K Number
K152085
Date Cleared
2016-02-24

(212 days)

Product Code
Regulation Number
862.1160
Reference & Predicate Devices
Predicate For
N/A
AI/MLSaMDIVD (In Vitro Diagnostic)TherapeuticDiagnosticis PCCP AuthorizedThirdpartyExpeditedreview
Intended Use

For the quantitative in vitro determination of Carbon Dioxide in serum and plasma. Carbon Dioxide measurements are used in the diagnosis and treatment of numerous potentially serious disorders associated with changes in body acid-base balance.

This in vitro diagnostic device is intended for Rx Only.

Device Description

The Liquid CO2-2 (LCO2-2) kit assay consists of ready to use reagent solutions.

AI/ML Overview

The provided text describes the acceptance criteria and performance of the LIQUID CO2-2 (LCO2-2) device, which is an in vitro diagnostic for quantitative determination of Carbon Dioxide in serum and plasma.

Here's the breakdown of the information requested:

1. Table of Acceptance Criteria and Reported Device Performance:

Performance CharacteristicAcceptance CriteriaReported Device Performance
Precision(Not explicitly stated as a single numerical criterion, but evaluated consistent with CLSI EP5-A2 guidelines)QC Level 3: SD 0.79, CV 4.5%QC Level 2: SD 0.63, CV 5.5%SP Level 1: SD 0.75, CV 6.7%SP Level 2: SD 0.93, CV 5.0%SP Level 3: SD 1.33, CV 3.8%
Linearity/Reportable RangeDeviation from linearity < 5%Reportable Range: 10 to 40 mEq/LLinear Regression: Y = 0.99 + 0.75Correlation Coefficient (r): 0.999
Open Vial StabilityPercentage deviation of stable to fresh should be ≤5%Supports a reconstituted claim of 28 days when stored at +2°C to +8°C.
Real Time (Shelf Life) StabilityAll controls should be within rangeSupports a 2-year shelf life when stored at +2 to +8°C.
Limit of Blank (LoB)(Not explicitly stated as a numerical criterion, but determined per CLSI EP17-A2)0.97 mEq/L
Limit of Detection (LoD)(Not explicitly stated as a numerical criterion, but determined per CLSI EP17-A2)1.98 mEq/L
Limit of Quantitation (LoQ)(Not explicitly stated as a numerical criterion, but determined by precision)4.5 mEq/L (as determined by the lowest concentration at which precision is still met)
Analytical Specificity (Interference)Recovery within ±10% of the initial value of Carbon Dioxide concentration of 20 mEq/L and 35 mEq/LHemoglobin: No significant interference up to 1000mg/dLTotal Bilirubin: No significant interference up to 60mg/dLConjugate Bilirubin: No significant interference up to 30mg/dLTriglycerides: No significant interference up to 2000mg/dLIntralipid®: No significant interference up to 2000mg/dLAscorbic Acid: No significant interference up to 6.0mg/dL
Method Comparison (vs. Predicate)(Not explicitly stated as a single numerical criterion, but linear regression and correlation coefficient are provided for comparison)Linear Regression: Y = 0.97x - 0.11Correlation Coefficient (r): 0.994
Matrix Comparison (Serum vs. Lithium Heparin Plasma)(Not explicitly stated as a single numerical criterion, but linear regression and correlation coefficient are provided for comparison)Linear Regression: Y = 0.97x + 0.94Correlation Coefficient (r): 0.984
Reference Interval Verification (Expected Values)All values reported in the range for Healthy IndividualsAll values from 30 normal donors were within the quoted ranges for Carbon Dioxide (20 – 31 mEq/L).

2. Sample size used for the test set and the data provenance:

  • Precision: 80 samples for each level (QC Level 3, QC Level 2, SP Level 1, SP Level 2, SP Level 3). The samples included serum-based control material and unaltered human serum samples (spiked or diluted).
  • Linearity: 11 levels, tested in replicates of five.
  • Method Comparison: 97 serum patient samples.
  • Matrix Comparison: 50 matched patient sample pairs (serum and lithium heparin plasma).
  • Reference Interval Verification: Human serum from 30 normal donors.

Data provenance is not explicitly stated in terms of country of origin but is implied to be clinical laboratory testing. The studies appear to be prospective, specifically designed for device validation.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts (e.g., radiologist with 10 years of experience):

The document does not mention the use of experts to establish ground truth. These are in vitro diagnostic tests, where the "ground truth" for method comparison and similar studies is typically established by the results from a legally marketed (predicate) device or established analytical methods. For reference intervals, the ground truth is based on established clinical ranges and validated literature.

