We describe the validation methodology for the NIRS based FORE-SIGHT ELITE
®
(CAS Medical Systems, Inc., Branford, CT, USA) tissue oximeter for cerebral and somatic tissue oxygen saturation (StO
2
) ...measurements for adult subjects submitted to the United States Food and Drug Administration (FDA) to obtain clearance for clinical use. This validation methodology evolved from a history of NIRS validations in the literature and FDA recommended use of Deming regression and bootstrapping statistical validation methods. For cerebral validation, forehead cerebral StO
2
measurements were compared to a weighted 70:30 reference (REF CX
B
) of co-oximeter internal jugular venous and arterial blood saturation of healthy adult subjects during a controlled hypoxia sequence, with a sensor placed on the forehead. For somatic validation, somatic StO
2
measurements were compared to a weighted 70:30 reference (REF CX
S
) of co-oximetry central venous and arterial saturation values following a similar protocol, with sensors place on the flank, quadriceps muscle, and calf muscle. With informed consent, 25 subjects successfully completed the cerebral validation study. The bias and precision (1 SD) of cerebral StO
2
compared to REF CX
B
was −0.14 ± 3.07%. With informed consent, 24 subjects successfully completed the somatic validation study. The bias and precision of somatic StO
2
compared to REF CX
S
was 0.04 ± 4.22% from the average of flank, quadriceps, and calf StO
2
measurements to best represent the global whole body REF CX
S
. The NIRS validation methods presented potentially provide a reliable means to test NIRS monitors and qualify them for clinical use.
Increased hemoglobin (Hb) concentration accompanying hypoxemia is a compensatory response to maintain tissue oxygen delivery. Near infrared spectroscopy (NIRS) is used clinically to detect ...abnormalities in the balance of cerebral tissue oxygen delivery and consumption, including in children with congenital heart disease (CHD). Although NIRS-measured cerebral tissue O2 saturation (ScO2) correlates with arterial oxygen saturation (SaO2), jugular bulb O2 saturation (SjbO2), and Hb, little data exist on the interplay between these factors and cerebral O2 extraction (COE). This study investigated the associations of ScO2 and ΔSaO2-ScO2 with SaO2 and Hb and verified the normal range of ScO2 in children with CHD.
Children undergoing cardiac catheterization for CHD were enrolled in a calibration and validation study of the FORE-SIGHT NIRS monitor. Two pairs of simultaneous arterial and jugular bulb samples were drawn for co-oximetry, calculation of a reference ScO2 (REF CX), and estimation of COE. Pearson correlation and linear regression were used to determine relationships between O2 saturation parameters and Hb. Data were also analyzed according to diagnostic group defined as acyanotic (SaO2 ≥ 90%) and cyanotic (SaO2 < 90%).
Of 65 children studied, acceptable jugular bulb samples (SjbO2 absolute difference between samples ≤10%) were obtained in 57 (88%). The ΔSaO2-SjbO2, ΔSaO2-ScO2, and ΔSaO2-REF CX were positively correlated with SaO2 and negatively correlated with Hb (all P < .001). Although by diagnostic group ScO2 differed statistically (P = .002), values in the cyanotic patients were within the range considered normal (69% ± 6%). COE estimated by the difference between arterial and jugular bulb O2 content (ΔCaO2-CjbO2, mL O2/100 mL) was not different for cyanotic and acyanotic patients (P = .10), but estimates using ΔSaO2-SjbO2, ΔSaO2-ScO2, or ΔSaO2-ScO2/SaO2 were significantly different between the cyanotic and acyanotic children (P < .001).
Children with adequately compensated chronic hypoxemia appear to have ScO2 values within the normal range. The ΔSaO2-ScO2 is inversely related to Hb, with the implication that in the presence of reduced Hb, particularly if coupled with a decreased cardiac output, the ScO2 can fall to values associated with brain injury in laboratory studies.
