Clinical trial NCT06994494: Noninvasive Continuous BP Monitoring in Newborns Based on Pulsatile Signal Morphological Features Using NIRS
Official title: Noninvasive Continuous BP Monitoring in Newborns Based on Pulsatile Signal Morphological Features Using NIRS
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Unstable Blood Pressure
Hypotension
Keywords: Non-invasive blood pressure monitoring
Arterial Line
NIRS
wearable device
Cerebral oximetry
Lead sponsor: Massachusetts General Hospital
Sponsor class: OTHER
Collaborators: name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
First posted: 2025-05-29
Enrollment: 80
Sex: ALL
Minimum age (years): 24
Maximum age (years): 44
Standard ages: CHILD
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: The study population will include 80 neonates of ≥24 weeks and \<44 weeks postmenstrual age, with or without A-line BP monitoring for clinical reasons. Subjects will be recruited from the Neonatal Intensive Care Unit at MGH and BWH.

Brief summary: The goal of this study is to evaluate if a novel near-infrared spectroscopy (NIRS) device can accurately estimate blood pressure in newborns at risk for unstable blood pressure. The main questions it aims to answer are:

* Can NIRS accurately estimate blood pressure when compared to the gold standard, arterial line blood pressure
* Can NIRS accurately estimate blood pressure when compared to infants with cuff blood pressure monitoring

Researchers will compare NIRS-based estimates to arterial line blood pressure readings and manual cuff measurements to optimize and validate the FlexNIRS device for neonates to accurately estimate blood pressure continuously and noninvasively.

Participants will wear a small, noninvasive NIRS sensor on the forehead.

Detailed description: Continuous blood pressure monitoring is important for critically ill newborns to prevent brain injury caused by dysregulated changes in cerebral perfusion driven by hyper- or hypo-tension episodes. These can harm the underdeveloped cerebral vasculature and result in germinal matrix/intraventricular hemorrhage (GM/IVH), which may impact neurodevelopmental outcome in preterm infants. In addition, continuous blood pressure monitoring is beneficial to management of many other conditions in neonates: including hypoxic-ischemic encephalopathy (HIE); for monitoring respiratory issues such as respiratory distress syndrome (RDS) and pulmonary hypertension related to meconium aspiration syndrome; for managing the vascular resistance in conditions like patent ductus arteriosus (PDA) and congenital heart failures: for ensuring adequate tissue perfusion during critical illness like sepsis and necrotizing enterocolitis (NEC); and for maintaining vascular tone when using inotropes or vasopressors.

The gold standard for continuous BP monitoring in newborns is via arterial line (A-line BP). However, it involves catheterization of the umbilical or a peripheral artery and can lead to complications such as vasospasm, nerve damage, ischemia, thrombosis, and, in severe cases, limb amputation. Due to these risks, A-line BP monitoring is only used when deemed necessary in critically ill neonates. Instead, the standard care involves intermittent arm sphygmomanometer checks, but this method offers suboptimal precision and can miss clinically important hypo-/hyper-tensive episodes.

Existing noninvasive alternatives, including volume-clamp photoplethysmography cuffs, pulse-transit-time, and tonography, are problematic due to large error and safety concerns. They have been validated primarily for adults and are not tailored for neonates who pose unique challenges due to their fragile limbs, underdeveloped vasculature, immature cardiac function, and mean arterial BP often being less than a third of an adult's (30 mmHg). Machine learning (ML) techniques show promise in identifying important pulse wave features for determining BP, although they have not been fully validated in neonate populations.

To address this critical need for accurate, continuous, and noninvasive BP monitoring in newborns, we propose employing a near-infrared spectroscopy (NIRS) technique on the head, focusing on pulsation tones and shapes in cerebral hemodynamics, which are sensitive to BP changes. Our team has developed a wearable, battery-operated NIRS device, called FlexNIRS, capable of providing continuous photoplethysmogram (PPG) with a high temporal resolution of 266 Hz. In adults, we have shown that the time derivative of its optical pulse waveforms d/dt(PPG) is related to pulsatile blood flow, and found strong correlations between specific features of d/dt(NIRS-PPG) and blood pressure changes. Based on these findings, we hypothesize that NIRS-PPG collected in the brain is most ideal for neonates, especially given their fragile peripheries, and the head site allowing more robust measure of deep brain with less external factors, such as pressure from the sensor itself, room temperature, and extra arterial resistance that builds up in local peripheries. Importantly, we have tested the FlexNIRS in a preterm newborn and found pulsatile morphology patterns comparable to those in adults. Thus, we aim to validate this novel technique for BP assessment in the newborn population.

The aims are to collect FlexNIRS data from up to 80 newborns, divided evenly across Massachusetts General Hospital (MGH) and Brigham and Women's Hospital (BWH), who are at risk for unstable blood pressure, including those undergoing invasive A-line BP monitoring for clinical reasons.