4. Adjudication method (e.g., 2+1, 3+1, none) for the test set:

Not applicable. This document describes analytical performance studies for an in vitro diagnostic device, not studies involving human readers or subjective interpretations requiring adjudication.

5. If a multi reader multi case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance:

Not applicable. This is an in vitro diagnostic device study, not an AI-assisted human reader study.

6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done:

Yes, all presented performance data (Precision, Linearity, Stability, Detection Limits, Interference, Method Comparison, Matrix Comparison) are for the device (LCO2-2) operating in a standalone, automated manner on an RX Daytona plus system, without human intervention in the analytical measurement workflow.

7. The type of ground truth used (expert consensus, pathology, outcomes data, etc):

  • Method Comparison: The predicate device (Siemens ADVIA Chemistry Carbon Dioxide Liquid (CO2 L) on an ADVIA 1650 system) serves as the reference or "ground truth" for comparison.
  • Traceability (Calibrator): The calibrator is traceable to Sodium Carbonate NIST reference material 351.
  • Reference Interval Verification: Referenced from literature (Tietz NW. Clinical Guide to Laboratory Tests. 3rd ed.) and verified against human serum from normal donors.

8. The sample size for the training set:

Not applicable. This document details the analytical validation of an in vitro diagnostic reagent, not the development or training of a machine learning algorithm.

9. How the ground truth for the training set was established:

Not applicable. As this is not an AI/machine learning device, there is no "training set" in the conventional sense. The "ground truth" for the calibrators and predicate device is established through their respective validation processes and traceability to reference materials/methods.

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Food and Drug Administration 10903 New Hampshire Avenue Document Control Center - WO66-G609 Silver Spring, MD 20993-0002

RANDOX LABORATORIES LTD PAULINE ARMSTRONG QA/RA MANAGER 55 DIAMOND ROAD ARDMORE BT29 4QY,GREAT BRITAIN

February 24, 2016

Re: K152085

Trade/Device Name: LIOUID CO2-2 (LCO2-2) Regulation Number: 21 CFR 862.1160 Regulation Name: Bicarbonate/carbon dioxide test system Regulatory Class: II Product Code: KHS Dated: January 20, 2015 Received: January 27, 2015

Dear Pauline Armstrong:

We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food. Drug. and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.

If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21. Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.

Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Parts 801 and 809); medical device reporting (reporting of medical device-related adverse events) (21 CFR 803); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820); and if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.

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If you desire specific advice for your device on our labeling regulations (21 CFR Parts 801 and 809), please contact the Division of Industry and Consumer Education at its toll-free number (800) 638 2041 or (301) 796-7100 or at its Internet address

http://www.fda.gov/MedicalDevices/Resourcesfor You/Industry/default.htm. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to

http://www.fda.gov/MedicalDevices/Safety/ReportaProblem/default.htm for the CDRH's Office of Surveillance and Biometrics/Division of Postmarket Surveillance.

You may obtain other general information on your responsibilities under the Act from the Division of Industry and Consumer Education at its toll-free number (800) 638-2041 or (301) 796-7100 or at its Internet address

http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm.

Sincerely yours.

Katherine Serrano -S

For: Courtney H. Lias, Ph.D. Director Division of Chemistry and Toxicology Devices Office of In Vitro Diagnostics and Radiological Health Center for Devices and Radiological Health

Enclosure

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DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration

Indications for Use

Form Approved: OMB No. 0910-0120 Expiration Date: January 31, 2017 See PRA Statement below.

510(k) Number (if known) K152085

Device Name LIQUID CO2-2 (LCO2-2)

Indications for Use (Describe)

For the quantitative in vitro determination of Carbon Dioxide in serum and plasma. Carbon Dioxide measurements are used in the diagnosis and treatment of numerous potentially serious disorders associated with changes in body acid-base balance.

This in vitro diagnostic device is intended for Rx Only.

Type of Use (Select one or both, as applicable)

[X] Prescription Use (Part 21 CFR 801 Subpart D)

Over-The-Counter Use (21 CFR 801 Subpart C)

CONTINUE ON A SEPARATE PAGE IF NEEDED.

This section applies only to requirements of the Paperwork Reduction Act of 1995,

DO NOT SEND YOUR COMPLETED FORM TO THE PRA STAFF EMAIL ADDRESS BELOW.

