Conditions: Pre-Eclampsia Hypertension in Pregnancy Pregnancy Complications Hypertension, Pregnancy-Induced
Keywords: Severe range blood pressure Pre-eclampsia Gestational hypertension Wide pulse pressure High-risk pregnancy Pregnancy complications
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 65
Healthy volunteers: no

Brief summary:
Primary objective: To determine whether the addition of intravenous furosemide with usual antihypertensives is associated with a reduction in mean systolic blood pressure from baseline compared to treatment with placebo plus usual antihypertensives (intravenous labetalol, intravenous hydralazine, or oral immediate release nifedipine) for the management of severe antepartum hypertension.

Secondary objectives:

To determine whether the addition of intravenous furosemide with usual antihypertensives is associated with a reduction in mean diastolic blood pressure compared to treatment with placebo plus usual antihypertensives listed above.

Detailed description:
Blood pressure is a measure of blood flow and resistance in blood vessels. In normal pregnancy, total blood volume increases while systemic vascular resistance decreases, thereby leading to an overall reduction in blood pressure with return to baseline at term. Hypertensive disorders in pregnancy, including preeclampsia, are a polymorphic syndrome characterized by elevated blood pressures which can affect multiple organ systems. Although the exact mechanism of preeclampsia has yet to be determined, previous studies have shown that there may be two distinct phenotypes - one characterized by vasoconstriction and diminished micro-circulation and the other involving a hyperdynamic high cardiac output state.

Given its potential for both significant maternal and fetal morbidity, hypertensive disorders in pregnancy comprise a substantial proportion of antepartum admissions. Management of acute severe hypertension (systolic blood pressure greater than or equal to 160 or diastolic blood pressure greater than or equal to 110) is important to reduce the risk of stroke, hypertensive encephalopathy, placental abruption, and heart failure or myocardial infarction. In the antepartum and intrapartum period, the use of antihypertensives including labetalol, nifedipine, and hydralazine have been well-described. Despite these options for blood pressure control, preeclampsia can be a progressive disorder that may not respond to the aforementioned agents.

In preeclampsia manifested by high blood volume due to salt and water retention rather than vasoconstriction, standard antihypertensives may be less effective. Furosemide is a commonly used diuretic that can lower blood pressure by inhibiting the absorption of sodium, chloride, and water, thereby decreasing the volume of blood that the heart pumps. The onset of action of action of IV furosemide is 5 minutes, with peak effect at 30 minutes, and duration of action of 2 hours.

Previous studies have demonstrated the safety and efficacy of furosemide to treat preeclampsia in the antepartum and postpartum period as well as its utility in treating heart failure in pregnant women. To our knowledge, no randomized studies exist that investigate the use of furosemide in treating hypertension in the antepartum period. We aim to determine the utility of the addition of furosemide to usual antihypertensives in this clinical setting.

This will be a prospective double-blinded randomized placebo control trial of women with a diagnosis of preeclampsia with severe features at ≥20 weeks of gestation with persistent antepartum hypertension (sustained systolic blood pressure ≥160 or diastolic blood pressure ≥110 mmHg) and a wide pulse pressure (\>60 mmHg) who meet all inclusion criteria and have no exclusion criteria. It is routine that laboratory studies are performed on admission for all women with hypertensive disorders. If electrolyte disturbances exist, therapy will not be initiated unless the electrolyte is normalized or repleted.

After informed consent and upon meeting inclusion criteria with severe range hypertension with wide pulse pressure, the study personnel will inform pharmacy personnel who will then randomly assigned the patient to groups by opening the next previously prepared sequential and numbered opaque study envelope. Participants will be randomized to furosemide plus an antihypertensive versus placebo containing normal saline and an antihypertensive. The pharmacy staff will send the assigned treatment, which will be administered by the bedside nurse. The vials containing the treatment will be indistinguishable as both furosemide and normal saline placebo are clear, colorless solutions. Thus, the provider, nurse, and patient will be blinded to the treatment. The choice of antihypertensive will be determined by the primary obstetric provider. At our institution, this will be one or more of the recommended medications for urgent blood pressure control as outlined by the American College of Obstetricians and Gynecologists Practice Bulletin on gestational hypertension and preeclampsia. These include IV labetalol, IV hydralazine, or immediate-release oral nifedipine. As meta-analyses have not shown that one of the aforementioned antihypertensives is superior than another, and all are reasonable options, the choice of antihypertensive will be left up to the obstetric provider. This will also improve the generalizability of the study as it does not interfere with what is typically done in clinical practice.

As a procedure of the study, patients will have their blood pressure recorded at least every 15 minutes up to one hour after administration of the study drug. Thereafter, as part of routine care, patients in both groups will receive similar antepartum surveillance, including blood pressure and pulse assessment every four hours or more frequently if vital signs are abnormal, daily weight measurement, and daily urinary output measurements.

Study Procedures

1. Antepartum patient diagnosed with a hypertensive disorder in pregnancy.
2. Patient approached for study participation and informed consent obtained if interested.
3. Patient develops severe range BP (systolic blood pressure \> or = 160 and/or diastolic blood pressure\> or =10) with increased pulse pressure (\>60mmHg). This will be considered baseline BP.
4. When ordering provider's choice of antihypertensive, pharmacy notified that patient is study participant and randomizes patient by choosing from sequential opaque envelope.
5. a. Patient randomized to treatment arm and receives 40mg /4 milliliters IV furosemide in addition to usual antihypertensive.

   b. Patient randomized to placebo and receives 4 milliliters normal saline in addition to usual antihypertensive.
6. Blood pressure check every 15 minutes after administration of furosemide/placebo for four recordings (15, 30, 45, 60 minutes)

Arms:
arm 1: When patient meets inclusion criteria and is randomized to treatment drug, she receives 40mg /4 milliliters (mL) IV furosemide in addition to usual antihypertensive. arm 2: When patient meets inclusion criteria and is randomized to placebo, she receives one dose of 4mL normal saline in addition to usual antihypertensive.