Aim 1 (A-line cohort): Conduct continuous FlexNIRS measurements on neonates with an A-line BP placed for clinical reasons for 3-24 hours per day, as long as the A-line BP remains in place for clinical reasons. We plan to enroll 20 infants at each site for this Aim.

Aim 2 (Cuff cohort): Conduct continuous FlexNIRS measurements on neonates for 3-24 hours per day, with blood pressure measured using a cuff every 1-4 hours as part of the research. We plan to enroll 20 infants at each site for this Aim.

This data will be used to refine our FlexNIRS-based blood pressure estimation algorithms and correlate results with invasive A-line BP as the gold standard or periodic BP cuff readings performed by clinical staff. This research will provide invaluable data demonstrating method feasibility and initial clinical utility. The successful execution of this aim will guide us to a larger clinical study.

Each measurement will involve monitoring infants with one or two FlexNIRS devices for 3-24 hours a day, for at least one day, and potentially for the duration of clinical A-line BP monitoring or periodic BP measurements using a cuff to up to 3 days. This will be done without disturbing the newborn's state or interfering with clinical care. Periodic cuff BP measurements will primarily be taken from the newborn's arm; if not feasible, they will be taken from the leg, with study coordinators noting the adjustment.

FlexNIRS data will be co-registered with bedside vital signs, such as EKG and pulse oximetry. For the A-line cohort, we will co-register A-line BP and, if available, manual cuff BP measurements taken at care times for cross validation. For the Cuff cohort, we will co-register bedside vital signs and manual cuff BP measurements.

One FlexNIRS sensor will be securely attached to the infant's forehead using a medical-grade adhesive designed for preterm use. When feasible, a second FlexNIRS device will be attached to the infant body distal to the head (e.g., foot, leg, arm, abdomen, chest, back). Skin integrity will be checked every care time (3-6 hours), making adjustments or removing the sensor if necessary, especially during care routines or imaging procedures.

We will evaluate and optimize the study logistics, including the wearability of the device, and the blood pressure estimation algorithms. Eligible newborn infants will be enrolled as soon as possible, after the A-line is inserted for medical reasons. Optical measurements will be performed ideally 3-24 hours per day, for at least one day, but possibly as long as the neonate is under A-line BP monitoring. Monitoring non-consecutive days is allowed. If the enrolled newborn infant does not have an A-line deployed, cuff-based blood pressure measurement will be performed as frequently as every hour, up to every four hours. Once the patient is enrolled, we will start FlexNIRS monitoring after confirming with bedside nurse. One sensor will be attached on the infant's forehead, and in some cases a second FlexNIRS sensor will be attached to the lower body distal to the head using a medical-grade adhesive, cloth headbands, or caps, avoiding any pressure. The sensors will be repositioned as needed, to ensure skin integrity. Hospital staff will help as needed to secure the devices on the infants and monitor for detachments. If needed, the sensors will be covered with a single use black cloth to shield room light. The FlexNIRS, tablet and auxiliary box are sanitized before and after each neonatal use. The subject's vitals (blood pressure and EKG) will be acquired using a custom External Auxiliary box in the MGH NICU or the Moberg CNS Monitor in the BWH NICU throughout the FlexNIRS device measurements. A research pulse oximeter may be attached to the baby's foot. Information from the patient's chart including delivery data, imaging, EEG, head ultrasound (HUS) exams, lab work, neurologic exams, medications, procedures, and clinical assessments will also be recorded for correlation with the optical data. Finally, data including general demographics, past medical history, and past social history will also be collected from the patient's EPIC chart.

The potential risks to subjects are minimal and limited to the following:

* Confidentiality - Subjects' medical information will be collected for the study, posing a risk of loss of privacy. Subject confidentiality will be protected in accordance with all HIPAA standards. Each subject will be assigned a code name, and research data will be de-identified, stored on a secure server, and accessed only by authorized personnel. Data will be used exclusively for research, and non-electronic consent forms will be stored securely. The research data obtained from each subject will be in the form data series acquired with the FlexNIRS device, GE bedside monitor, and the clinical data extracted from the subject's chart, which will all be de-identified and assigned a code. The de-identified files will be transferred and stored on a sever computer in the NICU offices at MGH or BWH to which both the PI, Site PI and Co-investigators will have access. The data collected will be used exclusively for research purposes. Non-electronic consent forms will be stored in a locked filing cabinet in the same location. E-consent, demographic, and clinical information will be stored using the electronic data capture REDCap database. Access to the REDCap database is logged and able to be audited. Only individuals listed on the protocol and response for data collection will have access to the data through the secure, password-protected REDCap databased hosted through MGB. Analyses will be performed using de-identified data.
* FlexNIRS Light Sources - The optical device used in the protocol is investigational. While no adverse effects have been reported with similar devices, unreported effects may occur. The device uses low-power LEDs within safety limits, posing no risks to the subject's skin and eyes.
* FlexNIRS Battery - The FlexNIRS is a wearable device powered by a rechargeable Lithium-Ion battery (LP503040JH, IEC62133-2:2017 certified). The lithium-ion battery has no more risk associated with it than a small smartphone battery.
* FlexNIRS Electrical - The device is low current and the various modules are all electrically isolated to protect the subject. It is still possible that sweat may enter into the components, causing malfunction of the device with no harm to the subject.
* FlexNIRS sensors contact to the skin - The optical sensors at this stage of the research are reusable and will be thoroughly disinfected before being reused to eliminate the risk of infection in study subjects. They require good contact with the skin and do not cause pain or distress. They might cause some minor skin irritation, but this effect would disappear rapidly. This effect is no greater than that encountered with clinical EEG monitoring sensors. During the session, we will regularly check the skin to determine safe placement and check skin integrity. The attachments will be readjusted as necessary.
* The research pulse oximeter is a standard physiology device and will be used as labeled.
* Manual cuff-based BP measurements are already performed as part of clinical routine at each care times, as often as 1-3 hours interval.

