PROtecting Maternal Brains From Injury and Stroke (PROMIS)
Phase: NA
Conditions: Preeclampsia, Maternal Hypertension
Sponsor: Columbia University

PROMIS STUDY DESIGN AND DETAILED PROTOCOL 
Study Title: PROtecting Maternal brains from Injury and Stroke (PROMIS) 
NCT05726279 
Last Date Used: 2/28/2025 
 
Design 
PROMIS (PROtecting Maternal brains from Injury and Stroke) was a Phase II, prospective, 
non-blinded, non-randomized, pilot clinical trial of cerebral hemodynamic monitoring in 
participants admitted to the hospital for treatment of preeclampsia with severe features in 
the postpartum period (within 6 weeks of delivery).  
Participants were recruited in the first 24 hours of presentation of preeclampsia with select 
severe features (Supplemental Table 1) and placed into one of two consecutive study 
arms: an initial observational arm (monitoring cerebral autoregulation only; N=25) and a 
subsequent interventional arm (autoregulation-guided blood pressure management; 
N=25). The duration of the study intervention was 24 hours. Other interventions for 
preeclampsia, such as administration of high-dose magnesium sulfate, were not changed 
from standard of care treatment. 
For the observational arm, the first patient was enrolled on 4 May 2023 and the 
observational arm was completed 7 March 2024. The interventional arm enrolled the first 
patient on 6 January 2025. The trial was stopped early on 28 February 2025 due to slow 
recruitment and end of the funding period. 
Aims 
The primary purpose of this study was to demonstrate the feasibility and safety of 
incorporating non-invasive bedside neuromonitoring approaches into clinical care of 
postpartum preeclampsia patients. These include monitoring the brain tissue oxygenation 
index (TOI), as a proxy for cerebral blood flow (CBF), using near-infrared spectroscopy 
(NIRS) and arterial blood pressure (ABP) using finger plethysmography. 
Aim 1: Observational Arm 
Calculate personalized limits of cerebral autoregulation in 25 patients with postpartum 
preeclampsia, using continuous monitoring of ABP and CBF. 

• Hypothesis 1: Over 24 hours of standard clinical care, guideline-based BP 
management will result in ≥10% of time during which MAP exceeds personalized 
upper or lower limits of autoregulation, calculated using an established threshold 
for autoregulatory dysfunction. 
Aim 2: Interventional Arm 
Pilot the use of autoregulation-guided BP goals in 25 patients with postpartum 
preeclampsia. 
• Hypothesis 2: Targeted BP management using autoregulation-guided goals will 
result in less time spent outside limits of autoregulation, compared with Aim 1 
patients managed according to current guidelines. 
o Hypothesis 2a: It is feasible and safe to implement autoregulation-guided 
blood pressure management in this patient population. 
o Hypothesis 2b: An exploratory effect size of autoregulation-guided blood 
pressure management on physiologic measures can be determined. 
Flowchart of overall study procedure for both arms found in Supplemental Figure 1 
 

 
Supplemental Figure 1: Flowchart of inclusion, treatment arm assignment, and study 
procedures in the PROMIS trial. BP= blood pressure; mmHg= millimeters of mercury  
Methods and Measurements 
Data Collection and Online Processing 
In this study, the TOI was measured using NIRS probes (Foresight-Elite, Edwards Life 
Sciences, Irvine, CA) and ABP was measured using finger plethysmography (ClearSight or 
Acumen IQ cuff, Edwards Life Sciences, Irvine, CA) (Supplemental Image 1). This study 
used the Edwards Hemosphere device, an FDA-approved device, to collect the real-time 
hemodynamic and cerebral oxygenation data. Both CBF and ABP data was sampled at a 
frequency of 0.5 Hz and all data was processed and analyzed using ICM+ neuromonitoring 
software (https://icmplus.neurosurg.cam.ac.uk/) at bedside. The study also utilizes a 
portable sphygmomanometer device (WatchBP Home, Microlife U.S.A., Inc, Clearwater, 
Florida) to measure baseline blood pressure and heart rate. 
Limits of Cerebral Autoregulation Algorithm 

Refer to the methods section of Continuous Blood Pressure and Cerebral Blood Flow 
Monitoring in Postpartum Preeclampsia with Severe Features (Woolcock Martinez et al.) 
for details on computing individualized limits of cerebral autoregulation and optimal MAP 
(MAPopt). 
 