Interventions: intervention 1: Furosemide intervention 2: Placebo
Intervention descriptions: intervention 1: Furosemide, a loop diuretic intervention 2: Normal saline

Protocol document:
Prot_SAP_000.pdf: 
A randomized control trial of furosemide or placebo with usual antihypertensives in the antepartum management of 
severe hypertension with wide pulse pressure 
Version 2 
Protocol Number I 
 
 
1 
 
A randomized control trial of furosemide or placebo with usual antihypertensives in the 
antepartum management of severe hypertension with wide pulse pressure 
Protocol Number I Version 2 
02/21/20 
 
Principal Investigator: Pai-Jong Stacy Tsai, MD, MPH, MCR 
Sub-Investigator: Melanie Maykin, MD 
 
Research Site: Kapi’olani Medical Center for Women and Children 
1319 Punahou Street 
Honolulu, Hawaii  
(808) 983-6000 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


A randomized control trial of furosemide or placebo with usual antihypertensives in the antepartum management of 
severe hypertension with wide pulse pressure 
Version 2 
Protocol Number I 
 
 
2 
Protocol Title:  A randomized control trial of furosemide or placebo with usual 
antihypertensives in the antepartum management of severe hypertension with wide pulse 
pressure 
Version Date: 2/21/20 
Protocol Number: I 
 
Principal Investigator:  Pai Jong Stacy Tsai, MD 
Sub-Investigator(s): Melanie Maykin, MD 
Research Site(s): Kapiolani Medical Center for Women and Children 
 
Section I:  Purpose and Background 
1. Purpose   
 
Primary objective: To determine whether the addition of intravenous furosemide with usual 
antihypertensives is associated with a reduction in mean systolic blood pressure from 
baseline compared to treatment with placebo plus usual antihypertensives (intravenous 
labetalol, intravenous hydralazine, or oral immediate release nifedipine) for the management 
of severe antepartum hypertension.  
 
Secondary objectives: 
To determine whether the addition of intravenous furosemide with usual antihypertensives is 
associated with a reduction in mean diastolic blood pressure compared to treatment with 
placebo plus usual antihypertensives listed above. 
 
 
2. Background  
Introduce and provide support for the research being proposed.  Basic 
information relevant to the context of the research question and study design 
should be included in this section.  Additionally, this section should be written in 
a way that a person who is not an expert in the field can understand.   
 
Blood pressure is a measure of blood flow and resistance in blood vessels. In normal 
pregnancy, total blood volume increases while systemic vascular resistance decreases, 
thereby leading to an overall reduction in blood pressure with return to baseline at term. 
Hypertensive disorders in pregnancy, including preeclampsia, are a polymorphic 
syndrome characterized by elevated blood pressures which can affect multiple organ 
systems1. Although the exact mechanism of preeclampsia has yet to be determined, 
previous studies have shown that there may be two distinct phenotypes – one 
characterized by vasoconstriction and diminished micro-circulation and the other 
involving a hyperdynamic high cardiac output state2,3.  
 
Given its potential for both significant maternal and fetal morbidity, hypertensive 
disorders in pregnancy comprise a substantial proportion of antepartum admissions. 
Management of acute severe hypertension (systolic BP³ 160 or diastolic BP³ 110) is 
important to reduce the risk of stroke, hypertensive encephalopathy, placental abruption, 
and heart failure or myocardial infarction4. In the antepartum and intrapartum period, the 
use of antihypertensives including labetalol, nifedipine, and hydralazine have been well-
described4. Despite these options for blood pressure control, preeclampsia can be a 
progressive disorder that may not respond to the aforementioned agents. 


A randomized control trial of furosemide or placebo with usual antihypertensives in the antepartum management of 
severe hypertension with wide pulse pressure 
Version 2 
Protocol Number I 
 
 
3 
 
 
In preeclampsia manifested by high blood volume due to salt and water retention rather 
than vasoconstriction, standard antihypertensives may be less effective. Furosemide is a 
commonly used diuretic that can lower blood pressure by inhibiting the absorption of 
sodium, chloride, and water, thereby decreasing the volume of blood that the heart 
pumps. The onset of action of action of IV furosemide is 5 minutes, with peak effect at 
30 minutes, and duration of action of 2 hours5. 
 
Previous studies have demonstrated the safety and efficacy of furosemide to treat 
preeclampsia in the antepartum and postpartum period as well as its utility in treating 
heart failure in pregnant women6,7. To our knowledge, no randomized studies exist that 
investigate the use of furosemide in treating hypertension in the antepartum period. We 
aim to determine the utility of the addition of furosemide to usual antihypertensives in 
this clinical setting. 
 
 
 
 
References 
 
1. Grindheim G, Estensen ME, Langesaeter E, Rosseland LA, Toska K. Changes in blood 
pressure during healthy pregnancy: a longitudinal cohort study. J Hypertens. 2012 
Feb;30(2):342-50. doi: 10.1097/HJH.0b013e32834f0b1c. PubMed PMID: 22179091. 
2. Phillips JK, Janowiak M, Badger GJ, Bernstein IM. Evidence for distinct preterm and 
term phenotypes of preeclampsia. J Matern Fetal Neonatal Med. 2010 Jul;23(7):622-
6. doi: 10.3109/14767050903258746. PubMed PMID: 20482241; PubMed Central 
PMCID: PMC2885458. 
3. Easterling TR, Benedetti TJ, Schmucker BC, Millard SP. Maternal hemodynamics in 
normal and preeclamptic pregnancies: a longitudinal study. Obstet Gynecol. 1990 
Dec;76(6):1061-9. PubMed PMID: 2234714. 
4. ACOG Practice Bulletin No. 202: Gestational Hypertension and Preeclampsia. Obstet 
Gynecol. 2019 Jan;133(1):e1-e25. doi: 10.1097/AOG.0000000000003018. PubMed 
PMID: 30575675. 
5. https://www.uptodate.com/contents/furosemide-drug 
information?search=furosemide&source=panel_search_result&selectedTitle=1~148&usa
ge_type=panel&kp_tab=drug_general&display_rank=1 
 
6. Tamás P, Hantosi E, Farkas B, Ifi Z, Betlehem J, Bódis J. Preliminary study of the 
effects of furosemide on blood pressure during late-onset pre-eclampsia in patients with 
high cardiac output. Int J Gynaecol Obstet. 2017 Jan;136(1):87-90. doi: 
10.1002/ijgo.12019. Epub 2016 Nov 3. PubMed PMID: 28099709. 
7. Ascarelli MH, Johnson V, McCreary H, Cushman J, May WL, Martin JN Jr. Postpartum 
preeclampsia management with furosemide: a randomized clinical trial. Obstet 
Gynecol. 2005 Jan;105(1):29-33. doi: 10.1097/01.AOG.0000148270.53433.66. PubMed 
PMID: 15625138. 
8. Duley L, Meher S, Jones L. Drugs for treatment of very high blood pressure during 
pregnancy. Cochrane Data- base of Systematic Reviews 2013, Issue 7. Art. No.: 
CD001449. (Systematic Review and Meta-Analysis). PMID: 23900968  


A randomized control trial of furosemide or placebo with usual antihypertensives in the antepartum management of 
severe hypertension with wide pulse pressure 
Version 2 
Protocol Number I 
 
 
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9. Emergent therapy for acute-onset, severe hypertension during pregnancy and the 
postpartum period. Committee Opinion No. 692. American College of Obstetricians and 
Gynecologists. Obstet Gynecol 2017;129:e90–5. (Level III). PMID 28333820. 
 
