epoc Blood Urea Nitrogen Test, epoc Total Carbon Dioxide Test
Device Facts
| Record ID | K171247 |
|---|---|
| Device Name | epoc Blood Urea Nitrogen Test, epoc Total Carbon Dioxide Test |
| Applicant | Epocal, Inc. |
| Product Code | CDS · Clinical Chemistry |
| Decision Date | Jan 17, 2018 |
| Decision | SESE |
| Submission Type | Traditional |
| Regulation | 21 CFR 862.1770 |
| Device Class | Class 2 |
Indications for Use
The Blood Urea Nitrogen and Total Carbon Dioxide tests, as part of the epoc Blood Analysis System, is intended for use by trained medical professionals as an in vitro diagnostic device for the quantitative testing of samples of heparinized or unanticoagulated arterial, venous or capillary whole blood in the laboratory or at the point of care. Blood Urea Nitrogen measurements from the epoc Blood Analysis System are used in the diagnosis and treatment of certain renal and metabolic diseases. Total Carbon Dioxide measurements from the epoc Blood Analysis System are used in the diagnosis and treatment of disorders associated with changes in body acid-base balance.
Device Story
The epoc Blood Analysis System is a point-of-care diagnostic platform consisting of a handheld reader, host device, and single-use BGEM test cards. This submission adds BUN and TCO2 sensors to the existing card. The BUN sensor uses an enzymatic potentiometric method where urease hydrolyzes urea into ammonium ions, which are detected by an ion-selective electrode. The TCO2 test is calculated using the Henderson-Hasselbalch equation based on measured pH and pCO2, with calibration traceable to the IFCC reference method. The operator inserts a blood sample into the test card, which is then inserted into the reader for automated analysis. Results are displayed on the host device, allowing clinicians to make immediate decisions regarding renal function and acid-base status. The system provides rapid, bedside diagnostic information, reducing turnaround time compared to central laboratory testing.
Clinical Evidence
No clinical trials were performed. Evidence consists of analytical bench testing, including precision (CLSI EP05-A3), linearity (CLSI EP06-A), detection limits (CLSI EP17-A2), and interference studies (CLSI EP07-A2). Method comparison studies were conducted at 3 point-of-care sites comparing the epoc system against the Roche Cobas 8000 (BUN) and i-STAT CHEM8+ (TCO2). Results showed high correlation (R² > 0.94) across venous, arterial, and capillary samples. Matrix comparison confirmed suitability of lithium heparin, sodium heparin, and un-anticoagulated blood.
Technological Characteristics
The system uses an electrochemical multi-sensor array on a single-use test card. BUN sensing is enzymatic potentiometric (urease-based). TCO2 is calculated via the Henderson-Hasselbalch equation using measured pH and pCO2. The system is a handheld, point-of-care device. Calibration is performed using NIST-traceable standards. The device is designed for use with the epoc Reader and Host. Sterilization and specific material standards are not detailed beyond general laboratory equipment safety (IEC 61010-1).
Indications for Use
Indicated for trained medical professionals to perform quantitative testing of heparinized or un-anticoagulated arterial, venous, or capillary whole blood for BUN and TCO2 levels in laboratory or point-of-care settings. Used for diagnosis and treatment of renal, metabolic, and acid-base balance disorders.
Regulatory Classification
Identification
A urea nitrogen test system is a device intended to measure urea nitrogen (an end-product of nitrogen metabolism) in whole blood, serum, plasma, and urine. Measurements obtained by this device are used in the diagnosis and treatment of certain renal and metabolic diseases.
Predicate Devices
- i-STAT Chem8+ Cartridge (with i-STAT Portable Clinical Analyzer) (k053110)
Related Devices
- K061597 — EPOC BLOOD ANALYSIS SYSTEM · Epocal, Inc. · Sep 27, 2006
- K200107 — epoc Blood Analysis System · Epocal, Inc. · Jun 5, 2020
- K113726 — EPOC CHLORIDE TEST AND EPOC CREATININE TEST · Epocal, Inc. · Oct 5, 2012
Submission Summary (Full Text)
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# 510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION SUMMARY ASSAY ONLY TEMPLATE
A. 510(k) Number:
k171247
B. Purpose for Submission:
Addition of blood urea nitrogen (BUN) and total carbon dioxide (TCO₂) tests to a previously cleared device
C. Measurand:
Blood urea nitrogen and total carbon dioxide
D. Type of Test:
Quantitative, electromechanical biosensor for TCO₂
Enzymatic potentiometric-based sensing for BUN
E. Applicant:
Epocal, Inc.
F. Proprietary and Established Names:
epoc Blood Urea Nitrogen Test
epoc Total Carbon Dioxide Test
G. Regulatory Information:
1. Regulation section:
21 CFR 862.1770 Urea nitrogen test system
21 CFR 862.1160 Bicarbonate/carbon dioxide test system
2. Classification:
Class II
3. Product code:
CDS - Electrode, Ion Specific, Urea Nitrogen
JFL - pH Rate Measurement, Carbon-Dioxide
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4. Panel:
Clinical Chemistry (75)
H. Intended Use:
1. Intended use(s):
See Indication for use below.