Although the techniques we employ are non-invasive and present no significant risks to study subjects, we will take several precautions to ensure even minimal risks are prevented.

All neonates admitted to the NICUs are assessed for pain/discomfort every 3-4 hours during their care times using NPASS (Neonatal Pain, Agitation, and Sedation Scale), and both the RA and PIs will check in with the nurse every several hours to ensure there are no concerns regarding pain or discomfort attributable to the device. Additionally, the RA and PIs are responsible for assessing skin condition when the device is removed/repositioned. If there are any concerns regarding pain/discomfort or skin integrity attributable to the device, the measurement will be terminated immediately, and the study will be stopped for that patient.

There are no direct benefits of the proposed research to any of the subjects participating in this study and the results of the study will not be directly reported to participants. There may be long-term benefits in the form of improvement of blood pressure monitoring strategies for neonates with complications related to hyper- or hypo-tension, and improvement in outcome in the future.

Both correlation analyses and Bland-Altman plots will be used to assess our BP estimation in comparison to invasive A-line BP readings for the A-line cohort; and spline-interpolated cuff BP readings for the cuff cohort. For the Bland-Altman analysis, we aim for a limit of agreement of \~25% (\~7 mmHg). We used Bland-Altman estimation to calculate the desired sample size. A recent report from Rao et al. which compared invasive A-line BP and noninvasive measurements of BP, found a standard deviation of the difference between the measurements of \~6.5 mmHg18. As we anticipate that the differences between our noninvasive estimates of BP and either invasive A-line or cuff BP readings will be similar to the prior findings from Rao et al., we can use the Bland-Altman formula to estimate the 95% CI as: 1.96\*√(3/n)\*SD, where SD = standard deviation of the difference between measurements and n = sample size29. Solving for n, we can estimate that we will need \~ 10 patients enrolled in order to achieve the goal of a \~25% limit of agreement. Thus, monitoring 10 patients in each age group (near term and extremely preterm), totaling 20 patients per cohort per NICU, ensures a sufficient data set and degrees of freedom for evaluating other covariates.

All statistics will be performed after examination of the primary variables for distribution and to assure that all variables meet the assumptions for each statistical model. Additionally, we will perform each test using the primary variables alone as well as with statistical covariates when appropriate (e.g., controlling for demographic factors such as sex, gestational age, illness acuity, presence of seizures).

The Principal Investigator, Dr. Herzberg, will be responsible for monitoring and assuring the validity and integrity of the data, including the accuracy and completeness of source documents and informed consent. The Principal Investigator also assumes responsibility for staff compliance with this protocol, good clinical practice, and all applicable regulatory requirements. This will be accomplished with the assistance of the study coordinators and co-investigators and will be monitored on an ongoing basis. Quality control will be applied to each stage of data handling, and by following the data plan, to ensure that all data are reliable and have been processed correctly.

Eligibility criteria: Inclusion Criteria:

* Neonates ≥24 \& \<44 weeks postmenstrual age
* Hospitalization in MGH or BWH newborn service units
* For A-line BP monitoring: Neonates expected to maintain A-line monitoring for at least the next 12 hours
* For non-A-line monitoring: Neonates at risk for unstable blood pressure (e.g. clinical instability or need for inotropes) and no contraindications to manual cuff BP measurements every 1 to 4 hours

Exclusion Criteria:

* Contraindication to FlexNIRS device placement on the scalp/head
* Underlying congenital/genetic anomalies

Primary outcomes:
measure: FlexNIRS-based blood pressure estimation
timeFrame: 04/09/2025 - 11/30/2026
Secondary outcomes:
Other outcomes:
Locations:
city: Boston
country: United States
facility: Massachusettes General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
Study officials:
References:
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