 
 
 
 
 
Section II:  Criteria for Subject Selection 
1. Number of subjects 
List the number of subjects expected to participate.  For multi-center protocols 
include the overall projected total and site specific projected totals. 
 
This study expects to enroll 70 subjects and projects a retention rate of approximately 
80%. Fifty-six subjects are expected to complete the study. 
 
2. Demographics of subjects 
Describe the projected distribution of gender, age range, race and ethnicity of 
subjects.  Support for the inclusion or exclusion of certain vulnerable populations 
(i.e. pregnant women, minors, minorities, age groups, etc.) should be included. 
 
This study expects to enroll pregnant females at least 18 years of age and at least 20 
weeks of gestation with hypertensive disorder in pregnancy. No restrictions on race or 
ethnicity will be imposed. Since preeclampsia is a disease only encountered in 
pregnancy, and pregnant women are the only population to incur potential benefit from 
this body of evidence, it is vital that pregnant women be involved as subjects. 
 
3. Inclusion criteria  
Define subject eligibility based on scientific rationale and safety considerations. 
Include the timeframe of data collection for retrospective studies. 
 
 Inclusion Criteria 
 
• 
Subjects 18 years of age or older 
• 
Subjects with intrauterine pregnancy at or beyond 20 weeks of gestation 
• 
Subjects with a diagnosis of hypertensive disorder in pregnancy 
• 
Subjects with persistent (on repeat BP check 15 min apart) severe range blood 
pressure recordings (systolic BP³ 160 or diastolic BP³ 110) with wide pulse 
pressure (>60 mmHg) 
• 
Subject able to provide informed consent 
 
4. Exclusion criteria  
Define exclusion criteria to limit the study population and prevent subjects from 
being exposed to excess risk by the study.  Exclusion criteria should account for 
warnings, precautions, and contraindications listed in current product labeling.   
 
Exclusion Criteria 
• 
Subjects less than 18 years of age 
• 
Subjects with intrauterine pregnancy less than 20 weeks of gestation 
• 
Subjects with known fetal anomaly 
• 
Subjects with hypokalemia (K <3.0 mEq/L) on admission 


A randomized control trial of furosemide or placebo with usual antihypertensives in the antepartum management of 
severe hypertension with wide pulse pressure 
Version 2 
Protocol Number I 
 
 
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• 
Subjects with anuria (<50mL urine in 24 hours) or renal failure 
• 
Subjects previously taking diuretics or potassium supplements for any reason 
• 
Subjects with a known allergy/adverse reaction to furosemide 
• 
Subjects who are unable to understand and/or sign the informed consent 
• 
Active labor (³ 6cm dilated) or epidural in place 
 
5. Vulnerable subjects  
Provide justification for the necessary inclusion of vulnerable populations.  
Vulnerable subjects often need additional protection and certain restrictions and 
requirements may apply. Children, pregnant women, and prisoner are examples of 
vulnerable populations. 
 
Preeclampsia exclusively affects pregnant individuals. As such, pregnant subjects 
should be studied. To protect these patients, consent forms will be collected and we will 
reiterate that declining study participation will in no way affect the quality of care they will 
receive.   
  
Section III:  Methods and Procedures 
1. Methods and procedures 
Summarize the research design (observational, randomized, case-study, etc.) and 
include a schematic diagram if applicable.  Provide a sequential list identifying all 
the procedures of the study, distinguishing between experimental procedures and 
procedures resulting from routine care.  Explain procedures, situations, or 
materials that may be hazardous and subsequent precautions to reduce subject 
risk.  
 
This will be a prospective double-blinded randomized placebo control trial of women ≥20 
weeks of gestation with persistent antepartum hypertension (sustained SBP ≥160 or 
DBP ≥110 mmHg) and a wide pulse pressure (>60 mmHg) who meet all inclusion criteria 
and have no exclusion criteria. It is routine that laboratory studies are performed on 
admission for all women with hypertensive disorders. If electrolyte disturbances exist, 
therapy will not be initiated unless the electrolyte is normalized or repleted. 
 
After informed consent and upon meeting inclusion criteria with severe range 
hypertension with wide pulse pressure, the study personnel will inform pharmacy 
personnel who will then randomly assigned the patient to groups by opening the next 
previously prepared sequential and numbered opaque study envelope. Participants will 
be randomized to furosemide plus an antihypertensive versus placebo containing normal 
saline and an antihypertensive. The pharmacy staff will send the assigned treatment, 
which will be administered by the bedside nurse. The vials containing the treatment will 
be indistinguishable as both furosemide and normal saline placebo are clear, colorless 
solutions. Thus, the provider, nurse, and patient will be blinded to the treatment. The 
choice of antihypertensive will be determined by the primary OB provider. At our 
institution, this will be one or more of the recommended medications for urgent blood 
pressure control as outlined by the American College of Obstetricians and Gynecologists 
Practice Bulletin on gestational hypertension and preeclampsia. These include IV 
labetalol, IV hydralazine, or immediate-release oral nifedipine. As meta-analyses have 
not shown that one of the aforementioned antihypertensives is superior than another, 
and all are reasonable options, the choice of antihypertensive will be left up to the OB 


A randomized control trial of furosemide or placebo with usual antihypertensives in the antepartum management of 
severe hypertension with wide pulse pressure 
Version 2 
Protocol Number I 
 
 
6 
provider8,9. This will also improve the generalizability of the study as it does not interfere 
with what is typically done in clinical practice. 
 
