaths after mixing 3 Number of breaths used to calculate the FRC. Trigger signal O 2 Trigger signal to find the expirations (O 2 or CO 2 ). FRC calculation on insoluble Average Method to fit the FRC line. Reg. line or Average. Bag dead space 13 ml Dead space of the bag when empty. Valve dead space 103 ml Dead space of valve in rebreathing / wash-in mode. FRC skip at start exp. 30% Part of expiration not used in the calculations at the start. FRC skip at end exp. 15% Part of expiration not used in the calculations at the end. 7.4.6 Test Execution The LCI test contains 3 phases: Preparation, where the subject s resting tidal breathing is measured and used to prepare the correct amount of rebreathing volume. Wash-in, where the subject is rebreathing in the bag until the insoluble tracer gas is mixed with the lungs. Washout, where the subject is breathing in normal air until the insoluble tracer gas is washed out of the lungs. February 2016 COR-MAN-0000-001-IN /EN, D/2 41

Preparation: Press Test to prepare a new measurement. The subject shall breathe quietly. The Disposable Scrubber (CO 2 absorber) is designed for approx. 20 tests and should be replaced when either the inspired or expired CO 2 concentration exceeds certain limits, e.g. F I CO 2 > 2.5 % or F ET CO 2 > 6.5 % (see section 8.6 and 11.3). The material is non-indicating. With the subject breathing quietly the operator can press the Prepare Bag. The device automatically prepares the rebreathing bag by emptying (and automatically detecting when the bag is empty) and filling it with the desired volume of gas. A mixture of ambient air and gas from the cylinder is filled into the bag. Volume versus time with averaged VT VT and Freq versus time Numerical display Configuration of numerical display Configuration of graphical display FIGURE 27. LCI preparation. February 2016 COR-MAN-0000-001-IN /EN, D/2 42

Wash-in: When the bag is ready the Start Wash-in button is highlighted. If the subject is still breathing quietly the operator presses the Start Wash-in. Start Wash-in can be pressed during any phase of the breathing cycle. The device will open to the rebreathing bag at the end of the actual expiration or at the end of the subsequent expiration following the actual inspiration. The subject is still breathing quietly, and when the insoluble gas is mixed well between the bag and the lungs, the device will close to the rebreathing bag at the end of the next expiration, and the washout period is started. The wash-in takes typically one minute for a subject with healthy lungs. Insoluble gas during wash-in Wash-in mixing status FIGURE 28. Wash-in. If down going spikes are detected on the insoluble curve during wash-in a leak is present and has to be located and corrected before the start of washout. A leak will not destroy the wash-in, but will affect the washout and thereby the results (FRC and LCI). NOTE: It is difficult to see a leak during washout. February 2016 COR-MAN-0000-001-IN /EN, D/2 43

Washout: The subject continues to breathe quietly, and when the insoluble gas is washed out of the lungs, the test is completed. The wash-out takes typically 2 minutes for a subject with healthy lungs. When 2 or more LCI manoeuvres have FRC s within 10% they are marked online with a. The operator can stop the LCI test when 2 or more manoeuvres are marked with a - otherwise continue up to max. 5 manoeuvres. Accepted tests: FRC within 10% Online predicted FRC and LCI Washout status Insoluble gas during washout Washout time and no. of breaths FIGURE 29. Washout. If the patient coughs during the washout the manoeuvre can not be used and an extra manoeuvre must be collected. After the test the operator must manually change the mode to not be used see below. February 2016 COR-MAN-0000-001-IN /EN, D/2 44

7.4.7 Results Data is being saved automatically and results are shown immediately on the screen. The display of Multiple Breath Washout (MBW) results are organised in the following views: Tab \ Focus Results Details Graphs Data Table Data View 1-4 Data View 5-8 Display Main results of the MBW: Averaged LCI & FRC. Main results of the MBW: Averaged LCI & FRC, as well as detailed LCI & FRC for each manoeuvre. N/A Table display of LCI & FRC results for one or more MBW tests Graphic display of LCI & FRC results for one or more MBW tests The Results are displayed for the test in focus in the Date/Time list (see figure 30). Date & time of LCI tests Numerical results Washout of insoluble gas versus FRC turnovers FIGURE 30. LCI results. Pointing inside a plot gives an expanded view of each of the plots. February 2016 COR-MAN-0000-001-IN /EN, D/2 45