Supplemental Figure 2: Neuromonitoring Setup. The monitoring setup required a device, 
such as the Edwards Hemosphere device seen here, to collect the ABP and TOI, and a 
laptop with ICM+ neuromonitoring software installed to sample the data. The adhesive 
NIRS probes (Foresight-Elite, Edwards Life Sciences, Irvine, CA) were placed on the frontal 
scalp, above the brow bones. The non-invasive finger plethysmography (ClearSight or 
Acumen IQ cuff, Edwards Life Sciences, Irvine, CA) was placed on the first three digits of 
either hand between the distal interphalangeal joint and the proximal interphalangeal joint 
and was connected to the wrist cuff seen in the image. ICM+ would compute the tissue 
oxygenation index (TOx) in real time and displayed the values on the laptop. ICM+ was also 
capable of computing the limits of autoregulation from the NIRS and ABP data. All devices 
used were FDA approved. 
Assessment of Compliance 
Compliance with the protocol was assessed every four hours at bedside neuromonitoring 
checks performed by study personnel and the clinical team. This interval was selected to 
coincide with the timing of standard nursing checks and vital sign measurements in the 
postpartum setting. A standardized checklist was used for both study arms at each interim 
check to promote compliance to the neuromonitoring protocol. An ICM+ module was 
utilized in the interventional arm to maintain compliance with autoregulation-guided blood 
pressure management. The treating clinician could deviate from autoregulation-guided 

recommendations but was required to provide commentary in the modules. The checklist 
and ICM+ module are both detailed in the protocol sections below.  
Outcome Measures 
Primary Outcome  
The primary objective of this study was to assess the feasibility of non-invasively 
measuring cerebral hemodynamics to calculate autoregulation-guided blood pressure 
targets in patients with postpartum preeclampsia. Aim 1 was an observational cohort 
study of 25 patients treated according to standard of practice with fixed BP targets. In Aim 
2, we compared patients treated with autoregulation-guided BP targets to the 
observational cohort. For the primary analysis, we measured (in hours) the total time each 
patient had MAP values within their computed limits of autoregulation. The primary 
outcome was the percentage of time during which MAP was within limits of autoregulation 
during the 24 hours after initiation of monitoring (i.e., time within target range).  
Secondary Outcome: Safety  
Secondary outcomes included presence or absence of neurological symptoms, defined as 
≥8/10 headache pain, or blurred vision, assessed every four hours during the monitoring 
period by study personnel at the time of clinical vital sign checks. 
Safety outcomes included any new acute neurological deterioration, defined as decreased 
level of consciousness (Glasgow Coma Scale of 12 or less, indicating moderate to severe 
brain injury), new focal neurological deficits, or seizure. 
Exploratory Outcome: Efficacy/Effect Size 
The exploratory outcomes of this study included efficacy and effect size of autoregulation-
guided blood pressure management in increasing time spent within limits of cerebral 
autoregulation. 
Study Population 
Eligibility criteria are delineated in Supplemental Table 1 and were the same for both arms 
of the study. Eligible participants admitted to the obstetrics unit were identified by clinical 
providers and/or the research team throughout their admission for care. Patients who had 
given birth within the previous 6 weeks after a pregnancy lasting at least 20 weeks and 
were admitted to any inpatient obstetrics unit within 24 hours for active management of 
hypertension were screened for the study and, if eligible, approached and consented in 
accordance with the IRB-approved protocol. 

Supplement Table 1: PROMIS Study Inclusion and Exclusion Criteria 
Inclusion Criteria  
§ Admitted to the CUIMC within 6 
weeks of delivery after a pregnancy 
lasting 20 weeks.  
§ Admitted for treatment of 
preeclampsia with selected severe 
features within 24 hours of 
enrollment, defined as either: 
o measured systolic BP ≥160 
mmHg and/or diastolic BP ≥ 
110 mmHg on two or more 
occasions, 15 minutes apart. 
o severe headache refractory 
to medication with systolic 
BP ≥ 140 mmHg and/or 
diastolic ≥ 90 mmHg. 
§ If no severe features within 24 hours 
of enrollment: received IV 
magnesium within 12 hours of 
enrollment for treatment of 
selected features as indicated 
above 
Exclusion Criteria  
History of any of the following:  
§ Acute ischemic stroke 
§ Intracerebral hemorrhage 
§ Subarachnoid hemorrhage 
§ Eclamptic seizures 
§ Raynaud’s syndrome 
§ Any other neurological 
complication requiring transfer to 
the neurological intensive care unit 
or stroke step down unit. 
Inability to understand and consent to the 
study  
 