The pressure reactivity index (PRx) describes cerebral vessel reactivity by correlation of slow waves of intracranial pressure (ICP) and arterial blood pressure. In theory, slow changes in the ...relative total hemoglobin (rTHb) measured by near-infrared spectroscopy are caused by the same blood volume changes that cause slow waves of ICP. Our objective was to develop a new index of vascular reactivity, the hemoglobin volume index (HVx), which is a low-frequency correlation of arterial blood pressure and rTHb measured with near-infrared spectroscopy.
Gradual hypotension was induced in piglets while cortical laser-Doppler flux was monitored. ICP was monitored, and rTHb was measured continuously using reflectance near-infrared spectroscopy. The HVx was recorded as a moving linear correlation between slow waves (20 to 300 seconds) of arterial blood pressure and rTHb. Autoregulation curves were constructed by averaging values of the PRx or HVx in 5-mm Hg bins of cerebral perfusion pressure.
The laser-Doppler flux-determined lower limit of autoregulation was 29.4+/-6.7 mm Hg (+/-SD). Coherence between rTHb and ICP was high at low frequencies. HVx was linearly correlated with PRx. The PRx and HVx both showed higher values below the lower limit of autoregulation and lower values above the lower limit of autoregulation. Areas under the receiver operator characteristic curves were 0.88 and 0.85 for the PRx and HVx, respectively.
Coherence between the rTHb and ICP waveforms at the frequency of slow waves suggests that slow waves of ICP are related to blood volume changes. The HVx has potential for further development as a noninvasive alternative to the PRx.
Cerebral oximetry using near-infrared spectroscopy is a noninvasive optical technology to detect cerebral hypoxia-ischemia and develop interventions to prevent and ameliorate hypoxic brain injury. ...Cerebral oximeters are calibrated and validated by comparison of the near-infrared spectroscopy-measured cerebral O2 saturation (SctO2) to a "field" or reference O2 saturation (REF CX) calculated as a weighted average from arterial and jugular bulb oxygen saturations. In this study, we calibrated and validated the second-generation, 5 wavelength, FORE-SIGHT Elite with the medium sensor (source-detector separation 12 and 40 mm) for measurement of SctO2 in children with congenital heart disease.
After institutional review board approval and written informed consent, 63 children older than 1 month and ≥2.5 kg scheduled for cardiac catheterization were enrolled. Self-adhesive FORE-SIGHT Elite medium sensors were placed on the right and left sides of the forehead. Blood samples for calculation of REF CX were drawn simultaneously from the aorta or femoral artery and the jugular bulb before (T1) and shortly after (T2) baseline hemodynamic measurements. FORE-SIGHT Elite SctO2 measurements were compared to the REF CX (REF CX = 0.3 SaO2 + 0.7 SjbO2) using Deming regression, least squares linear regression, and Bland-Altman analysis.
Sixty-one subjects (4.5 standard deviation 4.4 years of age; 17 standard deviation 13 kg, male 56%) completed the study protocol. Arterial oxygen saturation ranged from 64.7% to 99.1% (median 96.0%), jugular bulb venous oxygen saturation from 34.1% to 88.1% (median 68.2%), the REF CX from 43.8% to 91.4% (median 76.9%), and the SctO2 from 47.8% to 90.8% (median 76.3%). There was a high degree of correlation in SctO2 between the right and left sensors at a given time point (within subject between sensor correlation r = 0.91 and 95% confidence interval CI, 0.85-0.94) or between T1 and T2 for the right and left sensors (replicates, within subject between time point correlation r = 0.95 and 95% CI, 0.92-0.96). By Deming regression, the estimated slope was 0.966 (95% CI, 0.786-1.147; P = .706 for testing against null hypothesis of slope = 1) with a y intercept of 2.776 (95% CI, -11.102 to 16.654; P = .689). The concordance correlation coefficient was 0.873 (95% CI, 0.798-0.922). Bland-Altman analysis for agreement between SctO2 and REF CX that accounted for repeated measures (both in times and sensors) found a bias of -0.30% (95% limits of agreement: -10.56% to 9.95%).