As a procedure of the study, patients will have their blood pressure recorded at least 
every 15 minutes up to one hour after administration of the study drug. Thereafter, as 
part of routine care, patients in both groups will receive similar antepartum surveillance, 
including blood pressure and pulse assessment every four hours or more frequently if 
vital signs are abnormal, daily weight measurement, and daily urinary output 
measurements. 
 
Study Procedures 
 
1. Antepartum patient diagnosed with a hypertensive disorder in pregnancy. 
2. Patient approached for study participation and informed consent obtained if interested. 
3. Patient develops severe range BP (SBP>160 and/or DBP>110) with increased pulse 
pressure (>60mmHg). This will be considered baseline BP. 
4. When ordering provider's choice of antihypertensive, pharmacy notified that patient is study 
participant and randomizes patient by choosing from sequential opaque envelope.  
5. a. Patient randomized to treatment arm and receives 40mg /4mL IV furosemide in addition 
to usual antihypertensive. 
b. Patient randomized to placebo and receives 4mL normal saline in addition to usual 
antihypertensive. 
6. Blood pressure check every 15 minutes after administration of furosemide/placebo for four 
recordings (15, 30, 45, 60 minutes) 
 
 
2. Data analysis  
Specify statistical and analytical methods (statistical power, sample size, 
significance level, etc.).   
 
 
The primary outcome variable is reduction in mean systolic BP during the 1-hour period 
after drug administration. BP will be taken every 15 minutes for 1 hour and averaged. 
Intention-to-treat analysis will be performed. This study will use a two-sided t-test with 
the null hypothesis set at the standard significance level (p –value < 0.05), to determine 
if the addition of furosemide to usual antihypertensive significantly reduces blood 
pressure.   
 
Change in average BP from baseline will be tested comparing the group receiving 
furosemide and the group receiving placebo using Mann-Whitney U, as BP usually 
presents as a non-parametric continuous variable. Multivariate regression will be used to 
adjust for potential confounders, such as maternal age, BMI, diabetes, baseline BP, 
antihypertensive chosen by the primary obstetrician, number of doses of 
antihypertensive, and gestational age. Comparative testing will be done to explore 
differences between the furosemide and placebo groups. Continuous variables satisfying 
the assumption of normality will be tested using the Student t-test and means and 
standard deviations will be reported. Otherwise, variables will be tested using the Mann-
Whitney U test and will be reported using medians and interquartile ranges. The χ2 or 


A randomized control trial of furosemide or placebo with usual antihypertensives in the antepartum management of 
severe hypertension with wide pulse pressure 
Version 2 
Protocol Number I 
 
 
7 
Fisher exact test will be utilized to test categorical variables and sample sizes and 
percentages will be reported.  
 
A power calculation was completed using OpenEpi, Version 3, open source calculator—
SSMean. The assumption of normality and that both groups will have the same common 
variance was applied. We set the standard deviation value as 20mmHg in the power 
calculation, which is based on pilot data from our own practice as well as data found in a 
randomized clinical trial using furosemide versus placebo (Ascarelli et al, Ob/Gyn 2005). 
A 15mmHg reduction in mean systolic blood pressure in the placebo group compared 
with the IV furosemide group was considered to be clinically significant as this 
represents an attainable, yet safe reduction from severe to mild range blood pressure. 
Using the 2-group Student t-test of equal means, 28 patients per study arm for a total of 
56 patients would be required to detect a difference of 15mmHg with 80% power and a 
significance level of p=0.05. Once data has been collected, we will test for normality and 
use the appropriate statistical tests. 
 
To account for patients who withdraw from the study or who need to be excluded after 
consent, 35 per arm or 70 total patients are to be enrolled. A randomization schedule will 
be created using block randomization with 10 blocks of 10 participants allocating 
randomization numbers to drug or placebo. The numbers will be sequentially assigned to 
participants by the pharmacist on duty. The hospital pharmacy will maintain the master 
list of the randomization log with patient study identifiers. 
 
Data monitoring 
Describe data monitoring methods for studies with more than minimal risk (i.e. 
data monitoring committee).  Explain adverse event reporting procedures.   
 
This is a greater than minimal risk study. Adverse events will be reported to the sub-
investigator and primary investigator by the nurse and/or the obstetric provider. 
Furthermore, the sub-investigator will be actively following study participants closely to 
monitor for adverse events. If found, these will be reported to the institutional review 
board according to their reporting polices. 
 
3. Data storage, security, and confidentiality 
Describe where data will be stored and how data will be secured during the study.  
Provide information on confidentiality measures (coding, storage mechanisms, 
etc.).  Indicate who will have access to the data and how the data will be used. If 
subject identifiers will be released, describe to whom and for what purpose the 
data will be released. 
 
Data will be stored on a password-protected computer and maintained for 10 years after 
study completion. The data will be recorded in Microsoft Excel and will only be 
transmitted electronically through UCERA’s encrypted email service among other study 
personnel in the same encrypted network. Access to subject data will be limited to the 
principal investigator, sub-investigators, and study staff.  Data will be de-identified when 
data collection is complete, at which time each subject will be given a subject ID number. 
A key containing subject ID numbers will be maintained by the investigator and sub-
investigator. Data will only be used for research purposes. 
 


A randomized control trial of furosemide or placebo with usual antihypertensives in the antepartum management of 
severe hypertension with wide pulse pressure 
Version 2 
Protocol Number I 
 
 
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4. Data Sharing 
Describe plans for data sharing, particularly for publication purposes. Many 
journals now require authors to disclose how de-identified individual level data 
will be shared. Some journals require data sharing plans to be posted in a public 
registry, such as Clinicaltrials.gov. Additional information about data sharing can 
be found here: 
https://grants.nih.gov/grants/sharing_key_elements_data_sharing_plan.pdf 
https://grants.nih.gov/grants/policy/data_sharing/data_sharing_workbook.pdf 
 
 
The following statements are in response to data sharing guidelines by Elsevier. 
 
Will individual participant data be available (including data dictionaries)?  
Individual participant data will be made available.  
 
What data in particular will be shared?  
Individual participant data that underlie the results reported any future manuscript, after 
deidentification (text, tables, figures, and appendices). 
 
What other documents will be available?   
There are no plans for additional documents to be made available. 
 
