1

CLINICAL VALIDATION

Pediatric Validation of the FORE-SIGHT ELITE® Tissue OximeterThis review describes the validation methodology and results for the FORE-SIGHT ELITE Absolute Tissue Oximeter on both cerebral and non-cerebral sites of pediatric patients to measure tissue oxygen saturation (StO2). The data from these studies on FORE-SIGHT ELITE substantiated pediatric use claims for a 2015 FDA clearance that also included use claims in adults and transitional adolescents (K143675). This FDA clearance built upon a lengthy history of expanded claims for the FORE-SIGHT Tissue Oximeter.16-18

MethodsTwo separate IRB-approved protocols were undertaken in multiple institutions to ensure accurate data in a complete pediatric popula-tion. Two different sensor sizes were used (Medium and Small) to pro-vide targeted penetration depths appropriate for the pediatric tissue and patient populations of interest. The study designs enrolled pedi-atric patients undergoing procedures in the Cath-Lab (cardiac cathe-terization laboratory) or babies in the NICU (Neonatal Intensive Care Unit), rather than in healthy volunteers as used in the adult validation studies, because it would be unethical to enroll healthy children in an invasive study of this nature.

All FORE-SIGHT ELITE Sensors emit 5 wavelengths of light (690, 730, 770, 805, and 870 nm) from an LED light source with two detectors (placed 12 mm and 40 mm from the light source for Medium Sensors and 9 mm and 25 mm for Small Sensors), to measure and calculate StO2. The FORE-SIGHT algorithm compensates for background tissue light absorption and scattering, as well as skin pigmentation, in order to calculate accurate StO2.

1. Cath-Lab Protocol to Validate Medium and Small Sensors on Sub-jects ≥ 2.5 kg. The first protocol was for pediatric patients weighing ≥ 2.5 kg undergoing cardiac catheterization (Cath-Lab Protocol) at Boston Children’s Hospital, Duke University Medical Center, and Mon-roe Children’s Hospital at Vanderbilt to measure both cerebral and non-cerebral StO2. These patients had two sensors placed on their foreheads to measure cerebral StO2 and two additional sensors over their abdomen (anterior and posterior-flank). The subject’s weight determined the size of the sensors used, either Medium or Small (Table 1). As done in prior validation studies,1,2,5-10 these StO2 values were compared with an arteriovenous reference derived from ve-nous and arterial blood samples, taken at the same time as the StO2 measurement and analyzed with a co-oximeter for functional oxygen saturation. For both the cerebral and non-cerebral data, the arterial catheter was placed in the aorta or femoral artery. The venous blood sample location was different for the cerebral and non-cerebral mea-surements: the catheter was placed in the internal jugular vein (SijvO2) for the cerebral StO2 and in a central venous location (ScvO2) for the non-cerebral measurement. Because of the varied types of congenital heart disease in the subject pool, the selected sampling site of central venous blood for each subject was based upon a location unaffected by their particular congenital heart disease. Thus, the sampling sites included the inferior vena cava, superior vena cava, right atrium, right ventricle, left pulmonary artery and/or the right pulmonary artery.

The weighted co-oximetry reference equations for StO2 (Ref CX) used to validate the sensors (Table 1) were based on the assumption that 70% of blood in both cerebral and non-cerebral tissues is venous, while 30% is arterial.9-12 The blood in the internal jugular vein rep-resents venous blood in the brain whereas the selected central ve-nous location collects systemic venous blood that is representative of non-cerebral tissues. Posterior and anterior abdominal StO2 mea-surements were averaged before analysis to represent a composite non-cerebral StO2 value. FORE-SIGHT ELITE StO2 values were com-pared with the Ref CX vales to derive the accuracy performance data.

2. NICU Protocol to Validate Small Sensors on Subjects ≤ 5 kgThe second protocol was designed to capture StO2 data on ≤ 5 kg patients in the Neonatal Intensive Care Units of Children’s National Medical Center, Sharp Mary Birch Hospital, St. Louis Children’s Hospital, Boston Children’s Hospital, Monroe Children’s Hospital at Vanderbilt, and Duke University Medical Center, including premature neonates and very low birth-weight babies. This NICU Protocol included both cerebral and non-cerebral StO2 measurements. Subjects were enrolled who already had an umbilical venous catheter to ethically obtain an appropriate central venous blood sample from the inferior vena cava for the non-cerebral validation.