This study calibrated and validated the FORE-SIGHT Elite tissue oximeter to accurately measure SctO2 in pediatric patients with the medium sensor.
The CAS neonatal NIRS system determines absolute regional brain tissue oxygen saturation (SnO2) and brain true venous oxygen saturation (SnvO2) non-invasively. Since NIRS-interrogated tissue contains ...both arterial and venous blood from arterioles, venules, and capillaries, SnO2 is a mixed oxygen saturation parameter, having values between arterial oxygen saturation (SaO2) and cerebral venous oxygen saturation (SVO2). To determine a reference for SnO2, the relative contribution of SvO2 to SaO2 drawn from a brain venous site vs. systemic SaO2 is approximately 70:30 (SvO2:SaO2). If the relationship of the relative average contribution of SvO2 and SaO2 is known and does not change to a large degree, then NIRS true venous oxygen saturation, SnvO2, can be determined non-invasively using SnO2 along with SaO2 from a pulse oximeter.
Anesthetic exposure during pregnancy is viewed as a relatively routine medical practice. However, recent rodent studies have suggested that common anesthetic agents can damage the developing brain. ...Here we assessed this claim in a higher order species by exposing previously instrumented near-term pregnant sheep at gestational day 122 (±1) to a combination of midazolam, sodium thiopental, and isoflurane at clinically relevant doses and means of anesthetic delivery (i.e., active ventilation). Four hours of maternal general anesthesia produced an initial increase in fetal systemic oxygenation and a sustained increase in fetal cerebral oxygenation, as determined by in utero near-infrared spectroscopy. Postexposure monitoring failed to identify changes in physiologic status that could be injurious to the fetal brain. Finally, through the histologic assessment of noninstrumented sheep at the same gestational time point, we found no evidence for a direct fetal neuro-toxic effect of our triple-drug regimen. Collectively, these results appear to corroborate the presumed safety of inhalational anesthetic use during pregnancy.
Background: Barth syndrome (BTHS) is a rare X-linked disorder that is characterized by mitochondrial abnormalities, cardio-skeletal myopathy, exercise intolerance, and premature mortality. The effect ...on endurance exercise training on exercise tolerance, cardio-skeletal function, and quality of life in BTHS is unknown.
Methods: Four young adults (23 ± 5 years, n = 4) with BTHS participated in a 12-week, supervised, individualized endurance exercise training program. Exercise training was performed on a cycle ergometer for 30–45′ three times per week at a moderate intensity level. Exercise tolerance was measured by graded exercise testing and peak oxygen consumption, heart function via two-dimensional and M-mode echocardiography, skeletal muscle function by near-infrared spectroscopy, and quality of life through the Minnesota Living with Heart Failure questionnaire.
Results: There were no adverse events during exercise testing or training for any participant. Peak oxygen consumption modestly (~5%) improved in three or four participants. Mean quality of life questions regarding dyspnea and side effects from medications significantly improved following exercise training. Mean resting heart function or skeletal muscle oxygen extraction during exercise did not improve after exercise training.
Conclusion: Endurance exercise training is safe and appears to modestly improve peak exercise tolerance and certain measures of quality of life in young adults with BTHS. However, compared to improvements resulting from endurance exercise training seen in other non-BTHS mitochondrial myopathies and heart failure, these improvements appear blunted. Further research into the most beneficial mode, intensity and frequency of exercise training in BTHS is warranted.