When will data be available (start and end dates)?  
Beginning 9 months and ending 36 months following any publication.  
 
With whom?  
Researchers who provide a methodologically sound proposal.  
 
For what types of analyses?  
To achieve aims in the approved proposal.  
 
By what mechanism will data be made available?  
The data will be deposited to Mendeley Data, a data repository that is supported by 
Elsevier and the American Journal of Obstetrics & Gynecology. 
 
5. Transition from research participation (if applicable) 
Describe how subjects who terminate participation will be transitioned to regular 
care (such as, taper study medication, return to primary care provider). 
 
Subjects who terminate participation will resume regular care as determined by her 
primary treatment team. The investigators will discontinue collecting data on the 
individual and the choice of medications for acute blood pressure control will no longer 
be influenced by the investigators or study protocol. 
 
Section IV:  Risk/Benefit Assessment 
1. Risk category (Contact HPHRI if you need assistance determining risk level) 
State the risk of participating in the study as either Minimal or Greater than 
Minimal.  Risk is defined as the potential harm associated with the research that a 


A randomized control trial of furosemide or placebo with usual antihypertensives in the antepartum management of 
severe hypertension with wide pulse pressure 
Version 2 
Protocol Number I 
 
 
9 
reasonable person would find injurious. Minimal Risk means that the probability 
or magnitude of harm or discomfort anticipated in the research are not greater 
than those ordinarily encountered in daily life or during the performance of 
routine physical or psychological examinations or tests. 
 
Participation in this study presents greater than minimal risk to subjects but not greater 
than the risks incurred by their existing disease process. As patients admitted with 
severe preeclampsia are required to have intravenous access, no additional invasive 
lines would be placed for the sole purpose of administering the study medications. 
Additionally, furosemide is already used for the aforementioned indication (severe range 
blood pressure with wide pulse pressure) in pregnant women. As furosemide is an 
approved drug being used for its approved indication in this study (ACC/AHA [Whelton 
2017], risks incurred to the patient are outweighed by the potential benefit of treating a 
life-threatening condition (severe range blood pressure). 
 
2. Potential risk(s) 
Describe any potential risks associated with the study (physical, psychological, 
sociological, economic, and/or legal).  If possible, estimate the probability of a 
given risk and potential reversibility. 
 
Potential risks associated with participation in this study include the known 
pharmacologic effect of furosemide, which include fluid/electrolyte loss as well as rare 
side effects such as.  
 
Cardiovascular: Necrotizing angiitis, orthostatic hypotension, thrombophlebitis, vasculitis 
Central nervous system: Dizziness, headache, paresthesia, restlessness, vertigo 
Dermatologic: Acute generalized exanthematous pustulosis, bullous pemphigoid, 
erythema multiforme, exfoliative dermatitis, pruritus, skin photosensitivity, skin rash, 
Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria 
Endocrine & metabolic: Glycosuria, hyperglycemia, hyperuricemia, increased serum 
cholesterol, increased serum triglycerides 
Gastrointestinal: Abdominal cramps, anorexia, constipation, diarrhea, gastric irritation, 
mouth irritation, nausea, pancreatitis, vomiting 
Genitourinary: Bladder spasm 
Hematologic & oncologic: Agranulocytosis, anemia, aplastic anemia, eosinophilia, 
hemolytic anemia, leukopenia, purpura, thrombocytopenia 
Hepatic: Hepatic encephalopathy, intrahepatic cholestatic jaundice, liver enzymes 
increased 
Hypersensitivity: Anaphylaxis, anaphylactoid reaction, anaphylactic shock 
Immunologic: DRESS syndrome 
Neuromuscular & skeletal: Muscle spasm, weakness 
Ophthalmic: Blurred vision, xanthopsia 
Otic: Deafness, tinnitus 
Renal: Interstitial nephritis (allergic), renal disease 
Miscellaneous: Fever 
 
Source: https://www.uptodate.com/contents/furosemide-drug 
information?search=furosemide&source=panel_search_result&selectedTitle=1~148&usa
ge_type=panel&kp_tab=drug_general&display_rank=1 


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severe hypertension with wide pulse pressure 
Version 2 
Protocol Number I 
 
 
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3. Protection against risk(s) 
Describe how the study will minimize or prevent any potential risks.  Techniques 
to minimize risk include subject monitoring, withdrawal criteria, and follow-up 
procedures. 
 
Subjects will be monitored for side effects and dosage levels will be adjusted if the 
subject experiences side effects from furosemide. Subjects will not receive additional 
furosemide if side effects are deemed significant. Subjects will be allowed to withdraw 
from the study at any time without consequence.  If new information about the study 
becomes available, subjects will be informed and re-consented if applicable.   
 
 
4. Potential benefit(s) to the subject 
Describe any potential medical benefit(s) for subject participation.  State if 
participation results in no benefit to the subject. 
 
The direct medical benefits to the subject for participating in the study include acute 
control of severe hypertension, which reduces the risk of stroke, placental abruption, 
hypertensive encephalopathy, and myocardial infarction. An additional benefit may 
include prolongation of pregnancy at critical gestational ages which may reduce the risks 
of prematurity which includes respiratory distress, intraventricular hemorrhage, 
necrotizing enterocolitis, and metabolic and thermic dysregulation. 
 
5. Alternative to participation 
Describe any alternative therapies or courses of action available to the subject if 
they decide not to participate in the study. 
 
Should a subject decide not to participate in the study, they will receive the standard of 
care for severe hypertension, which typically includes IV labetalol, IV hydralazine, or oral 
immediate-release nifedipine. However, furosemide is an adjunct that may be 
administered to the patient per the primary clinician’s decision, unrelated to the study. 
 
Section V:  Subject Identification, Recruitment and Consent/Assent  
(If you are requesting a waiver of consent this section can be deleted) 
1. Method of subject identification and recruitment 
Describe how subjects will be identified and recruited.  Include steps to minimize 
undue influence if recruitment includes an investigator’s students, employees, 
and/or patients. 
 
 
Contact will be initiated in person at the time of severe range blood pressure and 
meeting inclusion criteria by the antepartum care provider. If eligible, individuals who are 
involved in the study and identified as key study personnel will provide information about 
the study to the subject and if the subject is interested will proceed with obtaining 
informed consent. Subjects will be informed of the voluntary nature of the study and 
informed of alternative treatment options.   
 