2. Indication(s) for use:
The Blood Urea Nitrogen and Total Carbon Dioxide tests, as part of the epoc Blood Analysis System, is intended for use by trained medical professionals as an in vitro diagnostic device for the quantitative testing of samples of heparinized or un-anticoagulated arterial, venous or capillary whole blood in the laboratory or at the point of care.
Blood Urea Nitrogen measurements from the epoc Blood Analysis System are used in the diagnosis and treatment of certain renal and metabolic diseases.
Total Carbon Dioxide measurements from the epoc Blood Analysis System are used in the diagnosis and treatment of disorders associated with changes in body acid-base balance.
3. Special conditions for use statement(s):
For prescription use and point-of-care use.
For in vitro diagnostic use only.
4. Special instrument requirements:
epoc Blood Analysis System
I. Device Description:
The epoc BUN test is being added as an additional sensor to the existing single use test card that is used with the epoc Blood Analysis System. The epoc TCO₂ test is being added based on the standard Henderson-Hasselbalch equation (using the measured pCO₂ and pH values); this test is metrologically traceable to the IFCC TCO₂ reference method. The test card is inserted into the epoc Reader and all analytical steps are performed automatically. The epoc Blood Analysis System is an in vitro diagnostic device system for the quantitative testing of blood gases, electrolytes, and metabolites in venous, arterial, and capillary whole blood samples. The epoc System is comprised of 3 major subsystems: epoc Host, epoc Reader and epoc BGEM Test Card. The main accessory used with the epoc System includes the epoc Care-Fill Capillary Tubes used to collect and introduce capillary blood samples into the epoc Test Card.
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The epoc test card panel configuration currently includes sensors for the determination of pH, pCO₂, pO₂, Na, K, iCa, Cl, Glu, lactate, creatinine, and hematocrit in arterial, venous, and capillary blood samples cleared previously in k061597, k090109, k092849, k093297, and k113726. This premarket notification adds blood urea nitrogen (BUN) and total carbon dioxide (TCO₂) quantitation to the epoc BGEM Test Card and Blood Analysis System.
## J. Substantial Equivalence Information:
1. Predicate device name(s):
i-STAT Chem8+ Cartridge (with i-STAT Portable Clinical Analyzer)
2. Predicate 510(k) number(s):
k053110
3. Comparison with predicate:
| Similarities | | |
| --- | --- | --- |
| Item | Candidate Device: epoc Blood Urea Nitrogen test and epoc Total Carbon Dioxide test (k171247) | Predicate Device: BUN and TCO₂ Tests using the i-STAT Chem8+ Cartridge (with i-STAT Portable Clinical Analyzer) (k053110) |
| Intended use | Intended for use by trained medical professionals as an in vitro diagnostic device for the quantitative testing of samples of heparinized or un-anticoagulated arterial, venous or capillary whole blood in the laboratory or at the point of care.
BUN are used in the diagnosis and treatment of certain renal and metabolic diseases.
TCO₂ measurements are used in the diagnosis and treatment of disorders associated with changes in body acid-base balance. | Same |
| Sample type | Venous, arterial and capillary whole blood | Same |
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| Similarities | | |
| --- | --- | --- |
| Item | Candidate Device: epoc Blood Urea Nitrogen test and epoc Total Carbon Dioxide test (k171247) | Predicate Device: BUN and TCO2 Tests using the i-STAT Chem8+ Cartridge (with i-STAT Portable Clinical Analyzer) (k053110) |
| Technology | An electrochemical multi-sensor array integrated into a single-use test that is interpreted by a handheld reader and associated software | Same |
| Reportable ranges (TCO2) | 5-50 mmol/L | Same |
| Differences | | |
| --- | --- | --- |
| Item | Candidate Device: epoc Blood Urea Nitrogen test and epoc Total Carbon Dioxide test (k171247) | Predicate Device: BUN and TCO2 Tests using the i-STAT Chem8+ Cartridge (with i-STAT Portable Clinical Analyzer) (k053110) |
| Measured Parameter | pH; Carbon Dioxide, Partial Pressure (pCO2); Oxygen, Partial Pressure (pO2); Sodium (Na); Potassium (K); Ionized Calcium (iCa); Chloride (Cl); Glucose (Glu); Lactate (Lac); Creatinine (Crea); Hematocrit (Hct); Blood Urea Nitrogen (BUN); Total CO2 (TCO2) | Sodium (Na); Potassium (K); Ionized Calcium (iCa); Chloride (Cl); Glucose (Glu); Creatinine (Crea); Hematocrit (Hct); Urea Nitrogen (BUN); Total CO2 (TCO2) |
| Calculated Parameter | Bicarbonate (cHCO3-); Calculated Total Carbon Dioxide (cTCO2); (only available when measured TCO2 is not available) Base Excess (BE); Oxygen Saturation (cSO2); Alveolar Oxygen (A); Arterial Alveolar Oxygen Tension Gradient (A-a); Arterial Alveolar Oxygen Tension Ratio (a/A); Anion Gap (AGap, AGapK); Estimated Glomerular Filtration Rate (eGFR, eGRF-a); Hemoglobin (cHgb) BUN/Creatinine ratio (BUN/Crea) | Anion Gap (AnGap); Hemoglobin (Hgb) |
| Reportable ranges BUN | 3-120 mg/dL | 3-140 mg/dL |
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| Differences | | |
| --- | --- | --- |
| Item | Candidate Device: epoc Blood Urea Nitrogen test and epoc Total Carbon Dioxide test (k171247) | Predicate Device: BUN and TCO2 Tests using the i-STAT Chem8+ Cartridge (with i-STAT Portable Clinical Analyzer) (k053110) |
| Sample volume | At least 92 μL | 95 μL |
## K. Standard/Guidance Document Referenced (if applicable):
CLSI EP05-A3, Evaluation of Precision of Quantitative Measurement Procedures; Approved Guideline—Third Edition; 2014.
