Furosemide vs. Placebo for Severe Antepartum Hypertension

Sponsor

Melanie Maykin, MD (Other)

Overall Status

Completed

CT.gov ID

NCT04615624

Collaborator

(none)

Enrollment

Location

Arms

15.8

Actual Duration (Months)

4.1

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Pre-Eclampsia Hypertension in Pregnancy Pregnancy Complications Hypertension, Pregnancy-Induced	Drug: Furosemide Other: Placebo	Phase 3

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

Antepartum patient diagnosed with a hypertensive disorder in pregnancy.
Patient approached for study participation and informed consent obtained if interested.
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.
When ordering provider's choice of antihypertensive, pharmacy notified that patient is study participant and randomizes patient by choosing from sequential opaque envelope.
1. Patient randomized to treatment arm and receives 40mg /4 milliliters IV furosemide in addition to usual antihypertensive.

Patient randomized to placebo and receives 4 milliliters normal saline in addition to usual antihypertensive.

Blood pressure check every 15 minutes after administration of furosemide/placebo for four recordings (15, 30, 45, 60 minutes)

Study Design

Study Type:

Interventional

Actual Enrollment :

65 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Triple (Participant, Care Provider, Investigator)

Masking Description:

After informed consent and upon meeting inclusion criteria, 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. 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.

Primary Purpose:

Treatment

Official Title:

A Randomized Control Trial of Furosemide or Placebo With Usual Antihypertensives in the Antepartum Management of Severe Hypertension With Wide Pulse Pressure

Actual Study Start Date :

Jan 4, 2021

Actual Primary Completion Date :

Apr 22, 2022

Actual Study Completion Date :

Apr 29, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Furosemide When patient meets inclusion criteria and is randomized to treatment drug, she receives 40mg /4 milliliters (mL) IV furosemide in addition to usual antihypertensive.	Drug: Furosemide Furosemide, a loop diuretic
Placebo Comparator: Placebo When patient meets inclusion criteria and is randomized to placebo, she receives one dose of 4mL normal saline in addition to usual antihypertensive.	Other: Placebo Normal saline

Arm

Intervention/Treatment

Experimental: Furosemide

When patient meets inclusion criteria and is randomized to treatment drug, she receives 40mg /4 milliliters (mL) IV furosemide in addition to usual antihypertensive.

Drug: Furosemide

Furosemide, a loop diuretic

Placebo Comparator: Placebo

When patient meets inclusion criteria and is randomized to placebo, she receives one dose of 4mL normal saline in addition to usual antihypertensive.

Other: Placebo

Normal saline

Outcome Measures

Primary Outcome Measures

Change in systolic blood pressure [0 minutes and 60 minutes post-dose]
Change in mean systolic BP during the 1-hour period after drug administration.

Secondary Outcome Measures

Change in diastolic blood pressure [0 minutes and 60 minutes post-dose]
Change in mean diastolic blood pressure during the 1-hour period after drug administration.

Other Outcome Measures

Gestational age at delivery [2 weeks after delivery]
Gestational age in weeks and days at the time of birth
Time from admission to delivery [2 weeks after delivery]
Time in days and hours from admission to birth
Time from treatment to delivery [2 weeks after delivery]
Time in days and hours from treatment to birth
Induction of labor [1-2 weeks after delivery]
Proportion of women who required induction of labor
Mode of Delivery [1-2 weeks after delivery]
Type of delivery
Eclampsia [1-2 weeks after delivery]
Proportion of women who developed seizure
Apgar scores of neonate [1-2 weeks after birth]
Neonatal clinical assessment (Apgar is not an abbreviated term). Minimum value 0; maximum value 9; Tool is used for assessment and not an accurate prognostic tool to predict outcomes.
Proportion of newborns admitted to Intensive Care Nursery [1-2 weeks after birth]
Neonatal Intensive Care Unit admission
Neonatal Intensive Care Unit length of stay in days [1-2 weeks after birth]
Length of stay in the Intensive Care Nursery

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

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 BP greater than or equal to 160 or diastolic greater than or equal to BP 110) with wide pulse pressure (>60 mmHg)
Subject able to provide informed consent

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 milliequivalent per liter) on admission
Subjects with anuria (<50 milliliters 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
Subjects who are in active labor defined as 6 centimeters of cervical dilation or more
Subjects who have an epidural (neuraxial anesthesia) in place