2. Consent process 


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List study team members authorized to obtain consent and describe the process 
of informed consent. 
 
 
Informed consent will be primarily conducted by the sub-investigators, principal 
investigator, and trained residents and fellows who have completed the necessary 
training for research clearance. The subject will be approached with study information as 
close to the time at which she meets inclusion criteria, which in many cases will be at the 
time of admission. If the study participant is not ready to make a decision regarding their 
participation at the time of informed consent, then the study personnel will return later 
that day or the next. The informed consent process will consist of reviewing the informed 
consent documents and asking the subject a series of questions to ensure 
comprehension (see subject/representative comprehension below).   
 
3. Subject capacity (if applicable) 
Describe how capacity will be assessed and by whom.  State the anticipated 
degree of impairment relative to the subject’s ability to consent. 
 
Capacity will be assessed by the admitting provider at the time of the admission history 
and physical by directed clinical interview and exam. This includes the ability to 
understand information about treatment; the ability to appreciate how that information 
applies to their situation; the ability to reason with that information; and the ability to 
make a choice and express it. We anticipate there to be no degree of impairment relative 
to the subject’s ability to consent.  
 
4. Subject/Representative comprehension 
Describe how it will be determined that the subject /representative understood the 
information presented during the informed consent process.  If children or 
decisionally impaired adults will participate, include a plan to assess 
comprehension during the assent process. 
 
To determine comprehension of the informed consent, subjects will be asked a series of 
questions. These include: 
 
1. Can you briefly recount the purpose of the study and your involvement? 
2. What is your understanding of your decision to participate in the study, to decline 
participation, or to discontinue participation after being initially involvement and how 
this impacts the care you receive? 
3. In case you have further questions about the study or your involvement, are you 
aware that you may contact the investigators? 
   
 
5. Documentation of consent 
If not addressed in the process of consent section, explain how consent will be 
documented and where documentation will be stored. 
 
Consent will be documented on the Hawai‘i Pacific Health Research Institute IRB-
approved informed consent form and by the subinvestigator’s password-protected 
electronic log. Paper documentation will be stored by the subinvestigator in a locked-file 


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cabinet and electronic documentation will be stored on a password-protected computer. 
A copy of the signed consent form will be provided to the subject and will be scanned 
into the electronic medical record.  
 
6. Costs to the subject 
There will be no costs incurred by the subject as a result of participating in the study as 
this is part of global inpatient pregnancy care and the medications in this study are 
commonly used in the inpatient setting for the aforementioned medical indications. 
 
7. Payment for participation 
There will be no payment for participation in this study. 
 
  
 
 
 
 

ICF_001.pdf: 
IRB APPROVED 
Oct 02, 2020 
 
 
1 
RESEARCH SUBJECT CONSENT FORM 
 
TITLE: 
A randomized control trial of furosemide or placebo with usual 
antihypertensives in the antepartum management of severe 
hypertension with wide pulse pressure 
 
PROTOCOL NO.: 
2020-033 
 
WIRB® Protocol #20203025 
 
SPONSOR: 
Pai-Jong Stacy Tsai 
 
INVESTIGATOR: 
Pai-Jong Stacy Tsai, MD, MPH 
 
1319 Punahou Street 
 
Suite 824 
 
Honolulu, HI 96826 
 
USA 
 
STUDY-RELATED 
PHONE NUMBER(S): 
808-983-6000 (24 hours) 
 
RESEARCH CONSENT SUMMARY 
 
You are being asked for your consent to take part in a research study. This document provides a 
concise summary of this research. It describes the key information that we believe most people 
need to decide whether to take part in this research. Later sections of this document will provide 
all relevant details. 
 
What should I know about this research? 
 
• Someone will explain this research to you. 
• Taking part in this research is voluntary. Whether you take part is up to you. 
• If you don’t take part, it won’t be held against you. 
• You can take part now and later drop out, and it won’t be held against you 
• If you don’t understand, ask questions. 
• Ask all the questions you want before you decide. 
 
How long will I be in this research? 
 
We expect that your taking part in this research will last about 1 hour. You will continue to be 
observed while you are in the hospital for any side effects related to your participation in the 
research. 
 
Why is this research being done? 
 
The purpose of this research is to confirm whether furosemide decreases your blood pressure 
when it is too high.  


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What happens to me if I agree to take part in this research? 
 
If you decide to take part in this research study, the general procedures include: when your blood 
pressure is high and needs to be treated, you will be given furosemide or placebo (no furosemide) 
with the medication that your doctor orders to lower your blood pressure. Your blood pressure will 
be checked at least four times (every 15 minutes for one hour) after receiving the medications. 
Otherwise, the care you receive will not be affected by participating in the study.  
 
Could being in this research hurt me? 
 
The most important risks or discomforts that you may expect from taking part in this research are 
fluid/electrolyte loss if you are selected to receive furosemide and an increased number of blood 
pressure checks after you receive furosemide or placebo.  
 
Will being in this research benefit me? 
 
The most important benefits that you may expect from taking part in this research include better 
control of your high blood pressure, which may lower your risk of stroke, problems with the 
placenta, and negative effects on your heart.  
 
Possible benefits to others include helping to find effective therapies to control high blood 
pressure in pregnancy.  
 
What other choices do I have besides taking part in this research? 
 
Instead of being in this research, your choice would be to receive usual care.  Not participating in 
the study will not affect the care you receive.  
 
DETAILED RESEARCH CONSENT 
 
You are being invited to take part in a research study.  A person who takes part in a research 
study is called a research subject, or research participant.  
 
What should I know about this research? 
 
• Someone will explain this research to you. 
• This form sums up that explanation. 
• Taking part in this research is voluntary. Whether you take part is up to you. 
• You can choose not to take part. There will be no penalty or loss of benefits to which you 
are otherwise entitled. 
• You can agree to take part and later change your mind. There will be no penalty or loss of 
benefits to which you are otherwise entitled. 
• If you don’t understand, ask questions. 
• Ask all the questions you want before you decide. 


IRB APPROVED 
Oct 02, 2020 
 
 
3 
 
Why is this research being done? 
 
The purpose of this research is to see if using intravenous furosemide (also known commonly as 
a ‘water pill’ and blood pressure medication) helps to control blood pressure for pregnant women 
with very high blood pressure.  
 
