Liquid Blood Phantoms to Validate NIRS Oximeters: Yeast Versus Nitrogen for Deoxygenation

Liquid blood phantoms are a tool to calibrate, test and compare near-infrared spectroscopy (NIRS) oximeters. They comprise a mixture of saline, blood and Intralipid, which is subsequently oxygenated and deoxygenated to assess the entire range of tissue oxygen saturation (StO) from 0% to 100%. The aim was to investigate two different deoxygenation methods: yeast versus nitrogen (N) bubbling. The phantom was oxygenated with pure O in both experiments, but deoxygenated by bubbling N in the first and by addition of yeast and glucose in the second experiment. A frequency domain NIRS instrument (OxiplexTS) was used as reference and to monitor changes in the reduced scattering coefficient (μ') of the phantom. Both deoxygenation methods yielded comparable StO values. The deoxygenation was slower by a factor 2.8 and μ' decreased faster when bubbling N. The constant bubbling of N mechanically stresses the Intralipid emulsion and causes a decrease in μ', probably due to aggregation of lipid droplets. Deoxygenation by N requires a more complex, air tight phantom. The gas flow cools the liquid and temperature needs to be monitored more closely. Consequently, we recommend using yeast for phantom deoxygenation

Detailed statistical analysis plan for the SafeBoosC III trial : a multinational randomised clinical trial assessing treatment guided by cerebral oxygenation monitoring versus treatment as usual in extremely preterm infants

Background: Infants born extremely preterm are at high risk of dying or suffering from severe brain injuries. Treatment guided by monitoring of cerebral oxygenation may reduce the risk of death and neurologic complications. The SafeBoosC III trial evaluates the effects of treatment guided by cerebral oxygenation monitoring versus treatment as usual. This article describes the detailed statistical analysis plan for the main publication, with the aim to prevent outcome reporting bias and data-driven analyses. Methods/design: The SafeBoosC III trial is an investigator-initiated, randomised, multinational, pragmatic phase III trial with a parallel group structure, designed to investigate the benefits and harms of treatment based on cerebral near-infrared spectroscopy monitoring compared with treatment as usual. Randomisation will be 1:1 stratified for neonatal intensive care unit and gestational age (lower gestational age (< 26 weeks) compared to higher gestational age ( 65 26 weeks)). The primary outcome is a composite of death or severe brain injury at 36 weeks postmenstrual age. Primary analysis will be made on the intention-to-treat population for all outcomes, using mixed-model logistic regression adjusting for stratification variables. In the primary analysis, the twin intra-class correlation coefficient will not be considered. However, we will perform sensitivity analyses to address this. Our simulation study suggests that the inclusion of multiple births is unlikely to significantly affect our assessment of intervention effects, and therefore we have chosen the analysis where the twin intra-class correlation coefficient will not be considered as the primary analysis. Discussion: In line with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines, we have developed and published this statistical analysis plan for the SafeBoosC III trial, prior to any data analysis. Trial registration: ClinicalTrials.org, NCT03770741. Registered on 10 December 2018

Cerebral near-infrared spectroscopy monitoring versus treatment as usual for extremely preterm infants : a protocol for the SafeBoosC randomised clinical phase III trial

Background: Cerebral oxygenation monitoring may reduce the risk of death and neurologic complications in extremely preterm infants, but no such effects have yet been demonstrated in preterm infants in sufficiently powered randomised clinical trials. The objective of the SafeBoosC III trial is to investigate the benefits and harms of treatment based on near-infrared spectroscopy (NIRS) monitoring compared with treatment as usual for extremely preterm infants. Methods/design: SafeBoosC III is an investigator-initiated, multinational, randomised, pragmatic phase III clinical trial. Inclusion criteria will be infants born below 28 weeks postmenstrual age and parental informed consent (unless the site is using 'opt-out' or deferred consent). Exclusion criteria will be no parental informed consent (or if 'opt-out' is used, lack of a record that clinical staff have explained the trial and the 'opt-out' consent process to parents and/or a record of the parents' decision to opt-out in the infant's clinical file); decision not to provide full life support; and no possibility to initiate cerebral NIRS oximetry within 6 h after birth. Participants will be randomised 1:1 into either the experimental or control group. Participants in the experimental group will be monitored during the first 72 h of life with a cerebral NIRS oximeter. Cerebral hypoxia will be treated according to an evidence-based treatment guideline. Participants in the control group will not undergo cerebral oxygenation monitoring and will receive treatment as usual. Each participant will be followed up at 36 weeks postmenstrual age. The primary outcome will be a composite of either death or severe brain injury detected on any of the serial cranial ultrasound scans that are routinely performed in these infants up to 36 weeks postmenstrual age. Severe brain injury will be assessed by a person blinded to group allocation. To detect a 22% relative risk difference between the experimental and control group, we intend to randomise a cohort of 1600 infants. Discussion: Treatment guided by cerebral NIRS oximetry has the potential to decrease the risk of death or survival with severe brain injury in preterm infants. There is an urgent need to assess the clinical effects of NIRS monitoring among preterm neonates. Trial registration: ClinicalTrial.gov, NCT03770741. Registered 10 December 2018