CLSI EP06-A, Evaluation of the linearity of Quantitative Measurement Procedures: a Statistical Approach; Approved Guideline—Second Edition; 2003.
CLSI EP07-A2, Interference Testing in Clinical Chemistry; Approved Guideline - Second Edition; 2002.
CLSI EP09-A3, Measurement Procedure Comparison and Bias Estimation Using Patient Samples; Approved Guideline - Third Edition; 2013.
CLSI EP17-A2, evaluation of detection capability for clinical laboratory measurement procedures; approved guideline - Second Edition.
IEC 61010-1, Safety requirements for electrical equipment for measurement, control and laboratory use – Part 1: General requirements; IECEE, 2010.
CLSI H11-A4, Procedures for the Collection of Arterial Blood Specimens; Approved Standard—Forth Edition; 2004.
## L. Test Principle:
### Urea Nitrogen (BUN) Sensor
The sensor module consists of an epoxy foil supporting array of foil electrode contacts on the outer side (or contact surface) and an array of sensor membranes on the inner side (or sensor surface). The epoc BUN electrode design is an enzymatic potentiometric-based sensing device. The BUN electrode uses the enzyme urease to hydrolyze urea to ammonium ions, as follows:
$$
\mathrm{Urea} + \mathrm{H_2O} + 2\mathrm{H^+} + \mathrm{Urease} \rightarrow 2\mathrm{NH_4^+} + \mathrm{CO_2}
$$
A potentiometric ion-selective electrode then detects the enzymatically-produced ammonium ion. The sensor is designed as a two-layer device, each layer providing the functions described above. The concentration of ammonium ions is obtained from the measured potential using the Nernst equation.
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# Total Carbon Dioxide
The epoc System calculates total carbon dioxide using the measured and reported values of pH and $p\mathrm{CO}2$ according to the standard Henderson-Hasselbalch equation:
Calculated $\mathrm{TCO}_2$ ( $\mathrm{cTCO}_2$ ) = $\mathrm{cHCO}_3^-$ + 0.0307 x $p\mathrm{CO}_2$
where: $\mathrm{LOG~cHCO_3^- = pH + LOG~}p\mathrm{CO}_2 - 7.608$
This calculated $\mathrm{TCO}_2$ ( $\mathrm{cTCO}_2$ ) value is metrologically traceable to the epoc pH and $p\mathrm{CO}_2$ measurements, which are in turn traceable to primary standard reference materials for pH and $p\mathrm{CO}_2$ .
The measured $\mathrm{TCO}_2$ is achieved by calibrating a function of pH and $p\mathrm{CO}_2$ against the accepted IFCC Reference Measurement Procedure for Total Carbon Dioxide by mathematically modifying the calculated $\mathrm{TCO}_2$ equation in order to match the IFCC reference values. Hence, the measured $\mathrm{TCO}_2$ will be metrologically traceable to the IFCC $\mathrm{TCO}_2$ reference method.
# M. Performance Characteristics (if/when applicable):
# 1. Analytical performance:
# a. Precision/Reproducibility:
# Internal Precision Study
The precision study was conducted following the CLSI EP5-A3 guideline. Two levels of aqueous controls were tested in duplicate on 2 separate runs per day over 20 days using 4 lots of test cards and 11 epoc Blood Analysis Systems. The total precision results are shown in the table below:
| Total Precision: BUN | | | | |
| --- | --- | --- | --- | --- |
| Level | Mean (mg/dL) | N | SD | %CV |
| Low | 7.1 | 320 | 0.32 | 4.5 |
| High | 51.7 | 320 | 1.16 | 2.3 |
| Total Precision: TCO2 | | | | |
| --- | --- | --- | --- | --- |
| Level | Mean (mmol/L) | N | SD | %CV |
| L1 | 16.2 | 320 | 1.02 | 6.3 |
| L3 | 30.7 | 320 | 0.92 | 3.0 |
External precision studies at POC sites:
Additional precision studies were performed at 3 point-of-care (POC) sites with multiple POC operators.