About 70 subjects will take part in this research. 
 
How long will I be in this research? 
 
We expect that your taking part in this research will last for about 1 hour. After you receive 
treatment your blood pressure will be checked every 15 minutes for up to 1 hour. You will 
continue to be observed for any side effects related to your participation in the research while 
you are in the hospital.  
 
What happens to me if I agree to take part in this research? 
 
If you decide to participate in this research you will be asked to provide informed consent. After 
consent has been provided you will be put into a study group by chance (like a coin toss/ like 
drawing straws). You have a 1 out of 2 chance of being placed in each group. You cannot choose 
your study group. One group will receive a placebo (saline solution) and one group will receive 
furosemide intravenously. Participants in both groups will also receive the usual care for their 
high blood pressure.  
 
Furosemide is a drug that has been approved by the Food and Drug Administration (FDA) for the 
treatment of high blood pressure. However, in this study the use of furosemide is investigational. 
 
After you receive furosemide or placebo your blood pressure will be checked every 15 minutes 
for up to 1 hour (4 times).  
 
This study is blinded, which means that during the research, you and the study doctor will not 
know which group you are in. Your study doctor can find out in case of an emergency. 
 
What are my responsibilities if I take part in this research? 
 
If you take part in this research, you will be responsible to:  
 
• Alert your care providers of any medical issues that you experience.  
 
Could being in this research hurt me? 
 
There are no known side effects associated with saline solution (placebo group). 
 
The most common side effect associated with furosemide is fluid/electrolyte loss.  


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Oct 02, 2020 
 
 
4 
 
Rare side effects include:  
 
• Cardiovascular: Low blood pressure, inflammation in blood vessels 
• Central nervous system: Dizziness, headache, tingling, restlessness, vertigo 
• Dermatologic: Assorted rashes, itching, sensitivity to the sun, skin sloughing  
• Endocrine & metabolic: Elevated sugar level in your urine or blood, increased uric acid 
in your blood, increased serum cholesterol, increased serum fats 
• Gastrointestinal: Abdominal cramps, loss of appetite, constipation, diarrhea, upset 
stomach, mouth irritation, nausea, inflamed pancreas, vomiting 
• Genitourinary: Bladder spasm 
• Hematologic & oncologic: Decreased white blood cells or red blood cells, bruising, low 
platelets.  
• Hepatic: Mental confusion, increased bile acids in your liver causing jaundice, liver 
enzymes increased 
• Hypersensitivity: Mild or severe allergic reactions 
• Immunologic: hypersensitivity reaction that could be characterized by fever, skin rash, 
lymph node swelling, blood abnormalities and internal organ involvement. 
• Neuromuscular & skeletal: Muscle spasm, weakness 
• Ophthalmic: Blurred or yellowed vision 
• Otic: Deafness, ringing in your ears 
• Renal: inflammation in your kidneys  
• Miscellaneous: Fever 
 
The FDA has determined that furosemide is a pregnancy category C drug. This means that 
studies in animals have shown adverse effects of the drug on the fetus, however, the effects on 
human fetuses are unknown. As a category C drug, the potential benefits of this drug may 
warrant use in pregnant women despite potential risks. 
 
There may be additional risks that are unknown at this time. 
 
Will it cost me money to take part in this research? 
 
In some cases, insurance does not pay for services ordinarily covered because these services 
were performed in a research study. You should check with your insurance to see what services 
will be covered by your insurance and what you will be responsible to pay. 
 
The study sponsor will provide the study drug/placebo. This will not be charged to your 
insurance. 
 
Will being in this research benefit me? 
 
We cannot promise any benefits to you or others from your taking part in this research. However, 
possible benefits to you include improvements in your blood pressure which can reduce your risk 
of stroke, placenta problems, and negative effects of very high blood pressure on your heart.  


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5 
 
Possible benefits to others include improvements in treatment for high blood pressure during 
pregnancy. 
 
What other choices do I have besides taking part in this research? 
 
Instead of being in this research, your choices may include: 
 
• Routine treatment, which includes intravenous labetalol, intravenous hydralazine, or oral 
nifedipine. 
• Your provider may also treat you with intravenous furosemide unrelated to the study if 
they feel it is in your best interest. 
 
What happens to the information collected for this research? 
 
Your private information and your medical record will be shared with individuals and 
organizations that conduct or watch over this research, including: 
 
• The research sponsor  
• People who work with the research sponsor 
• Government agencies, such as the Food and Drug Administration 
• The Institutional Review Board (IRB) that reviewed this research 
• Hawai‘i Pacific Health. 
 
We may publish the results of this research. However, we will keep your name and other 
identifying information confidential. 
 
We protect your information from disclosure to others to the extent required by law. We cannot 
promise complete secrecy. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time. 
 
Data collected in this research might be used for future research or distributed to another 
investigator for future research without your consent, only after it has been de-identified. 
 
Who can answer my questions about this research? 
 
If you have questions, concerns, or complaints, or think this research has hurt you or made you 
sick, talk to the research team at the phone number listed above on the first page. 
 


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Oct 02, 2020 
 
 
6 
This research is being overseen by an Institutional Review Board (“IRB”). An IRB is a group of 
people who perform independent review of research studies. You may talk to them at (800) 562-
4789, help@wirb.com if: 
 
• You have questions, concerns, or complaints that are not being answered by the research 
team. 
• You are not getting answers from the research team. 
• You cannot reach the research team. 
• You want to talk to someone else about the research. 
• You have questions about your rights as a research subject. 
 
Compensation in case of injury:  
 
No financial compensation or coverage will be routinely provided by the sponsor or study 
doctor.  If you require treatment for any injury or illness related to procedures required by the 
study, or if you suffer side effects while in the study, you should contact your study doctor, Dr. 
Stacy Tsai at 808-983-6000, who will give you the necessary medical care and advice.  The cost 
of this medical care and advice will be billed to you or your medical insurance in the usual 
manner. 
 
By signing this consent form, you will not give up any legal rights. 
 
Can I be removed from this research without my approval? 
 
The person in charge of this research can remove you from this research without your approval. 
Possible reasons for removal include: 
 
• It is in your best interest 
• You have a side effect that requires stopping the research 
• You are unable to take the research medication 
 
We will tell you about any new information that may affect your health, welfare, or choice to 
stay in this research. 
 