The burden time for this collection of information is estimated to average 79 hours per response, including the time to review instructions, search existing data sources, gather and maintain the data needed and complete and review the collection of information. Send comments regarding this burden estimate or any other aspect of this information collection, including suggestions for reducing this burden, to:

Department of Health and Human Services Food and Drug Administration Office of Chief Information Officer Paperwork Reduction Act (PRA) Staff PRAStaff(@fda.hhs.gov

"An agency may not conduct or sponsor, and a person is not required to respond to, a collection of information unless it displays a currently valid OMB number."

FORM FDA 3881 (8/14)

Page 1 of 1

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510(K) SUMMARY, LIQUID CO2-2 (LCO2-2)

1. SAFETY AND EFFECTIVENESS AS REQUIRED BY 21 CFR 807.92 STATEMENT

This summary of the 510(k) safety and effectiveness information is being submitted in accordance with the requirement 21 CFR 807.92.

SUBMITTER NAME AND ADDRESS 2.

Name: Dr Pauline Armstrong

Address: Randox Laboratories Limited 55 Diamond Road, Crumlin, County Antrim, BT29 4QY, United Kingdom.

Telephone: +44 (0) 28 9442 2413 Fax: +44 (0) 28 9445 2912 E-mail: Pauline.Armstrong@randox.com

Date of Summary Preparation: February 9, 2016

3. 510k NUMBER, DEVICE PROPRIETARY NAME, COMMON NAME, PURPOSE FOR SUBMISSION, REGULATORY CLASSIFCATION, PANEL, PRODUCT CODE AND 21 CFR NUMBER

510k No: K152085

Device Proprietary Name: Liquid CO2-2 (LCO2-2)

Common Name: Liquid CO2-2 (LCO2-2)

Purpose for Submission: New Device

ProductCodeRegulation NameClassificationRegulation SectionPanel
KHSBicarbonate/Carbon Dioxidetest systemClass II21 CFR862.1160ClinicalChemistry(75)

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4. PREDICATE DEVICE PROPRIETARY NAMES AND 510 (k) NUMBERS

Predicate Device Proprietary Name:

Siemens ADVIA Chemistry Carbon Dioxide Liquid (CO2 L)

510 (k) Number: K100289

5. INTENDED USE

For the quantitative in vitro determination of Carbon Dioxide in serum and plasma. Carbon Dioxide measurements are used in the diagnosis and treatment of numerous potentially serious disorders associated with changes in body acidbase balance.

This in vitro diagnostic device is intended for Rx only.

6. DEVICE DESCRIPTION

The Liquid CO2-2 (LCO2-2) kit assay consists of ready to use reagent solutions.

CATALOGUE NUMBER: CD8357

R1. Liquid CO2-2 Reagent4 x 18 ml
CAL. Liquid CO2-2 Calibrator1 x 10 ml

REAGENT COMPOSITION

ContentsConcentration in the test
R1. Liquid CO₂-2 ReagentPhosphoenolpyruvate (PEP)NADH analogueMicrobial Phosphoenolpyruvate Carboxylase(PEPC)Mammalian Malate Dehydrogenase (MDH)BufferSodium Azide12.5 mmol/l0.6 mmol/l>400 U/I>4100 U/IpH 7.60.08%
CAL. Liquid CO₂-2 CalibratorSee Lot Specific Insert

MATERIALS REQUIRED BUT NOT PROVIDED

Randox Assayed Multisera Level 2 (Cat. No. HN 1530) and Level 3 (Cat. No. HE 1532); 510(k) # K942458 0.9% NaCl solution for sample dilutions (if required)

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7. PREDICATE DEVICE COMPARISON TABLE

Table 1 Comparison of Liquid CO2-2 test system for the RX Daytona plus to predicate device

CHARACTERISTICSLiquid CO2-2 (LCO2-2) Assay forRX daytona plus(New Device)Siemens ADVIA Chemistry CarbonDioxide Liquid (CO2_L)ADVIA SYSTEMS K100289(Predicate Device)
Similarities
INTENDED USEFor the quantitative in vitro determination ofCarbon Dioxide in serum and plasma. CarbonDioxide measurements are used in thediagnosis and treatment of numerouspotentially serious disorders associated withchanges in body acid-base balanceSame
ASSAY PROTOCOLEnzymatic MethodSame
INSTRUMENTMODEAutomatic InstrumentSame
STORAGE(UNOPENED)Reagents are stable up to the expiry datewhen stored unopened at +2 to +8°CSame
CALIBRATIONFREQUENCYEveryday, with a change ofreagent lot or as indicated by quality controlprocedures.Same
SAMPLE TYPESerum, heparinized plasma samples aresuitable.Same
TEST RANGE10 - 40 mEq/LSame
Differences
REAGENTCOMPOSITION
Liquid CO2-2 ReagentPhosphoenolpyruvate (PEP)NADH analogueMicrobial PhosphoenolpyruvateCarboxylase (PEPC)Mammalian MalateDehydrogenase (MDH)BufferSodium AzideCAL. Liquid CO2-2 CalibratorSee Lot Specific Insert1.BufferBufferpH 6.5Phosphoenolpyruvate (PEP) 63 mmol/lNADH analogue 3.0 mmol/lMicrobial PhosphoenolpyruvateCarboxylase (PEPC) ≥2000 U/IMammalian MalateDehydrogenase (MDH) ≥20000 U/ISodium Azide 0.08%
12.5 mmol/l
0.6 mmol/l
>400 U/I
>4100 U/IpH 7.60.08%
CONTROLFREQUENCY
Two levels of control should be assayedat least once a dayFollow laboratory accreditation requirements.