To validate cerebral StO2 with a Small Sensor, FORE-SIGHT ELITE was directly compared with the predicate FDA-cleared FORE-SIGHT I (Table 1). Unlike the other FORE-SIGHT validation studies, this cere-bral validation did not include invasive measurements because of the challenge for medical centers to obtain consent to insert an internal jugular venous catheter in very small subjects. A FORE-SIGHT ELITE Small Sensor was placed on the subject’s forehead for 2 minutes, fol-lowed by a FORE-SIGHT I Small Sensor as the reference for 2 minutes. This sequence was repeated once for each subject with all sensors be-ing applied in the same position, wherever adequate space allowed.

To validate non-cerebral StO2, a FORE-SIGHT ELITE Small Sensor was placed on the posterior and anterior abdomen in 6 different locations (left flank, right flank, liver, and over the intestines in the right-lower quadrant, left-lower quadrant, and mid-lower quadrant), for 2 minutes each. A venous blood sample was taken from the umbilical venous catheter and peripheral oxygen saturation from pulse oximetry was used for the arterial blood sample to avoid unnecessary blood draws. Blood from the umbilical venous catheter best represents venous blood to the non-cerebral sites in these small patients.13,14 For analysis, all body locations per subject were averaged to represent a global non-cerebral measurement and compared with the systemic Ref StO2 (Table 1).

Table 1: Protocol, sensor sizes, and reference equations used in pediatric FORE-SIGHT ELITE validation study

Patient weight

Protocol used

Cerebral sensor size(s)

Non-cerebral sensor size(s)

Cerebral reference equation (Ref CX)

Non-cerebral reference equation (Ref CX)

≥ 8 kg Cath-Lab Medium Medium (0.7 x SijvO2)+ (0.3 x SaO2) (0.7 x ScvO2) + (0.3 x SaO2)

3 to 8 kg Cath-Lab Medium & Small Medium & Small (0.7 x SijvO2) + (0.3 x SaO2) (0.7 x ScvO2) + (0.3 x SaO2)

≤ 5 kg NICU Small Small StO2 (FORE-SIGHT 1) (0.7 x SuvO2) + (0.3 x SaO2)

2

CLINICAL VALIDATION

Sensor size Sensor location Number of subjects Bias ± precision (1 SD) StO2range Reference figure

Primary analysis

Medium Cerebral 72 0.05 ± 5.06% 48-92% 1a, 1b

Medium Non-cerebral 68 -0.03 ± 5.52% 53-88% 2a, 2b

Small Cerebral 73 -0.01 ± 5.38% 50-90% 4a, 4b

Small Non-cerebral 57 0.03 ± 5.69% 66-96% 5a, 5b

Secondary analysis

Medium Body 74 0.03 ± 5.15% 48-92% 3a, 3b

Small Body 77 0.00 ± 5.50% 50-96% 6a, 6b

Table 2: Summary of pediatric validation results

The results from the Ref CX equations (Table 1) were compared with the tissue oximeter’s StO2 values to derive the bias and precision. The Medium Sensor analysis used data only from the Cath-Lab Protocol, while the Small Sensor analysis combined values from both the Cath-Lab and NICU protocols.

ResultsThe Medium Sensor was validated on 74 subjects with the Cath-Lab Protocol (40 Male; 48 Caucasian, 9 African American, 4 Hispanic, 2 Asian, 1 American Indian, 10 Other/Unknown; 3.3-73.3 kg, 0.1-16.7 years). The Medium Sensor had a bias and precision (1 standard deviation) of 0.05 ± 5.06% for the cerebral measurement and -0.03 ± 5.52% for the non-cerebral saturation (Figures 1a, 1b, 2a, 2b, Table 2). In a secondary analysis, the cerebral and non-cerebral measurements were combined to determine the accuracy of a whole body measurement, i.e., 0.03 ± 5.15% (Figures 3a, 3b, Table 2).

The Small Sensor was applied to 77 subjects from both the Cath-Lab and NICU protocols (41 Male; 29 Caucasian, 20 African-American, 15 Hispanic, 3 Asian, 1 American Indian, 2 Multiracial, 7 Other/ Unknown; 0.5-7.7 kg; 1-317 days; 23-42 weeks gestational age. The bias and precision of the Small Sensor cerebral site was -0.01 ± 5.38%, 0.03 ± 5.69% for the non-cerebral sites, and 0.00 ± 5.50% for the whole body (Figures 4a, 4b, 5a, 5b, 6a, 6b, Table 2).