ABSTRACT
Transit timing variations (TTVs) can be induced by a range of physical phenomena, including planet–planet interactions, planet–moon interactions, and stellar activity. Recent work has shown ...that roughly half of moons would induce fast TTVs with a short period in the range of 2–4 orbits of its host planet around the star. An investigation of the Kepler TTV data in this period range identified one primary target of interest, Kepler-1513 b. Kepler-1513 b is a $8.05^{+0.58}_{-0.40}$ R⊕ planet orbiting a late G-type dwarf at $0.53^{+0.04}_{-0.03}$ au. Using Kepler photometry, this initial analysis showed that Kepler-1513 b’s TTVs were consistent with a moon. Here, we report photometric observations of two additional transits nearly a decade after the last Kepler transit using both ground-based observations and space-based photometry with TESS. These new transit observations introduce a previously undetected long period TTV, in addition to the original short period TTV signal. Using the complete transit data set, we investigate whether a non-transiting planet, a moon, or stellar activity could induce the observed TTVs. We find that only a non-transiting perturbing planet can reproduce the observed TTVs. We additionally perform transit origami on the Kepler photometry, which independently applies pressure against a moon hypothesis. Specifically, we find that Kepler-1513 b’s TTVs are consistent with an exterior non-transiting ∼Saturn mass planet, Kepler-1513 c, on a wide orbit, $\sim 5~{{\ \rm per \, cent}}$ outside a 5:1 period ratio with Kepler-1513 b. This example introduces a previously unidentified cause for planetary interlopers in the exomoon corridor, namely an insufficient baseline of observations.
Abstract
Convergent disk migration has long been suspected to be responsible for forming planetary systems with a chain of mean-motion resonances (MMRs). Dynamical evolution over time could disrupt ...the delicate resonant configuration. We present TOI-1136, a 700 ± 150 Myr old G star hosting at least six transiting planets between ∼2 and 5
R
⊕
. The orbital period ratios deviate from exact commensurability by only 10
−4
, smaller than the ∼10
−2
deviations seen in typical Kepler near-resonant systems. A transit-timing analysis measured the masses of the planets (3–8
M
⊕
) and demonstrated that the planets in TOI-1136 are in true resonances with librating resonant angles. Based on a Rossiter–McLaughlin measurement of planet d, the star’s rotation appears to be aligned with the planetary orbital planes. The well-aligned planetary system and the lack of a detected binary companion together suggest that TOI-1136's resonant chain formed in an isolated, quiescent disk with no stellar flyby, disk warp, or significant axial asymmetry. With period ratios near 3:2, 2:1, 3:2, 7:5, and 3:2, TOI-1136 is the first known resonant chain involving a second-order MMR (7:5) between two first-order MMRs. The formation of the delicate 7:5 resonance places strong constraints on the system’s migration history. Short-scale (starting from ∼0.1 au) Type-I migration with an inner disk edge is most consistent with the formation of TOI-1136. A low disk surface density (Σ
1 au
≲ 10
3
g cm
−2
; lower than the minimum-mass solar nebula) and the resultant slower migration rate likely facilitated the formation of the 7:5 second-order MMR.
Abstract
We report the discovery of TOI-2180 b, a 2.8
M
J
giant planet orbiting a slightly evolved G5 host star. This planet transited only once in Cycle 2 of the primary Transiting Exoplanet Survey ...Satellite (TESS) mission. Citizen scientists identified the 24 hr single-transit event shortly after the data were released, allowing a Doppler monitoring campaign with the Automated Planet Finder telescope at Lick Observatory to begin promptly. The radial velocity observations refined the orbital period of TOI-2180 b to be 260.8 ± 0.6 days, revealed an orbital eccentricity of 0.368 ± 0.007, and discovered long-term acceleration from a more distant massive companion. We conducted ground-based photometry from 14 sites spread around the globe in an attempt to detect another transit. Although we did not make a clear transit detection, the nondetections improved the precision of the orbital period. We predict that TESS will likely detect another transit of TOI-2180 b in Sector 48 of its extended mission. We use giant planet structure models to retrieve the bulk heavy-element content of TOI-2180 b. When considered alongside other giant planets with orbital periods over 100 days, we find tentative evidence that the correlation between planet mass and metal enrichment relative to stellar is dependent on orbital properties. Single-transit discoveries like TOI-2180 b highlight the exciting potential of the TESS mission to find planets with long orbital periods and low irradiation fluxes despite the selection biases associated with the transit method.
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