Study Arms 
This is a non-randomized, non-blinded trial. The first 25 participants enrolled in PROMIS 
were placed in the observational arm; the second 25 were placed in the interventional arm. 
Aim 1 Observational Study Protocol 

The study was executed according to Supplemental Figure 2. After the team enrolled 
participants and obtained written informed consent, subjects were connected to the 
neuromonitoring setup. The team recorded the time at which the participant was 
connected to the neuromonitoring setup. Baseline blood pressure and heart rate were 
measured by the study sphygmomanometer device. Blood pressure reading from the finger 
plethysmography device was also recorded. Baseline symptoms and Glasgow coma scale 
rating were recorded. All medications dosed within the past 24 hours were documented, 
including medication name, dosing amount, and frequency. Participants receiving high-
dose intravenous magnesium sulfate had their bolus dose, infusion rate, and start/stop 
times recorded. Participants complete a migraine questionnaire as shown in 
Supplemental Figure 3. 
After monitoring was initiated, study personnel performed bedside checks every four 
hours. During these bedside checks, personnel ensured that data was still properly being 
collected and that the participant was tolerating the device. Interim checks also include 
recording the following data: 
1. Time of the interim check 
2. Heart rate, systolic blood pressure and diastolic blood pressure measured with the 
study sphygmomanometer  
3. Systolic and diastolic blood pressure seen on the neuromonitoring Hemosphere 
screen (and measured by the study finger plethysmography)  
4. If a neurologist had been consulted or brain imaging had been obtained (y/n) within 
the past 4 hours 
5. Patient symptoms at time of check 
a. If patient endorsed a headache: headache pain level at time of check 
6. Medications (including dosing and frequency) administered in the previous 4 hours, 
including but not limited to magnesium sulfate, anti-hypertensives, analgesics, and 
anti-emetics. 
a. If received magnesium: start/stop times of infusions 
b. Most recent magnesium serum level was documented, including the 
date/time the specimen was collected 
7. Glasgow coma scale  
8. All blood pressure readings taken by the clinical team within the past 4 hours 
Data was entered into REDCap at the 4, 8, 12, 16, 20, and 24-hour marks. 
Participants were disconnected from the neuromonitor if they completed 24 hours of 
monitoring, if they no longer tolerated the study, or if they were discharged from the 
hospital. The time of disconnection from the Hemosphere was recorded. Blood pressure 

and heart rate readings were taken with the study sphygmomanometer at time of 
disconnection. The finger plethysmography blood pressure readings shown on the 
Hemosphere device was also recorded. Glasgow coma scale, all symptoms, all 
medications administered (including dosing and frequency) since the last interim check, 
and all blood pressure readings made by the clinical team since the last interim check 
were recorded. 
Supplemental Figure 3: Observational Arm Additional Data Collection Flow Diagram. 
Study monitoring began once the participant was connected to the neuromonitoring 
devices and continued for 24 hours or until the participant was discharged from the 
postpartum floor, whichever came first. The study personnel would perform an 
intermittent beside check every 4 hours at which point they would ensure the data was 
being collected properly, the participant was tolerating the device, and they would collect 
certain study and clinical variables 
 