ConclusionsFORE-SIGHT ELITE with Medium and Small Sensors have demonstrat-ed high accuracy in a broad range of pediatric patients: 136 subjects from 6 institutions, ranging in age from 1 day to 17 years and weights from 0.5 to 73.3 kg, with diverse skin tones. The FORE-SIGHT ELITE can now be used to accurately determine cerebral and non-cerebral StO2 values on any age patient via a range of sensor sizes (Table 3).

References1. K123700. (adult cerebral) FORE-SIGHT ELITE Absolute Tissue Oximeter.

FDA 510(k) premarket notification. 2. K133879. (adult non-cerebral) FORE-SIGHT ELITE Absolute Tissue

Oximeter. FDA 510(k) premarket notification. 3. K143675. (pediatric brain & non-cerebral; Small & Medium Sensors)

FORE-SIGHT ELITE Absolute Tissue Oximeter. FDA 510(k) premarket notification.

4. Kussman BD, Laussen PC, Benni PB, McElhinney DB, McGowan FX. Validation of the FORE-SIGHT Tissue Oximeter for measurement of somatic oxygenation in children. Proceedings of the 2011 Annual Meeting of the American Society of Anesthesiologists; Abstract A154.

5. K073036. (Small Sensor; infants & neonates) FORE-SIGHT, MC-2000 SERIES. FDA 510(K) premarket notification.

6. K083892. FORE-SIGHT, Model MC-2000 Series (MC-2000, MC-2010, MC2020, MC2030). FDA 510(k) premarket notification.

7. K091452. (pediatric; Medium Sensor) FORE-SIGHT, Model MC-2000 Series (MC 2000, MC2010, MC-2020, MC2030). FDA 510(k) premarket notification. (neonates)

8. K094030. (skeletal muscle in pediatrics) FORE-SIGHT Absolute Cere-bral and somatic oximeter MC 2000 SERIES, Models MC2000, MC2010, MC2020, MC2030. FDA 510(k) premarket notification.

9. Rais-Bahrami K, Rivera O, Short BL. Validation of a noninvasive neonatal optical cerebral oximeter in veno-venous ECMO patients with a cephalad catheter. J Perinatol 2006;26(10):628-35.

10. Benni P, Chen B, Dykes F, Wagoner SF, Heard M, Tanner AJ, Young TL, Rais-Bahrami R, Rivera O, Short BL. Validation of the CAS neonatal NIRS system by monitoring vv-ECMO patients: preliminary results. Adv Exp Med Biol 2005; 566:195-201.

11. Ito H, Kanno I, Iida H, Hatazawa J, Shimosegawa E, Tamura H, Okudera T. Arterial fraction of cerebral blood volume in humans measured by positron emission tomography. Ann Nucl Med 2001;15(2):111-6.

12. Pang CC. Measurement of body venous tone. J Pharmacol Toxicol Methods 2000;44(2):341-60.

13. Plötz FB, van Lingen RA, Bos AP. Venous oxygen measurements in the inferior vena cava in neonates with respiratory failure. Crit Care 1998;2(2):57-60.

14. Shiao SY, Ou CN. Validation of oxygen saturation monitoring in neonates. Am J Crit Care 2007;16(2):168-78.

15. Bland JM, Altman DG. Statistical methods for assessing agreement between two methods of clinical measurement. Lancet 1986;1(8476):307-10.

16. Benkwitz C, Janssen DR, Doyle TP. Accuracy Performance of the FORE-SIGHT ELITE Tissue Oximeter in Context with Simultaneous Vital Sign Recording in Pediatric Patients Undergoing Cardiac Catheterization. Presented at the 9th Annual Meeting of the Congenital Cardiac Anesthesia Society (CCAS). March 2015.

17. Nasr V, Bergersen L, Benni PB, Bernier R, Anderson ME, Kussman BD. Validation of the FORE-SIGHT ELITE pediatric tissue oximeter in children. Presented at the 37th Annual Meeting of the Society of Cardiovascular Anesthesiologists (SCA Abstract #16; April 2015, Washington DC).