Photoplethysmography for blood volumes and oxygenation changes during intermittent vascular occlusions

Photoplethysmography (PPG) is an optical technique that measures blood volume variations. The main application of dual-wavelength PPG is pulse oximetry, in which the arterial oxygen saturation (SpO[Formula: see text]) is calculated noninvasively. However, the PPG waveform contains other significant physiological information that can be used in conjunction to SpO[Formula: see text] for the assessment of oxygenation and blood volumes changes. This paper investigates the use of near infrared spectroscopy (NIRS) processing techniques for extracting relative concentration changes of oxygenated ([Formula: see text]HbO[Formula: see text]), reduced ([Formula: see text]HHb) and total haemoglobin ([Formula: see text]tHb) from dual-wavelength PPG signals during intermittent pressure-increasing vascular occlusions. A reflectance PPG sensor was attached on the left forearm of nineteen (n = 19) volunteers, along with a reference NIRS sensor positioned on the same forearm, above the left brachioradialis. The investigation protocol consisted of seven intermittent and pressure-increasing vascular occlusions. Relative changes in haemoglobin concentrations were obtained by applying the modified Beer-Lambert law to PPG signals, while oxygenation changes were estimated by the difference between red and infrared attenuations of DC PPGs (A[Formula: see text] = [Formula: see text]A[Formula: see text] - [Formula: see text]A[Formula: see text]) and by the conventional SpO[Formula: see text]. The [Formula: see text]HbO[Formula: see text], [Formula: see text]HHb, [Formula: see text]tHb from the PPG signals indicated significant changes in perfusion induced by either partial and complete occlusions (p < 0.05). The trends in the variables extracted from PPG showed good correlation with the same parameters measured by the reference NIRS monitor. Bland and Altman analysis of agreement between PPG and NIRS showed underestimation of the magnitude of changes by the PPG. A[Formula: see text] indicated significant changes for occlusion pressures exceeding 20 mmHg (p < 0.05) and correlation with tissue oxygenation changes measured by NIRS, while SpO[Formula: see text] had significant changes after 40 mmHg (p < 0.05). Relative changes in haemoglobin concentrations can be estimated from PPG signals and they showed a good level of accuracy in the detection of perfusion and oxygenation changes induced by different degrees of intermittent vascular occlusions. These results can open up to new applications of the PPG waveform in the detection of blood volumes and oxygenation changes

Comparison of near-infrared oximeters in a liquid optical phantom with varying intralipid and blood content

The interpretation of cerebral tissue oxygen saturation values (StO2) in clinical settings is currently complicated by the use of different near-infrared spectrophotometry (NIRS) devices producing different StO2 values for the same oxygenation due to differences in the algorithms and technical aspects. The aim was to investigate the effect of changes in scattering and absorption on the StO2 of different NIRS devices in a liquid optical phantom. We compared three continuous-wave (CW) with a frequency domain (FD) NIRS device. Responsiveness to oxygenation changes was only slightly altered by different intralipid (IL) concentrations. However, alterations in haematocrit (htc) showed a strong effect: increased htc led to a 20-35% increased response of all CW devices compared to the FD device, probably due to differences in algorithms regarding the water concentration

Impact of Skull Thickness on Cerebral NIRS Oximetry in Neonates: An in silico Study

Monitoring of cerebral tissue oxygen saturation (StO2) by near-infrared spectroscopy (NIRS oximetry) has great potential to reduce the incidence of hypoxic and hyperoxic events and thus prevent long-term disabilities in preterm neonates. Since the light has to penetrate superficial layers (bone, skin and cerebrospinal fluid) before it reaches the brain, the question arises whether these layers influence cerebral StO2 measurement. We assessed this influence on the accuracy of cerebral StO2 values. For that purpose, we simulated light propagation with ‘N-layered medium’ software. It was found that with a superficial layer thickness of ≤6 mm, typical for term and preterm neonates, StO2 accurately reflects cerebral tissue oxygenation