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i. An external precision study was performed using three levels of commercially available controls. For each level of control, each operator ran a maximum 12 test cards from 3 lots. The results for within-run precision and total precision results are shown in the tables below:
| BUN | | | | | | |
| --- | --- | --- | --- | --- | --- | --- |
| Level | Mean (mg/dL) | N | Within Run | | Total Precision | |
| | | | SD | %CV | SD | %CV |
| L1 | 7.1 | 168 | 0.24 | 3.4 | 0.26 | 3.7 |
| L2 | 17.7 | 171 | 0.45 | 2.5 | 1.11 | 6.3 |
| L3 | 52.1 | 170 | 1.06 | 2.0 | 1.54 | 3.0 |
| TCO2 | | | | | | |
| --- | --- | --- | --- | --- | --- | --- |
| Level | Mean (mmol/L) | N | Within Run | | Total Precision | |
| | | | SD | %CV | SD | %CV |
| L1 | 15.9 | 172 | 0.44 | 2.8 | 0.50 | 3.1 |
| L2 | 19.7 | 172 | 1.00 | 5.1 | 1.12 | 5.7 |
| L3 | 30.4 | 169 | 0.58 | 1.9 | 1.05 | 3.4 |
ii. A whole blood precision study was performed using freshly collected lithium heparin venous whole blood samples. The 2 types of sample delivery methods were evaluated (syringe and capillary tubes) at all 3 POC sites. A total of 12 operators (4 operators per site) participated in the study. Within-run precision for each individual operator was calculated. The results of all sites and all operators are shown in the tables below:
| BUN Whole Blood Precision: Syringe Delivery Mode | | | | | |
| --- | --- | --- | --- | --- | --- |
| Level | N | Range (mg/dL) | Mean (mg/dL) | SD | %CV |
| Lo | 136 | 3.7 - 10.6 | 7.0 | 0.6 | 7.2% |
| Normal | 136 | 12.5 – 35.5 | 17.3 | 0.7 | 4.1% |
| Hi | 134 | 51.8 - 72.4 | 57.4 | 1.3 | 2.3% |
| BUN Whole Blood Precision: Capillary tube Delivery Mode | | | | | |
| --- | --- | --- | --- | --- | --- |
| Level | N | Range (mg/dL) | Mean (mg/dL) | SD | %CV |
| Lo | 135 | 5.9 - 9.7 | 7.6 | 0.5 | 7.0% |
| Normal | 135 | 11.9 – 20.8 | 15.6 | 0.6 | 3.9% |
| Hi | 136 | 51.3 - 60.3 | 55.5 | 1.6 | 2.9% |
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| TCO₂ Whole Blood Precision: Syringe Delivery Mode | | | | | |
| --- | --- | --- | --- | --- | --- |
| Level | n | Range (mmol/L) | Mean (mmol/L) | SD | %CV |
| Lo | 136 | 5.0 - 15.9 | 10.5 | 0.4 | 3.7% |
| Normal | 136 | 22.3 - 30.9 | 27.5 | 0.4 | 1.4% |
| Hi | 134 | 33.8 - 40.0 | 36.5 | 0.6 | 1.5% |
| TCO₂ Whole Blood Precision: Capillary tube Delivery Mode | | | | | |
| --- | --- | --- | --- | --- | --- |
| Level | n | Range (mmol/L) | Mean (mmol/L) | SD | %CV |
| Lo | 134 | 11.2 - 15.0 | 34.1 | 1.4 | 3.5% |
| Normal | 137 | 22.4 - 28.3 | 25.6 | 0.7 | 2.9% |
| Hi | 139 | 31.7 - 36.2 | 34.1 | 0.7 | 2.1% |
b. Linearity/assay reportable range:
The linearity study was performed based on the CLSI EP6-A guideline. Lithium heparin whole blood samples with nine levels of analyte concentrations spanning the entire measuring range of each assay were prepared and tested. Regression analysis was performed as per CLSI EP6-A guideline; results are shown below.
BUN
| Claimed Range | Test range | Slope | Intercept | R² |
| --- | --- | --- | --- | --- |
| 3-120 mg/dL | 4-120 mg/dL | 1.0204 | 0.3996 | 0.9979 |
TCO₂
| Claimed Range | Test range | Slope | Intercept | R² |
| --- | --- | --- | --- | --- |
| 5-50 mmol/L | 4-50 mmol/L | 0.9032 | 3.3176 | 0.9994 |
The results of the linearity studies support the claimed measuring ranges described in the tables above.
c. Traceability, Stability, Expected values (controls, calibrators, or methods):
Traceability:
Calibration of the epoc system is performed using both primary and secondary NIST traceable standards.