Aim 2 Interventional Arm Study Protocol  
Participants in the interventional arm were connected to the neuromonitoring device, 
underwent interim checks every four hours, and were disconnected in the same fashion as 
those in the observational arm are as described above (Supplemental Figure 2). However, 
participants enrolled in the interventional arm underwent an interim check (as seen in the 
observational arm) and MAP protocol overview at the following predetermined 4-hour 
intervals: 6:00, 10:00, 14:00, 18:00, 22:00, 2:00. At this time, study personnel presented to 
the participant’s bedside with the provider working on the study to complete an ICM+ 
module customized for the study (Supplemental Figure 5). Current MAP value and 
MAPopt target value were displayed. Study personnel reviewed a series of questions 

prompted by ICM+ with the provider, making selections based on provider feedback, 
shown below (Supplemental Figure 6): 
• Q1: Were there any problems adopting the last blood pressure target?  
o A: Options provided in the drop-down menu: "Yes" or "No” 
• Q1a (if “Yes” to Q1): What was the problem with adopting the previous target? 
o A: Options provided in the drop-down menu:  
§ “The recommended target was too high” 
§ “The recommended target was too low” 
§ ”Other” 
• Q1b (if “Other” to Q1a): Please specify 
o A: [Free text option] 
• Q2: Will you be adopting the advised blood pressure target? 
o A: Options provided in the drop-down menu: "Yes" or "No” 
• Q3a (if “No” to Q2): What is the reason for not adopting the advised MAP target? 
o A: Options provided in the drop-down menu:  
§ “The advised target is too high” 
§ “The advised target is too low” 
§ “The intervention to reach the advised target may harm the patient” 
§ ”Other” 
• Q3b (if “Other” to Q3a): Please specify 
o A: [Free text option] 
• Q4 (if “No” to Q2): What MAP will you be targeting? 
o A: [Data field for MAP entry] 
•  Q5a: What intervention are you planning to achieve the target? 
o A: Options provided in the drop-down menu:  
§ “None needed” 
§ “Increase BP with IV fluids bolus” 
§ “Increase BP with vasopressors” 
§ “Lower BP” 
§ ”Other” 
• Q5b (if “Other” to Q5a): Please specify. 
o A: [Free text option] 
• Q6: Any comments? 
o A: [Free text option] 
After reviewing the above questions with the provider, study personnel entered a pending 
order through the electronic medical record reflecting changes to the blood pressure 
regimen, aimed at guiding current MAP to MAPopt, for approval by the provider. All clinical 

decisions were made in the context of the overall clinical management and in 
collaboration with the maternal-fetal medicine team caring for the participant during 
admission. 
 
Supplemental Figure 4: Migraine Questionnaire 
Participants were provided with a questionnaire to elicit their history of headaches, 
including headaches during pregnancy, when connected to the neuromonitoring device. 
The forms were provided to participants at the time of connection to the neuromonitor, 

with officially translated versions made available for those whose primary language was 
Spanish. 
 
Supplemental Figure 5: Example Interventional Arm Treatment to MAPopt Workflow 
Study personnel and clinical team completed an ICM+ module at pre-specified timepoints. 
The module displayed the current MAP and the MAPopt based on the participant’s 
autoregulatory function. The team completed the questionnaire to determine changes to 
blood pressure management that maintain MAPopt. 
 

Supplemental Figure 6: Master Flowchart for Review Questions Prompted by ICM+ 
Module 
 
Sample Size 
The sample size was calculated to power the study to detect a difference in time spent 
outside personalized limits of autoregulation between the interventional and observational 
arms. All analyses were conducted according to an intention-to-treat principle. Thus, all 
patients enrolled (and consented) were included in the analysis regardless of their 
compliance with the protocol and the treatment schedule.  
Data from stroke patients, another population with labile blood pressure, showed that 
patients spent on average 65.7% (± 22.9%) of their monitored time within their 
personalized limits of autoregulation (time within target range) (Petersen et al., Stroke 
2020;51:914-921). Extrapolating from these data, with a total of 25 patients in the single 
interventional arm and a projected SD of 22.9%, we would have over 80% power to 
demonstrate an absolute increase of 15% in this metric compared to the observational 
cohort (a = 5%, two-sided t-test). Of note, one purpose of this trial was to determine an 
effect size for planning purposes for a larger randomized trial. 
Data Storage 
Data were managed in accordance with standard protocols and data protection laws 
aimed at ensuring that confidentiality is maintained at all times. 
Participant data was assigned a numerical deidentification code. An enrollment log 
documented the link between study number and participant identity and was stored in a 
locked cabinet and secured computer database (on a password-protected network drive). 
Continuous MAP and tissue oxygenation data were collected to calculate personalized 
limits of autoregulation. Data was transferred to secure local servers. Access to the 