Main LCI results Status of each wash-in Manoeuvres used in main results? FIGURE 31. Detailed results (expanded view). Innocor selects as default the best LCI manoeuvres by looking at the manoeuvres with FRC s within 10%. It first takes the manoeuvres with accepted status, i.e. the manoeuvres where the wash-in mixing is below 2%. If no one is accepted, it takes the manoeuvres with FRC s within 10% of all manoeuvres. The main LCI results are the average of the used LCI s and FRC s. If the patient coughs during the washout the manoeuvre shall not be used and the operator shall remove the under used see below. Pressing the tab 1, 2, 3 will bring up detailed graphs for the individual manoeuvres see figure 32. The displays can be user configured to show: - raw curves, - wash-in of insoluble gas, - washout of insoluble gas and - turnover plot. Iwi displayed in the upper left windows is the wash-in index at the end. To be accepted the number must be below 2%. February 2016 COR-MAN-0000-001-IN /EN, D/2 46

FIGURE 32. Results for a single manoeuvre. Pressing Setup will bring up the menu for configuration of the graphic. FIGURE 33. Setup menu for graphs. Pressing the Details tab on the measurement screen see figure 34 will bring up numerical results of each manoeuvre behind the test as well as the averaged result. February 2016 COR-MAN-0000-001-IN /EN, D/2 47

FIGURE 34. LCI numerical results. Press the Data Table tab to display the results in a tabular form for the selected tests, and thereby compare results of different days. The Table Setup can be used to configure the contents of the table. The table can be printed directly using the Report. Pressing the Data View tabs will display the results in XY plots for the selected tests. The data view can be configured via the Dataview Setup. Both the X-axis and the Y-axis can be defined with respect to what to display, grid and min/max on axes. Up to 5 parameters can be selected on the y-axis. Each parameter can be assigned to the left or right y-axis, and a 1st or 2nd order regression line can be fitted to the data. 7.4.8 After a Test Press one of the following buttons: Test to repeat a test on the same patient. A new test can be started immediately after the previous also if the previous has been interrupted. Report to print results. Delete to delete a test. Exit Meas. to exit to the Innocor main screen (menu). 7.4.9 Setup From the Innocor main screen (menu), use the Setup button to change test settings. Choose Ambient from the Setup screen to change ambient data (pressure, temperature and humidity). Press Misc to change system settings. Choose Gas Cylinder to enter the Gas Cylinder identification menu. Use this menu to mount a new gas cylinder on Innocor, or when changing gas cylinders. Choose User Params to define up to 5 user defined parameters (numbers). The name of the user parameters are limited to standard characters [a..z,a..z,0..9,_]. A user parameter is deleted by deleting the name of the parameter. User parameters are manual entered before or after a test. February 2016 COR-MAN-0000-001-IN /EN, D/2 48

Choose Date to set the time and date and to change formats. Choose Language to select the language. Choose Units to set the units used by Innocor. 7.4.10 Calibration Choose Calibration - Adjust O2 for calibration of the oxygen sensor. Follow the instructions on the screen. It is recommended to perform a one-point calibration using air (20.95% O 2 ) once every day. Choose Calibration - Adjust Flowmeter for calibration of the flowmeter. It is recommended to perform the calibration every day. Choose Calibration - Calculate gas delay for a calibration of the delay between the gas signal and the flow signal. This is not necessary for the LCI measurement, but it can be a good check of the Innocor device with respect to gas sample flow. The flow-gas delays are typically between 1,200 and 1,400 ms. Gas calibration will normally not be necessary because of the stability of the analyzer and the fact that only relative changes are determined in the LCI method. Press Exit Setup from the Setup screen to go back to the Innocor main screen (menu). 7.4.11 Data Exchange For data exchange, press the Data management button in the Innocor main menu. Insert an empty USB memory stick in the Innocor see figure 3. Press Script found Find and select the script: Copy Data to USB.idm Press Perform Move the USB memory stick to a standard computer. Locate the actual test files in the folder USB:\LCI named as LCIEnnnnmmm-ddmmyyyy-hhmm.LCI, where Ennnnmmm is the patient ID ddmmyyyy is the date of the test hhmm is the time of the test 7.4.12 Recommended Settings The setup menu is shown in figure 35. February 2016 COR-MAN-0000-001-IN /EN, D/2 49

FIGURE 35. Setup menu. It is recommended to use the factory default settings. Parameter Default Comments Bag volume VT ratio 1.5 Ratio to determine the bag volume based on the VT. Bolus fraction 20% Fraction of the bag volume coming from the gas bottle. A higher bolus fraction gives a higher O 2 concentration in the bag. O 2 limit 10% The wash-in is stopped if the O 2 gets lower than the O 2 limit. CO 2 limit 10% The wash-in is stopped if the CO 2 gets higher than the CO 2 limit. Scrubber type Serial 7.4.13 Termination of Program Remember to unscrew the gas cylinder (as a minimum 1½ turns) before you exit the Innocor application. When turning the gas cylinder 1½ turns counter-clockwise the main valve of the gas cylinder is closed. February 2016 COR-MAN-0000-001-IN /EN, D/2 50