The calibration fluid is prepared gravimetrically from pure materials and is handled anaerobically during the test card manufacturing process until it is sealed between metallized foils in each epoc test.
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For $TCO_{2}$
The pCO2-pH (and hence the $\mathrm{HCO^{-}}$ ) the stability in the calibration fluid as part of the epoc test card was previously cleared under k061597.
# d. Detection limit:
The study was performed as per the CLSI EP17-A2 guideline. Test samples were prepared from whole blood using lithium heparin anticoagulant. 4 blank and 4 low concentration samples were each prepared separately for BUN and $\mathrm{TCO_2}$ . Each sample was tested using two epoc BGEM Test Cards lots over 3 days.
A minimum of 64 replicates of measurements (16 replicates x 4 samples) per lot were used to calculate the LoB, LoD, and LoQ of BUN. For $\mathrm{TCO_2}$ , a minimum of 60 replicates of measurements per lot were used (15 replicates x 4 samples). The LoB was calculated as the $95^{\text{th}}$ percentile using the nonparametric method and a risk level, $\beta$ , of 0.05. The LoD was evaluated from the lowest analyte level that had at least $95\%$ of the replicates greater than the LoB. The limit of quantitation was determined according to accuracy goal based on total error (TE); for BUN the TE accuracy goal was $2\mathrm{mg / dL}$ and for $\mathrm{TCO_2}$ of $4\mathrm{mmol / L}$ . The results of the detection limits study are summarized below:
| Analyte | LoB | LoD | LoQ | Claimed Range |
| --- | --- | --- | --- | --- |
| BUN (mg/dL) | 2 | 3 | 3 | 3 - 120 |
| TCO2(mmol/L) | 4 | 4.3 | 4.3 | 5 - 50 |
# e. Analytical specificity:
An interferent testing of the BUN and $\mathrm{TCO_2}$ measurements on the epoc Blood Analysis System was performed per the CLSI EP07-A2 guideline. Potential interferences were evaluated at BUN concentrations of 8 and $20\mathrm{mg / dL}$ and $\mathrm{TCO_2}$ concentrations of 20 and $35\mathrm{mmol / L}$ . In each of these tests, human specimens were aliquoted into 2 samples. The test samples were spiked with interferent, while the control samples were spiked with the solvent of the interferent. The bias between the control sample and the test sample with added interferent was calculated. The concentration of interfering substance considered as causing no clinically significant interference is defined as a bias (difference between the test and the control sample) of: $1.77\mathrm{mg / dL}$ for BUN; $3.32\mathrm{mmol / L}$ for $\mathrm{TCO_2}$ concentrations $\leq 20\mathrm{mmol / L}$ and $2.95\mathrm{mmol / L}$ for $\mathrm{TCO_2}$ concentrations $>20\mathrm{mmol / L}$ .
# Summary of interference studies for BUN:
The interferences tested and found to be clinically non-significant are summarized below:
| Substance tested | Highest concentration tested showing no significant interference |
| --- | --- |
| Acetaminophen | 20 mg/dL |
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| Substance tested | Highest concentration tested showing no significant interference |
| --- | --- |
| Acetoacetic Acid (Li salt) | 21.6 mg/dL |
| Acetyl Salicylic Acid | 65.2 mg/dL |
| Ammonium ions | 5.35 mg/dL |
| Ascorbate (Na) | 6.8 mg/dL |
| Benzalkonium Chloride | 0.002% |
| Bilirubin Conjugated | 28.8 mg/dL |
| Bilirubin Unconjugated | 25 mg/dL |
| Bromide | 386 mg/dL |
| Cefazolin (Na) | 125.9 mg/dL |
| Ceftriaxone (Na) | 96.6 mg/dL |
| CO2 High (NaHCO3) | 630.6 mg/dL |
| Citrate (Na tribasic dihydrate) | 588 mg/dL |
| Dopamine HCl | 0.1 mg/dL |
| EDTA | 744 mg/dL |
| Ethanol | 400 mg/dL |
| Fluoride (Na) | 399 mg/dL |
| Gallamine Triethiodide | 4.46 mg/dL |
| Glucose | 504 mg/dL |
| Glutathione oxidized | 156 mg/dL |
| Glutathione reduced | 156 mg/dL |
| Glycolic Acid | 38 mg/dL |
| Hematocrit (High) | 60% vs 45% (Spun) |
| Hematocrit (Low) | 20% vs 45% (Spun) |
| Heparin (Na) | 20 U/mL |
| β-Hydroxybutyrate (Na) | 252 mg/dL |
| Hydroxyurea | 15.2 mg/dL |
| Ibuprofen | 50 mg/dL |
| Intralipid | 500 mg/dL |
| Iodide (Na) | 19.5 mg/dL |
| Lactate (Na) | 74 mg/dL |
| L-Cysteine | 12 mg/dL |
| L-dopa | 0.5 mg/dL |
| Lithium (Cl) | 13.5 mg/dL |
| Metamizole (Na) | 210.8 mg/dL |
| Methotrexate | 90 mg/dL |
| N-Acetyl Cysteine | 163 mg/dL |
| Nithiodote (Na Thiosulfate) | 264 mg/dL |
| Oxalate (K) Monohydrate | 4 mg/dL |
| Pentothal (Na) | 6.5 mg/dL |
| Perchlorate (Na) | 12.2 mg/dL |
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| Substance tested | Highest concentration tested showing no significant interference |
| --- | --- |
| pH – Low | pH <6.8 |
| pH – High | pH>8 |
| Protein – Low | 3.5 g/dL |
| Protein – High | 10 g/dL |
| Salicylic Acid (Na salicylate) | 69.5 mg/dL |
| Thiocyanate (K) | 16.7 mg/dL |
| Uric acid | 23.5 mg/dL |
Clinically significant interfering substances for BUN measurements are itemized below:
- Samples contaminated with benzalkonium salts used as coatings for in-dwelling lines may cause elevated BUN results. For proper line-flushing procedures refer to CLSI H11-A4.