18. Kussman BD, Benni PB, Bergersen LT, Bernier R, Anderson ME, Nasr V. Validation of the FORE-SIGHT ELITE tissue oximeter for measurement of somatic oxygenation in children. Presented at the 37th Annual Meeting of the Society of Cardiovascular Anesthesiologists (SCA Abstract #97; April 2015, Washington DC).

Table 3: Indications for use of FORE-SIGHT ELITE Sensors

Sensor size

Patient population

Cerebral use

Non-cerebral use

Small Pediatric < 8 kg < 5 kg

Medium Pediatric ≥ 3 kg ≥ 3 kg

Large* Adult & transitional adolescent ≥ 40 kg ≥ 40 kg

*previously validated1

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CLINICAL VALIDATION

Figure 1aMedium Sensor / Cerebral (left & right hemisphere)

REF CX (0.3 x SaO2) + (0.7 x SijvO2)

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72 subjectsWeight 3.3 - 73.3 kg252 data pointsBias = 0.05Precision (1SD) = 5.06

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Mean0.0

Figure 1b

Scatter plot and Bland-Altman plot14 of Medium Sensor cerebral data: FORE-SIGHT ELITE StO2 vs. blood co-oximetry REF CX = (0.3 x SaO2) + (0.7 x SijvO2)

There were 2 to 4 samples per subject from 2 sensors placed on the left and right forehead.

Scatter plot and Bland-Altman plot14 of all Medium Sensor dataThese aggregate plots capture the StO2 measurements from all cerebral and non-cerebral sensor sites.

Figure 3aMedium Sensor / Cerebral & Non-cerebral

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74 subjectsWeight 3.3 - 73.3 kg320 data pointsBias = 0.03Precision (1SD) = 5.15

StO2 (cerebral)StO2 (non-cerebral)

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REF CX = (0.3 x SaO2) + (0.7 x SvO2)

Average of REF CX and StO2

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Figure 3b

Scatter plot and Bland-Altman plot14 of Medium Sensor non-cerebral data: FORE-SIGHT ELITE StO2 vs. blood co-oximetry REF CX = (0.3 x SaO2) + (0.7 x ScvO2)

Average of REF CX and StO2

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Figure 2bFigure 2a

Medium Sensor / Non-cerebral

REF CX (0.3 x SaO2) + (0.7 x ScvO2)

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68 subjectsWeight 3.3 - 73.3 kg68 data pointsBias = -0.03Precision (1SD) = 5.52

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CLINICAL VALIDATION

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CASMED and FORE-SIGHT ELITE are registered trademarks of a CAS Medical Systems, Inc.

Figure 4aSmall Sensor / Cerebral

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73 subjectsWeight 0.5 - 7.7 kg73 data pointsBias = -0.01Precision (1SD) = 5.38

StO2 (FORE-SIGHT 1)StO2 (REF CX)

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REF (predicate FORE-SIGHT 1) or REF CX (0.3 x SaO2) + (0.7 x SijvO2)

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Average of REF CX and StO2

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tO2

Figure 4b

Scatter plot and Bland-Altman plot14 of Small Sensor cerebral data: FORE-SIGHT ELITE StO2 vs. predicate FORE-SIGHT 1 StO2 or vs. blood co-oximetry REF CX = (0.3 x SaO2) + (0.7 x SijvO2)

Scatter plot and Bland-Altman plot14 of Small Sensor non-cerebral data: FORE-SIGHT ELITE StO2 vs. blood co-oximetry REF CX = (0.3 x SaO2) + (0.7 x SuvO2)

Figure 5aSmall Sensor / Non-cerebral

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57 subjectsWeight 0.5 - 4.8 kg57 data pointsBias = 0.03Precision (1SD) = 5.69

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Average of REF CX and StO2

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Figure 5b

Figure 6aSmall Sensor / Cerebral & Non-cerebral

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77 subjectsWeight 3.3 - 7.7 kg130 data pointsBias = 0.00Precision (1SD) = 5.50

StO2 (cerebral)StO2 (non-cerebral)

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Average of REF CX and StO2

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Figure 6b

Scatter plot and Bland-Altman plot14 of all Small Sensor cerebral and non-cerebral dataThese aggregate plots capture the StO2 measurements from all cerebral and non-cerebral sensor sites.

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