servers was limited to study personnel, who had completed and passed IRB and HIPAA 
training. 
Subject biochemical and clinical data, collected as described in the study protocol, were 
maintained on a secure, encrypted, web-based online database, Research Electronic Data 
Capture (REDCap), also accessible only to study personnel. Raw data was identified only 
with the unique study identifier for each subject. 
Statistical Plan 
Baseline characteristics of included subjects were summarized by means and standard 
deviations (SD) for normally distributed continuous variables (as determined by the 
Shapiro-Wilks test), by medians and interquartile ranges (IQR) for skewed continuous 
variables, and by numbers (%) for categorical variables. For the analysis of continuous 
values, an independent sample t-test (or a Mann-Whitney U test where appropriate) was 
used. For the analysis of categorical variables, a Chi-squared test (or where appropriate 
Fisher’s exact test) was used.  
For the primary analysis, we computed the percentage of the 24-hour monitoring period 
during which MAP was within personalized limits of autoregulation. Time within target 
range, secondary outcomes, and safety outcomes of the interventional arm was compared 
to that of controls from our observational arm using appropriate statistical tests. 
All data were analyzed on an intention-to-treat basis, regardless of compliance with the 
treatment protocol. All participants who enrolled and consented were included in the 
analysis. 
Patient and Public Involvement 
Patients or the public were not involved in the design, or conduct, or reporting or 
dissemination plans of our research. 
Ethics and Dissemination 
Informed Consent 
The Institutional Review Board (IRB) approved this study prior to initiation of recruitment. 
Participants signed an informed consent form prior to enrollment following all established 
IRB guidelines. The consent form was written in language that a person with a 6th grade 
education could understand. At the time of recruitment, the research staff member gave a 
complete description of the study to the prospective participant in clear, easy-to-
understand language. For those interested in participating, a copy of the consent form was 

provided, and the research staff member reviewed the critical points and answered any 
questions. The staff member ensured that the person fully understood the details of the 
monitoring periods, including the duration and the frequency of all measurements. After 
answering any questions the participant had, if the person wished to participate, she 
signed the informed consent document, and the staff member co-signed it. The HIPAA 
Authorization for Research was also signed at this time.  
Spanish-Speaking Subjects 
This study served a large Spanish-speaking patient population. We developed strategies to 
accommodate this cultural diversity and minimize potential language barriers. The 
majority (approx. 90%) of our research staff was bilingual in Spanish and English. 
Hispanic/Latinx participants were provided with a copy of the consent form and HIPAA 
form in Spanish, depending on which language they were most comfortable speaking and 
reading. All verbal explanations and answers to ensuing questions were provided in the 
participants’ preferred language. If bilingual staff were unavailable, non-Spanish speaking 
staff members utilized the professional phone interpreter services provided through the 
hospital. 
Safety Considerations 
Data and Safety Monitoring Plan 
To monitor data and safety, we established an independent data safety monitoring board 
(DSMB) consisting of experts in their fields. Primary responsibilities included (i) periodic 
review and evaluation of the accumulated study data for participant safety, study conduct 
and progress; and (ii) to make recommendations to the project PI regarding the 
continuation, modification, or termination of the trial. Members convened by webinar once 
before the start of the trial and every 6 months thereafter. At the initial meeting, they 
reviewed and confirmed their acceptance of the protocols, established guidelines for 
review, defined a quorum, and drew guidelines for monitoring the study. Before each 
meeting, a formal detailed statistical report is provided, including the results of every 
aspect of the project: baseline variables, protocol adherence, adverse events reported and 
center performance in terms of recruitment, data quality, loss to follow-up and protocol 
deviations and violations. 
 