- Citrate will have no significant effect up to 6.0 mmol/L (176.5 mg/dL) after which it will decrease the BUN concentration by up to 0.26 mg/dL BUN per mmol/L citrate.
- EDTA will have no significant effect up to 4.5 mmol/L (167 mg/dL) after which it will decrease the BUN concentration by up to 0.43 mg/dL BUN per mmol/L EDTA.
- Glutathione reduced will have no significant effect up to 1.7 mmol/L (52.2 mg/dL), after which it will increase the BUN concentration by up to 1.91 mg/dL BUN per mmol/L glutathione reduced. Blood glutathione (GSH) in human subjects is ~0.79-1.05 mmol/L. Long term oral glutathione reduced supplementation (250-1,000 mg/day administered for 6 months) increases glutathione plasma levels by ~0.2-8 μmol/L (~0.01-0.25 mg/dL). Short-term, oral intake of glutathione reduced does not affect plasma glutathione levels.
- β-Hydroxybutyrate will have no significant effect up to 17.2 mmol/L (216.9 mg/dL), after which it will decrease the BUN concentration by up to 0.11 mg/dL BUN per mmol/L hydroxybutyrate. The reference range for β-hydroxybutyrate in plasma is <0.4 to 0.5 mmol/L. β-hydroxybutyrate concentration over 3 mmol/L are indicative of ketoacidosis; in very severe diabetic ketoacidosis the concentration may exceed 25 mmol/L.
- Hydroxyurea will have no significant effect up to 1.3 mmol/L (9.9 mg/dL), after which it will increase the BUN concentration by up to 1.61 mg/dL BUN per mmol/L hydroxyurea. The recommended dose of hydroxyurea for patients range from 15 mg/kg/day to 30 mg/kg/day. A treatment dose of 2,000 mg/day (~30mg/kg) results in maximum plasma concentration of ~800μmol/L with oral administration and ~1 mmol/L with intravenous method.
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- N-acetylcysteine will have no significant effect up to $9.2\mathrm{mmol / L}$ (150.1 mg/dL), after which it will increase the BUN concentration by up to 0.11 mg/dL BUN per mmol/L N-acetylcysteine. It has been reported that 1 mmol/L N-acetyl cysteine is therapeutically unattainable in plasma. The therapeutic level for N-acetyl cysteine is 0.3 mmol/L.
- Nithiodote will have no significant effect up to $4.1\mathrm{mmol / L}$ (64.8 mg/dL) after which it will decrease the BUN concentration by up to $0.41\mathrm{mg / dL}$ BUN per mmol/L Nithiodote. The expected peak sodium thiosulfate plasma concentration following a $12.5\mathrm{g}$ of Nithiodote is $16.7\mathrm{mmol / L}$ .
