Hemorrhagic Shock
Conditions
Brief summary
Based on encouraging results from animal studies, the investigators hypothesize that early administration of IV Premarin® in patients with hemorrhagic shock will safely reduce secondary injury, and improve survival.
Detailed description
Annually in the United States, approximately 30 million people require treatment for traumatic injuries in emergency departments. Two million of these patients require hospitalization, with several hundred thousand ultimately dying, often due to extreme blood loss. Importantly, these traumatic injuries are the leading cause of death and disability for children and young adults under the age of 44, with the total cost of trauma in the U.S. approaching $260 billion each year. Despite advances in pre-hospital care, early resuscitation, surgical interventions and intensive care monitoring aimed at the primary traumatic injury, many survivors never recover. A significant cause of this mortality and morbidity is thought due to potentially preventable secondary injury, namely oxidant injury, inflammation, and apoptosis beginning in the first few hours after the severe traumatic event. In spite of the current bleak outlook for many of these patients, a series of animal investigations have uncovered a promising solution to the problem of the secondary injury seen in hemorrhagic shock and other similar processes, namely the early administration of estrogen, a strong anti-oxidant, anti-inflammatory and anti-apoptotic compound. Based on encouraging results from animal studies, the investigators hypothesize that early administration of IV Premarin® in patients with hemorrhagic shock will safely reduce secondary injury, and improve survival.
Interventions
DRUGPremarin IV
One time dose of Premarin IV
DRUGPlacebo
One time dose of placebo.
Sponsors
University of Washington
Resuscitation Outcomes Consortium
University of Texas Southwestern Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
No
Inclusion criteria
1. Age≥ 18 yrs or \< 50 yrs 2. Blunt or penetrating trauma leading to presumed hemorrhagic shock 3. Pre-hospital or ED systolic blood pressure \< 90 4. Receiving medical treatment in the Emergency Department (ED) of Parkland Hospital or Baylor University Medical Center Emergency Department, Level I Trauma Centers in Dallas, Texas
Exclusion criteria
1. Those who would receive the study drug \> 120 minutes after the traumatic event 2. Time of injury is unknown 3. Known indication for IV estrogen 4. Known contraindication for estrogen 5. Estimated age \<18 or \> 50 years 6. Cardiopulmonary Resuscitation (CPR) prior to randomization 7. Known incarceration 8. Severe hypothermia (suspected T \< 28° C) 9. Drowning or asphyxia due to hanging 10. Burns total body surface area (TBSA) \> 20% 11. Isolated penetrating injury to the head 12. Known inclusion in another interventional trial related to this traumatic event prior to randomization 13. Known legal do not resuscitate (DNR) orders in place prior to randomization 14. Recognized spinal cord injury prior to study drug administration
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Survival | 28 Days | Survival is defined as the number of patients who were discharged from the hospital alive prior to 28 days post injury or the number of patients still alive in the hospital 28 days post injury. The trial examines the rate of enrolled patients on each arm who survived to 28 days. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Acute Respiratory Distress Syndrome (ARDS) Free Survival | 28 days | ARDS is a life-threatening condition characterized by inflammation of the lungs. The trial measures the number of days alive and without ARDS within 28 days post injury. Patients who die within 28 days are given value of 0, similarly, patients who live 28 days but have ARDS for all 28 days. A higher score (greater days) indicates better prognosis. Exudative stage is 0-6 days, proliferative stage is 7-10 days, Fibrotic stage is \>10-14 days. |
Countries
United States
Participant flow
Recruitment details
Clinical sites enrolled men and women age 18 to 55 who experienced hemorrhagic shock in the emergency medical services (EMS) setting between September 2009 and January 2012.
Participants by arm
| Arm | Count |
|---|---|
| Premarin IV Patients who were randomized to receive a single dose of 0.5 mg/kg Premarin® IV.
Premarin IV: One time dose of Premarin IV | 23 |
| Placebo Patients who were randomized to receive a single dose of 0.5 mg/kg placebo. Due of the faint yellow color of the reconstituted Premarin®, the placebo dose will be prepared with 0.14 ml of Vial 1 of Infuvite Adult Multivitamin and 14 ml of sterile water to generate a similar color and volume. This aliquot will be used only for those study patients who are randomized to the placebo arm. The placebo volume will be approximately equal to the volume which the patient would have received had the patient been randomized to the Premarin arm Considering the small amount of IV multivitamin needed for fluid tinting, it is not expected that the IV multivitamin will have any effect on patients with hemorrhagic shock.
Placebo: One time dose of placebo. | 25 |
| Total | 48 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Prisoner | 0 | 1 |
| Overall Study | Protocol Violation | 1 | 0 |
Baseline characteristics
| Characteristic | Premarin IV | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 33.9 years | 32.2 years | 33.0 years |
| Region of Enrollment United States | 23 participants | 25 participants | 48 participants |
| Sex: Female, Male Female | 3 Participants | 4 Participants | 7 Participants |
| Sex: Female, Male Male | 20 Participants | 21 Participants | 41 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 23 | 0 / 25 |
| serious Total, serious adverse events | 5 / 23 | 7 / 25 |
Outcome results
Primary
Survival
Survival is defined as the number of patients who were discharged from the hospital alive prior to 28 days post injury or the number of patients still alive in the hospital 28 days post injury. The trial examines the rate of enrolled patients on each arm who survived to 28 days.
Time frame: 28 Days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Premarin IV | Survival | 16 participants |
| Placebo | Survival | 21 participants |
p-value: 0.25295% CI: [1.16, 5.25]Barnard's unconditional Exact Test
Secondary
Acute Respiratory Distress Syndrome (ARDS) Free Survival
ARDS is a life-threatening condition characterized by inflammation of the lungs. The trial measures the number of days alive and without ARDS within 28 days post injury. Patients who die within 28 days are given value of 0, similarly, patients who live 28 days but have ARDS for all 28 days. A higher score (greater days) indicates better prognosis. Exudative stage is 0-6 days, proliferative stage is 7-10 days, Fibrotic stage is \>10-14 days.
Time frame: 28 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Premarin IV | Acute Respiratory Distress Syndrome (ARDS) Free Survival | 3.00 units on a scale | Standard Deviation 3.46 |
| Placebo | Acute Respiratory Distress Syndrome (ARDS) Free Survival | 3.33 units on a scale | Standard Deviation 3.01 |
p-value: 0.895t-test, 2 sided