The DSMB was available to receive reports of any spontaneously reported serious adverse 
events. They received continuously revised tabulations of three serious adverse events 
plausibly related to blood pressure changes, which investigators monitored and surveyed 
during the participation in the study: acute neurological deterioration, ischemic stroke, 

and intracranial hemorrhage. The DSMB had the authority to request additional 
information and recommend cessation of treatment for any individual trial participant. If 
the DSMB observed a significant increase in serious adverse events in the intervention 
group, compared to historical controls and rates observed in subjects enrolled in Aim 1 of 
the study, the DSMB chair would meet with the research team and recommend 
appropriate action. Working with the DSMB, the research team (P.I., co-investigators, 
consultants) could suspend the study or revise the protocol. If the members of the DSMB 
and the study team could not agree on a course of action, the IRB would be informed 
immediately, and the P.I. would propose a resolution to be approved by the IRB. The same 
reports given to the DSMB would be reviewed by the P.I. who would be vigilant to increases 
in adverse events. 
We did not anticipate any serious adverse events from minor blood pressure adjustments 
within the blood pressure range recommended by current guidelines; however, ischemic 
and/or hemorrhagic stroke were theoretically possible. These were monitored and 
reported as described above. The P.I. apprised the mentorship team and study personnel 
of all spontaneously reported and tabulated adverse events during regular study meetings 
and via email as they were reviewed. Serious, unanticipated and related adverse events 
would be reported in writing within 24 hours to the institutional board governing human 
research. The protocol’s Independent Safety Monitors would be informed of moderate or 
greater in severity (see below) adverse events within 1 day of the event becoming known to 
the P.I. In addition, the board reviewed the safety data after every 5 enrollments. 
Definition of Adverse Events: 
Adverse events were monitored for each subject participating in the study. The primary 
investigator determined whether an adverse event was attributed to the study protocol and 
graded the severity of the adverse event. Only serious adverse events would be reported 
and followed beyond hospital discharge.  
Safety Procedures 
This study featured assessment of blood pressure and neurological symptoms, including 
headache, vision changes, and other neurological deficits. Because issues of patient 
safety were inherent in assessing blood pressure and neurological assessments, protocols 
were in place for research staff to follow, should a participant demonstrate concerning 
symptoms or signs. In addition, protocols were in place in case of obstetrical emergencies 
during the period of study monitoring.  
In the interventional arm, to ensure that blood pressure management therapy did not 
present any safety risk to study subjects, we used specific safety-stopping rules. Given the 

rarity of pregnancy associated stroke and the small sample of 25 participants in the 
observational or interventional arm, the safety-stopping rule mandated a cessation of 
enrollment if any stroke is observed that was at least probably related to the intervention. 
Hypertensive emergency 
To minimize risk of harm, we implemented the following strict safety protocols. Any 
measured BP of ≥160/110 triggered closer monitoring of the patient and re-assessment 
every 15 minutes by the clinical team. Sustained systolic BP ≥180 on two consecutive 15-
minute checks, or any single systolic BP ≥220 or diastolic ≥120 mmHg triggered immediate 
“escape” from the trial protocol. 
  
Neurological symptoms or signs 
A brief neurological history was obtained by study personnel at the start of the study and 
throughout the monitoring period, including current neurological symptoms such as 
headache, vision changes, weakness, speech difficulty, numbness, or gait impairment. If a 
subject reported any of these symptoms, a board-certified or board-eligible neurologist 
would be notified immediately to perform a full neurological assessment and obtain 
further neurological testing as clinically warranted. Any acute change in neurological 
status triggered “escape” from the trial and immediate evaluation by the 24-hour in-house 
clinical stroke team, per standard hospital protocols.  
  
The study site had 24-hour coverage by resident neurologists and neurocritical care and/or 
stroke fellows who were board-eligible or board-certified in neurology. In addition, the 
study personnel included a board-certified vascular neurologist available 24/7 as backup 
in case of neurological emergency. 
  
Obstetrical emergencies 
All clinical obstetrical care was managed by the participants' inpatient obstetrics team. If 
an obstetrical emergency occurred while undergoing the cerebral autoregulation study in 
the Obstetrics Postpartum unit, the primary obstetrician or obstetrics team would be 
immediately notified. A maternal-fetal medicine fellow and attending physician were in 
house at all times, 24 hours/day, 7 days/week. 
 
Any adverse event would be reported immediately to the Institutional Review Board and 
any major adverse event would trigger an immediate convening of the DSMB to review the 
protocol and if indicated, stop the study. 
 
Funding 

This study was supported by the National Institutes of Health (NIH) National Center of 
Child Health and Human Development (R21HD110992). Edwards LifeSciences provided 
standard technical advice in accordance with equipment maintenance contracts, but did 
not provide financial support, nor did Edwards have a role in study design, data analysis, or 
interpretation of findings.