# Summary of interference studies for $\mathrm{TCO_2}$
The interferences tested and found to be clinically non-significant are summarized below:
| Substance tested | Highest concentration tested showing no significant interference |
| --- | --- |
| Acetaminophen | 20 mg/dL |
| Acetoacetic Acid (Li salt) | 21.6 mg/dL |
| Acetylsalicylic Acid | 65.2 mg/dL |
| Ammonium ions | 5.35 mg/dL |
| Ascorbate (Na) | 6.8 mg/dL |
| Benzalkonium Chloride | 0.001% |
| Bilirubin Conjugated | 26.8 mg/dL |
| Bilirubin Unconjugated | 25 mg/dL |
| Bromide | 386 mg/dL |
| Cefazolin (Na) | 125.9 mg/dL |
| Ceftriaxone (Na) | 96.6 mg/dL |
| Citrate (Na tribasic dihydrate) | 588 mg/dL |
| Dopamine HCl | 0.1 mg/dL |
| EDTA | 186mg/dL |
| Ethanol | 400 mg/dL |
| Fluoride (Na) | 399 mg/dL |
| Gallamine Triethiodide | 4.46 mg/dL |
| Glucose | 504mg/dL |
| Glutathione oxidized | 156 mg/dL |
| Glutathione reduced | 156 mg/dL |
| Glycolic Acid | 38 mg/dL |
| Hematocrit (High) | 60% vs 45% (Spun) |
| Hematocrit (Low) | 20% vs 45% (Spun) |
| Heparin (Na) | 20 U/mL |
| β-Hydroxybutyrate (Na) | 252 mg/dL |
| Hydroxyurea | 15.2 mg/dL |
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| Substance tested | Highest concentration tested showing no significant interference |
| --- | --- |
| Ibuprofen | 50 mg/dL |
| Intralipid | 500 mg/dL |
| Iodide (Na) | 19.5 mg/dL |
| Lactate (Na) | 74 mg/dL |
| L-Cysteine | 12 mg/dL |
| L-dopa | 0.5 mg/dL |
| Lithium (Cl) | 13.5 mg/dL |
| Metamizole (Na) | 210.8 mg/dL |
| Methotrexate | 90 mg/dL |
| N-Acetyl Cysteine | 163 mg/dL |
| Nithiodote (Na Thiosulfate) | 264 mg/dL |
| Oxalate (K) Monohydrate | 4 mg/dL |
| Pentothal (Na) | 6.5 mg/dL |
| Perchlorate (Na) | 12.2 mg/dL |
| pH – Low | pH <6.8 |
| Protein – Low | 3.5 g/dL |
| Protein – High | 10 g/dL |
| Salicylic Acid (Na salicylate) | 69.5 mg/dL |
| Thiocyanate (K) | 16.7 mg/dL |
| Uric acid | 23.5 mg/dL |
Clinically significant interfering substances for $\mathrm{TCO}_2$ measurements are itemized below:
- Samples contaminated with benzalkonium salts used as coatings for in-dwelling lines may cause significant decrease in $\mathrm{TCO}_2$ results. For proper line-flushing procedures refer to CLSI H11-A4.
- Citrate will have no significant effect up to $11.8\ \mathrm{mmol/L}$ ($347.0\ \mathrm{mg/dL}$) after which it will increase the $\mathrm{TCO}_2$ concentration by up to $0.24\ \mathrm{mmol/L}\ \mathrm{TCO}_2$ per mmol/L citrate.
- EDTA will have no significant effect up to $4.8\ \mathrm{mmol/L}$ ($178.7\ \mathrm{mg/dL}$) after which it will increase the $\mathrm{TCO}_2$ concentration by up to $0.57\ \mathrm{mmol/L}\ \mathrm{TCO}_2$ per mmol/L EDTA.
- N-acetyl cysteine will have no significant effect up to $9.6\ \mathrm{mmol/L}$ ($156.7\ \mathrm{mg/dL}$) after which it will increase the $\mathrm{TCO}_2$ concentration by up to $0.54\ \mathrm{mmol/L}\ \mathrm{TCO}_2$ per mmol/L N-acetyl cysteine. It has been reported that $1\ \mathrm{mmol/L}$ N-acetyl cysteine is therapeutically unattainable in plasma. The therapeutic level for N-acetyl cysteine is $0.3\ \mathrm{mmol/L}$.
{13}
f. Assay cut-off:
Not applicable.
# 2. Comparison studies:
a. Method comparison with predicate device:
Method comparison studies were performed at 3 POC sites by POC operators. Lithium heparin venous and arterial whole blood samples and fresh capillary whole blood samples were analyzed for BUN using the epoc Blood Analysis System (candidate device) and compared to matched lithium heparin plasma samples analyzed using BUN assay on the Roche Cobas 8000 Modular Analyzer. Lithium heparin venous and arterial whole blood samples and fresh capillary whole blood samples were analyzed for $\mathrm{TCO_2}$ using the epoc Blood Analysis System (candidate device) and the i-STAT CHEM8+/i-STAT system (predicate device). The results of the overall performance of the device at all the sites are summarized in the tables below.