8. RVU DESCRIPTION 8.1 OPERATING PRINCIPLE The Innocor RVU is a low resistance respiratory valve unit with a high level of hygiene due to a disposable valve insert. The RVU controls the breathing path of the subject to either breathing air or gas from the rebreathing bag. The subject is connected to the RVU via a bacterial filter to avoid contamination of the valve insert. The RVU is connected to the Innocor via a 6-tube containing tubes for controlling the pneumatic valves, bag filling and evacuation, and a tube for measuring the mouth piece pressure. A rebreathing bag is connected to the lower port of the RVU at the back. If the subject has very low ventilation and is not able to trigger a start of a rebreathing test a flow restrictor can be inserted at the lower port of the RVU at the front. Ambient air port with flow restrictor Respiratory Valve Unit Rebreathing bag port Bacterial filter Mouth piece Connection to Innocor 6-tube Rebreathing bag FIGURE 36. Respiratory Valve Unit (RVU) with rebreathing bag, bacterial filter and mouth piece. February 2016 COR-MAN-0000-001-IN /EN, D/2 51

8.2 VALVE INSERT CAUTION. The valve insert is not intended to be used sterilised / disinfected. Do not clean. The valve insert is intended to be replaced when changing the Innocor gas bottle, which corresponds to approx. 75 tests depending on use. The disposable valve insert is made of silicone, and is placed inside a plastic housing, which is easy to dissemble and assemble. Remember to power off the Innocor or enter the main menu of the Innocor software before changing the valve insert otherwise the gas bottle will be emptied. When done rotate the knob with the Innovision logo clockwise and the plastic housing becomes loose and can be taken apart. The old valve insert is removed and a new valve insert is fit on the metal plate inside the plastic housing. Put the other part of the plastic housing on top and press the two parts gently together until a click is heard. The RVU is now ready to use. Plastic housing Valve insert Plastic housing Bacterial filter port Knob Rebreathing bag port 6-tube Ambient air port with flow restrictor FIGURE 37. Assembly of RVU. The valve insert is mounted with a small fitting and a short tube to the bag filling / evacuation port inside the rebreathing bag port. This must not be removed; otherwise the mixing of the bolus and air gas will not be adequate. February 2016 COR-MAN-0000-001-IN /EN, D/2 52

Bag filling / evacuation port Fitting Ambient air port Rebreathing bag port Tube Rebreathing bag connector FIGURE 38. Valve insert 8.3 FLOW RESTRICTOR The flow restrictor, which can be used if the ventilation is too low to trigger the start of a rebreathing, contains 4 small membrane flaps. Flow restrictor FIGURE 39. Flow restrictor February 2016 COR-MAN-0000-001-IN /EN, D/2 53

8.4 RVU TEST The RVU operates via pneumatic gas and is designed to open to either the rebreathing bag port at the back or to the ambient air port at the front. The RVU valve can be tested using the service part of the Innocor software: Disconnect the rebreathing bag and flow restrictor Enter Setup Enter Service Press the Misc TAB Press the Valve TAB Press the Pneu 1 button, and check that the rebreathing bag port is closed Press the Pneu 2 button, and check that the ambient air port is closed 8.5 SPIROMETRY MODE Option: When running a spirometry test the flowmeter must be set in stand alone mode, where the inspiration / expiration flow only enters the flowmeter and bacterial filter in order to minimize the flow resistance. The flowmeter and holder are disconnected from the RVU, moved upwards and reconnected using the knob on the lower part of the holder. FIGURE 40. Flowmeter in spirometry mode CAUTION. Flowmeter must be removed from RVU port to stand-alone position for spirometry test. February 2016 COR-MAN-0000-001-IN /EN, D/2 54

8.6 LCI MODE / DISPOSABLE SCRUBBER (CO 2 ABSORBER) Option: For LCI testing a Disposable Scrubber (CO 2 absorber) can be mounted in the rebreathing port (see figure 7, last picture, and figure 41) to avoid build-up of CO 2 during the rebreathing period where the inert tracer gas is washed in. The absorber material is a Calcium Hydroxide mixture with the trade name ExtendAir CO 2 Absorbent. The absorbent material, which uses the same chemistry as a granular sodalime absorbent, is a microporous polyethylene sheet coiled to form a cartridge. The molded ribs in the material create channels through which the breathing gases flow. One of the unique features of an ExtendAir cartridge is that the breathing resistance of the absorbent is precisely controlled by the constant rib height and spacing, resulting in a uniform reaction zone within the absorbent. Also, dusting is avoided. FIGURE 41. Disposable Scrubber (CO 2 absorber). February 2016 COR-MAN-0000-001-IN /EN, D/2 55