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8. TEST PRINCIPLE (1,2)

PEPC + Mg++ Phosphoenolpyruvate + HCO3 Oxaloacetate + H2PO4 MDH Oxaloacetate + NADH analogue + H* ______ Malate + NAD* analogue

The reduction in absorbance at 415 nm caused by the oxidation of NADH analogue is proportional to the bicarbonate concentration in the sample.

I. Jacobs, N., et al "Laboratory Test Handbook" 2nd. ed., Williams and Wilkins 1990.

  1. Forrester, R.L., Wataji, L.J., Silverman, D.A., Pierre K.J., Clin, Chem. 1976; 22/2: 243-245.

9. PERFORMANCE CHARACTERISTICS

Analytical performance:

a. Precision/Reproducibility:

Precision was evaluated consistent with C.L.S.I documents EP5-A2 Precision studies were performed by one operator on two RX Daytona plus systems using serum based control material and unaltered human serum samples that were spiked with carbon dioxide concentrations or diluted to achieve concentrations based on normal ranges 20 - 31 mEq/L. Testing was conducted for two reagent lots of liquid CO2-2(LCO2-2), one lot on each RX Daytona plus system, twice per day for 20 non-consecutive days. Two replicates per run were performed for each sample. The assay was calibrated daily. The results of Lot 1 which is representative of both lots of Liquid CO2-2 (LCO2-2) reagent is summarized in the following table

Lot 1MEANWithin RunAmong RunAmong DayTotal
MethodProductN(mEq/L)SDCVSDCVSDCVSDCV
LCO2QC Level 38017.70.412.30.683.80.050.30.794.5
LCO2QC Level 28011.40.322.80.534.60.121.10.635.5
LCO2SP Level 18011.10.222.00.676.00.252.20.756.7
LCO2SP Level 28018.80.422.20.834.40.000.00.935.0
LCO2SP Level 38035.40.591.71.002.80.661.91.333.8
Table 2 Precision Summary

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b. Linearity/assay reportable range:

Linearity studies have been carried out in accordance with C.L.S.I. standard EP6-A. Linearity studies were performed at 11 levels to determine the analytical range of an assay - that is the range where the reported result is a linear function to the analyte concentration (or where deviation from linearity is less than 5%).

The linearity samples were prepared at 11 levels. Randox used a low serum pool sample around 4.0 mEq/l analyte concentration and a serum pool with a high concentration approximately 55 mEq/l using low and high serum pools. The low and high pools were mixed to make nine intermediate levels. Each level was run in replicates of five on two lots of Liquid CO2-2 (LCO2-2) reagent on one RX Daytona plus system. The observed values were compared to the expected values; the linear regression correlation between the expected values and the observed values are summarized in the following table:

Table 3 Linearity Summary including Regression equation and correlation coefficient.

Analyte TestedCO2 (mEq/L)
Linear Regression$Y = 0.99 + 0.75$
r0.999

The reportable range of the assay is 10 to 40 mEq/L

c. Traceability, Stability, Expected values (controls, calibrators, or methods):

Refer to K942458 Controls for Carbon Dioxide

The Liquid CO2-2 Calibrator is traceable to an internal master reference material that in turn is traceable to Sodium Carbonate NIST reference material 351. Calibrators are value assigned using one instrument and multiple repetitions. The mean, standard deviation and %CV are calculated and evaluated against acceptance criteria.

Open vial stability

Open vial stability of the Liquid CO2-2 Calibrator was assessed by preparing the material according to the package insert. Samples were stored at +2 to +8°C for 28 days and tested for Carbon Dioxide.

The acceptance criteria state the percentage deviation of stable to fresh should be ≤5%.

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Current open vial studies support a reconstituted claim of 28 days when stored at +2°C to +8°C.