BUN Regression Analysis Summary for epoc Blood Analysis System vs. Roche Cobas 8000 Modular Analyzer
| Venous Samples - BUN | | | | | |
| --- | --- | --- | --- | --- | --- |
| | N | Intercept | Slope | R² | Range (mg/dL) |
| Site 1 | 50 | 0.8 | 0.953 | 0.996 | 4-109 |
| Site 2 | 49 | 0.8 | 0.962 | 0.996 | 4-118 |
| Site 3 | 50 | -0.6 | 1.035 | 0.997 | 4-118 |
| All Sites | 149 | 0.2 | 0.990 | 0.995 | 4-118 |
| Arterial Samples - BUN | | | | | |
| --- | --- | --- | --- | --- | --- |
| | N | Intercept | Slope | R² | Range (mg/dL) |
| Site 1 | 42 | 0.9 | 0.973 | 0.995 | 7-106 |
| Site 2 | 49 | 0.9 | 0.943 | 0.996 | 8-118 |
| Site 3 | 50 | 1.0 | 1.028 | 0.997 | 3-107 |
| All Sites | 141 | 0.9 | 0.977 | 0.994 | 3-118 |
| Capillary Samples - BUN | | | | | |
| --- | --- | --- | --- | --- | --- |
| | N | Intercept | Slope | R² | Range (mg/dL) |
| Site 1 | 48 | 0.4 | 1.001 | 0.995 | 5-117 |
| Site 2 | 45 | 0.5 | 0.945 | 0.997 | 6-112 |
| Site 3 | 50 | 0.0 | 0.995 | 0.998 | 6-118 |
| All Sites | 143 | 0.2 | 0.986 | 0.996 | 5-118 |
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$\mathsf{TCO}_2$ Regression Analysis Summary for epoc Blood Analysis System vs i-STAT-CHEM8+ Cartridges (Venous, Arterial, and Capillary Samples)
| Venous Samples - TCO2 | | | | | |
| --- | --- | --- | --- | --- | --- |
| | N | Intercept | Slope | R² | Range (mmol/L) |
| Site 1 | 54 | -0.80 | 1.041 | 0.978 | 10-49 |
| Site 2 | 60 | -5.60 | 1.146 | 0.969 | 11-45 |
| Site 3 | 50 | -1.30 | 1.057 | 0.957 | 13-45 |
| All Sites | 164 | -2.80 | 1.086 | 0.953 | 10-49 |
| Arterial Samples - TCO2 | | | | | |
| --- | --- | --- | --- | --- | --- |
| | N | Intercept | Slope | R² | Range (mmol/L) |
| Site 1 | 53 | -2.5 | 1.125 | 0.965 | 11-41 |
| Site 2 | 53 | -2.3 | 1.098 | 0.972 | 7-44 |
| Site 3 | 54 | -0.8 | 1.024 | 0.974 | 19-41 |
| All Sites | 160 | -1.8 | 1.079 | 0.966 | 7-44 |
| Capillary Samples - TCO2 | | | | | |
| --- | --- | --- | --- | --- | --- |
| | N | Intercept | Slope | R² | Range (mmol/L) |
| Site 1 | 103 | 1.7 | 0.947 | 0.949 | 8-49 |
| Site 2 | 76 | -0.12 | 1.029 | 0.946 | 9-49 |
| Site 3 | 71 | -0.36 | 1.053 | 0.954 | 9-47 |
| All Sites | 250 | 0.65 | 0.999 | 0.946 | 8-49 |
# b. Matrix comparison:
A comparison was performed to demonstrate the equivalence between lithium heparin whole blood and un-anticoagulated venous whole blood and sodium heparin venous whole blood for testing BUN and $\mathrm{TCO_2}$ levels. The results of linear regression for heparinized (Na heparin) vs. lithium heparin, and non-anticoagulated venous samples vs lithium heparin are shown below:
| BUN | | | | |
| --- | --- | --- | --- | --- |
| Matrix | N | Intercept | Slope | R² |
| No Additive | 62 | 0.1 | 1.000 | 0.989 |
| Sodium heparin | 62 | 0.3 | 0.981 | 0.992 |
| TCO2 | | | | |
| --- | --- | --- | --- | --- |
| Matrix | N | Intercept | Slope | R2 |
| No Additive | 62 | 0.1 | 0.980 | 0.980 |
| Sodium heparin | 62 | 0.6 | 0.970 | 0.989 |
The results of the matrix comparison study support that lithium heparin, sodium heparin and non-anticoagulated whole blood specimens are suitable for use with the epoc Blood Urea Nitrogen Test and epoc Total Carbon Dioxide Test.
{15}
16
3. Clinical studies:
a. Clinical Sensitivity:
Not applicable.
b. Clinical specificity:
Not applicable.
c. Other clinical supportive data (when a. and b. are not applicable):
Not applicable.
4. Clinical cut-off:
Not applicable.
5. Expected values/Reference range:
The following expected values are provided in the product insert based on the literature:
| Analyte | Reference Range |
| --- | --- |
| TCO_{2} | 22-29 mmol/L (arterial) |
| | 23-30 mmol/L (venous) |
| BUN | 8-26 mg/dL |
- Tietz Textbook of Clinical Chemistry and Molecular Diagnostics, fourth edition, C.A. Burtis, E.R. Ashwood, and D.E. Bruns eds., Elsevier Saunders, St. Louis, 2006.
- E. Statland, Clinical Decision Levels for Lab Tests, Medical Economic Books, Oradell, Ni, 1987.
- Pruden E.L., Siggaard-Andersen 0., and Tietz N.W., Chapter 30 (Blood Gases and pH), of Tietz Textbook of Clinical Chemistry, Second Edition, ed. C.A. Burtis and E.R. Ashwood. W.B. Saunders Company, Philadelphia, 1994
N. Proposed Labeling:
The labeling is sufficient and it satisfies the requirements of 21 CFR Part 809.10.
O. Conclusion:
The submitted information in this premarket notification is complete and supports a substantial equivalence decision.