What happens if I agree to be in this research, but I change my mind 
later? 
 
If you decide to leave this research, contact the research team so that the investigator can stop 
study procedures and collecting data on you. 
 
Will I be paid for taking part in this research? 
 
You will not be paid for taking part in this research. 
 


IRB APPROVED 
Oct 02, 2020 
 
 
7 
AUTHORIZATION TO USE AND DISCLOSE PROTECTED HEALTH INFORMATION FOR 
A RESEARCH STUDY 
 
A federal law known as the Health Insurance Portability and Accountability Act (HIPAA) sets 
rules for protecting the privacy of patients’ health care records.  HIPAA requires health care 
providers, except in specific circumstances, to obtain written permission from research 
participants before using and disclosing their health information. 
 
This authorization allows the research team to use and disclose my health information associated 
with the research described in this consent form. 
 
What is the purpose of this authorization?  
 
By signing this document, I am authorizing or giving permission for the research study doctor 
and research staff to access, receive, use and disclose Protected Health Information (“PHI”) 
about me. The research will only use the information as described below and as allowed by law.  
 
What Protected Health Information (“PHI”) is covered by this authorization?  
 
The PHI that may be accessed, collected, and used by the research team includes: 
 
• Demographic information (e.g., my name, address, date of birth, etc.). This information could 
be used to identify me; 
• All information in medical records, results of physical examinations, medical history, lab 
tests, or certain health information such as tumor measurements, CT scans, MRIs, x-rays 
and pathology results relating to your high blood pressure held by providers, clinics, 
facilities at which you have been treated; 
• Information obtained from me in the Study as a result of tests or procedures; 
• Information about other medical conditions that may change my treatment; 
• Information on side effects (adverse events) I may have, and how these were treated. 
 
I understand my medical records may contain information about AIDS or HIV infection, 
venereal disease, treatment for alcohol and/or drug abuse, or mental health or psychiatric 
services and that the research team may have access to that information.  
 
Who may use and disclose my PHI? 
 
By signing this authorization form I give permission to Hawaii Pacific Health, my doctor(s) and 
other health care providers that have cared for me or performed diagnostic testing and procedures 
to disclose the above information to the research doctor and the research staff.     
 
I also authorize the research doctor and staff to use and disclose my research-related health 
information. 
 


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8 
Who may receive my PHI? 
 
I authorize the following persons or groups to receive research-related health information about 
me: 
 
• The research sponsor. “Sponsor” means any persons or companies that are: 
o working for or with the sponsor, or  
o owned by the sponsor. 
• Department of Health and Human Services (HHS) agencies, 
• The U.S. Food and Drug Administration (FDA), 
• Other federal, state, and local agencies having oversight over this research, 
• Governmental agencies to whom certain diseases (reportable diseases) must be reported, 
• Hawai‘i Pacific Health,  
• The Hawaii Pacific Health (HPH) Research Institute, HPH Officials, and the HPH Office 
of Compliance for purposes of overseeing the research study and making sure that my 
ethical rights are being protected. 
• University of Hawai‘i, 
• Western Institutional Review Board® (WIRB®).  
 
Why will this information be used and/or given to others? 
 
• to do the research,  
• to study the results, and  
• to monitor the research to be sure it was done correctly.   
 
If the results of this research are made public, information that identifies you will not be used. 
 
Is my PHI protected after it has been given to others? 
 
There is a risk that your information will be given to others without your permission or some of 
the recipients may not be required to comply with Federal privacy regulations. If this happens, 
your information may no longer be protected. 
 
Can I refuse to sign this authorization?  
 
You have the right to refuse to sign this authorization.  This would prevent those listed above 
from having access to, using, or disclosing your PHI for this research study. However, by 
refusing to sign this authorization, you understand that you cannot participate in this research 
study. 
 
Can I revoke (cancel) this authorization?  
 
You may change your mind and revoke (take back) this Authorization at any time. To revoke 
this Authorization, you must write to: Dr. Stacy Tsai, 1319 Punahou Street, Honolulu, HI 96826  
 


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9 
If you decide to revoke (cancel or “take back”) your authorization: 
 
• Your revocation will not become effective until the covered entities affected by the 
revocation receive or are informed/have knowledge of your revocation; 
• No new identifiable information will be accessed, collected or disclosed after the covered 
entity receives your revocation; 
• Information that was already collected may still be used and disclosed to others to 
maintain the integrity of the research; and  
• The researchers in this research study are not required to destroy or retrieve any of your 
health information that was created, used or disclosed for this research prior to receiving 
your written revocation.    
 
When will this authorization expire? 
 
Your authorization to use your PHI for this research study will not expire even if you terminate 
your participation in this research or you are removed from this research by the principal 
investigator.  
 
Will all recipients of my PHI be required to protect the information? 
 
Some of the persons or groups that receive your study information may not be required to 
comply with HIPAA privacy laws, and your information may lose its federal protection if those 
persons or groups disclose it.   
 
OTHER RESEARCH ACTIVITIES:   
 
In addition to the research uses described above, the researchers would like your authorization to store 
the PHI collected about you in a secured database or central repository for use in future related 
research. You are not required to authorize this additional use in order to participate in this research 
study. 
 
Please initial one of the following to indicate your preference regarding the use of your information  
for future research. 
 
_______ Yes, I authorize the use of my PHI for future research 
 
_______ No, I do not authorize the use of my PHI for future research 
 
If you authorize the use of your PHI for future research, your authorization will remain valid 
until revoked in writing by you. 
 


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Can I revoke my authorization for future research? 
 
You have the right to revoke your authorization for future research at any time. Your revocation 
must be submitted in writing, either on paper or electronically to: Dr. Stacy Tsai, 1319 Punahou 
Street, Honolulu, HI 96826, paijong@hawaii.edu. Your revocation will not become effective 
until the covered entity providers affected by the revocation receives or is informed/has 
knowledge of your revocation. 
 
Written Permission  
 
By signing this consent form I authorize the release of my PHI in connection with this research 
study. I understand that this authorization is voluntary.   I will receive a signed copy of this form. 
 
Statement of Consent:  
 
Your signature documents your consent to take part in this research. 
 
 
 
 
Signature of adult subject capable of consent 
 
Date 
 
 
 
 
Signature of person obtaining consent 
 
Date