Real Time Testing

This study was designed to verify and validate the predicted or desirable shelf life of the Liquid CO2-2 (LCO2-2) reagent and calibrator. Kits were stored at the routinely stored temperature of +2 to +8°C and tested at various time points. The acceptance criteria states that the all controls should be within range.

Current Real Time studies support a 2 year shelf life.

d. Detection limit:

Sensitivity studies have been carried out in accordance with C.L.S.I. guideline EP17-A2 'Evaluation of detection capability for clinical laboratory measurement procedures; Approved Guideline Second Edition'. A Limit of Blank (L.o.B.), a Limit of Detection (L.o.D.) and a Limit of Quantification were performed on two lots of reagents tested by two operators on one RX Daytona Plus system.

The Limit of Detection (LoD) for Carbon Dioxide on the RX Daytona Plus is 1.98 mEq/L based on 240 determinations, with 4 low level samples.

The Limit of Blank (LoB) is 0.97 mEq/L.

The Limit of Quantitation (LoQ) is 4.5 mEq/L as determined by the lowest concentration at which precision is still met.

e. Analytical Specificity:

Interference studies have been carried out in accordance with C.L.S.I. guideline EP7-A2 'Interference testing in clinical chemistry; Approved Guideline Second Edition' The effects of potential interferents were determined by calculating the mean value of the spiked interferent with the corresponding control solution. The spiked sample results were compared to control samples prepared without the potential interferents.

Acceptance Criteria:

The criteria for no significant interference is recovery within ±10% of the initial value of Carbon Dioxide concentration of 20 mEq/L and 35 mEq/L

Haemoqlobin No significant interference up to 1000mg/dL Total Bilirubin No significant interference up to 60mg/dL Conjugate Bilirubin No significant interference up to 30mg/dL

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TriglyceridesNo significant interference up to 2000mg/dL
Intralipid®No significant interference up to 2000mg/dL
Ascorbic AcidNo significant interference up to 6.0mg/dL

f. Method comparison with predicate device:

Correlation studies were carried out in accordance with C.L.S.I. guideline EP9-A2 'Method Comparison and Bias Estimation Using Patient Samples: Approved Guideline - Second Edition'.

97 serum patient samples spanning the range 12.5 to 39.4 mEq/L were tested by one operator on two lots of Liguid CO2-2 (LCO2-2) reagent on one RX Daytona plus analyzer and the predicate device tested on one ADVIA 1650 system across 3 working days with each sample tested in singlicate. The test method was compared to the predicate device and the following linear regression equation was obtained:

Y = 0.97x - 0.11 Correlation coefficient of r = 0.994

q. Matrix comparison:

Matrix method comparisons for Liquid CO2-2 (LCO2-2) assay was tested by one operator on one RX Daytona plus system and was assessed for two lots of reagents. Both serum and lithium heparin plasma were tested to determine whether method accuracy with plasma specimens are equivalent to serum results and that lithium heparin plasma does not interfere with either the method or the system.

Liquid CO2-2 (LCO2-2) matrix comparison on the RX Daytona plus (Lithium Heparin)

Patient samples were drawn in matched pairs - one sample serum (x) and the second sample lithium heparin plasma (v). 50 matched patient sample pairs were analyzed spanning the 13.9 to 38.1 mEq/L and the following linear regression equation was obtained:

Y = 0.97x + 0.94 Correlation coefficient of r = 0.984

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Expected values/Reference range:

Referenced from literature

A reference interval for Carbon Dioxide was verified using NCCLS C28-A3 guidelines. In a study, human serum from 30 normal donors were tested in singlicate on the RX daytona plus. The results obtained were ordered from lowest to highest before being examined for outliers using the Dixon test.

Upon confirmation there were no outliers; the values were compared to the quoted ranges for Carbon Dioxide. Results of the study indicate that all values reported in the range for Healthy Individuals.

Table 4 Reference Ranges

AnalyteExpected Values
Carbon Dioxide (3)20 – 31 mEq/L
  1. Tietz NW. Clinical Guide to Laboratory Tests. 3rd ed. Philadelphia, PA: WB Saunders Company; 1995:110-111.

10. CONCLUSION

Testing results indicate that the proposed device is substantially equivalent to the predicate device.

§ 862.1160 Bicarbonate/carbon dioxide test system.

(a)
Identification. A bicarbonate/carbon dioxide test system is a device intended to measure bicarbonate/carbon dioxide in plasma, serum, and whole blood. Bicarbonate/carbon dioxide measurements are used in the diagnosis and treatment of numerous potentially serious disorders associated with changes in body acid-base balance.(b)
Classification. Class II.