Early Norepinephrine in Trauma Patients With Hemorrhagic Shock

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

ENROLLING_BY_INVITATION

Clinical Phase

PHASE1/PHASE2

Total Enrollment

40 participants

Study Classification

INTERVENTIONAL

Study Start Date

2025-05-20

Study Completion Date

2027-08-18

Brief Summary

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The goal of this clinical trial is to learn if norepinephrine works to treat trauma patients with hemorrhagic shock. It will also learn about the safety of norepinephrine. The main questions it aims to answer are:

Does norepinephrine affect the short-term mortality (24-hour mortality)? Does norepinephrine affect the long-term mortality (30-day mortality), survival with favorable outcome, total volume of blood product and crystalloid given in 24 hours, estimated blood loss within 24 hours, resuscitation-related complications, and length of ICU and hospital stay? What medical problems do participants have when receiving norepinephrine? Researchers will compare norepinephrine to a placebo (a look-alike substance that contains no drug) to see if norepinephrine works to treat trauma patients with hemorrhagic shock.

Participants will:

Receive norepinephrine or a placebo intravenously within 1 hour after randomization, infused for 24 hours after randomization, and then discontinued.

Patients are monitored for outcomes and adverse events.

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Detailed Description

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Study Population: Adult trauma patients with hemorrhagic shock

Inclusion Criteria:

1. Adult trauma patients aged 18 to 65 years
2. Significant bleeding from traumatic events including

1. Exsanguinous external bleeding (500 ml or more), or
2. Evidence of internal bleeding (e.g., FAST positive, hemothorax, or bleeding seen on CT scan)
3. Hemorrhagic shock is defined as:

1. Hypotensive event suspected from hemorrhagic shock, characterized by

* Systolic blood pressure less than 90 mmHg,
* Mean arterial pressure less than 65 mmHg, or
* A decrease in blood pressure from baseline more than 30 mmHg (as recorded in the trauma bay, resuscitation room of the emergency department at Ramathibodi Hospital, trauma unit at Siriraj Hospital, or trauma ward/ ICU) OR
2. Signs of shock, including:

* Capillary refill time greater than 2 seconds,
* Base excess less than -6 mEq/L,
* Lactate level greater than 2 mmol/L)

Exclusion criteria

1. Prehospital cardiopulmonary resuscitation or cardiopulmonary resuscitation at the trauma bay.
2. Persistent shock for more than 12 hours prior to randomization.
3. Severe traumatic brain injury with Glasgow Coma Scale (GCS) score less than 9 (GCS 3-8)
4. Traumatic limb injury with acute limb ischemia
5. A history of limb ischemia, chronic heart disease, chronic lung disease, or chronic renal disease
6. Pregnant patients
7. Documented "Do Not Resuscitate" (DNR) order or who declined life-sustaining intervention before randomization
8. Allergic to norepinephrine or contraindications for its use (e.g., peripheral vascular thrombosis, mesenteric thrombosis, and fatal tachyarrhythmia)
9. Current use of ergotamine, monoamine oxidase inhibitors (MAOIs), or tricyclic antidepressants (TCAs)
10. Prior vasopressor administration before randomization.
11. Weight less than 30 kilograms (Extremely low body weight may increase the risk of weight-based dosing issues)

The independent nurse prepares the drug (norepinephrine or placebo) according to the randomization code associated with the study ID and then sends it to the trauma bay. The appearance of both norepinephrine and placebo preparations will be identical. Both patients and physicians will remain blinded after the intervention assignment. An emergency unblinding service is available if the clinician believes that clinical management depends on knowing whether the patient received norepinephrine or placebo. Attending physicians will also be unblinded in the event of serious adverse events that require discontinuation of the study.

Intervention group:

* Drug: Norepinephrine bitartrate (LEVOPHEDR, Pfizer inc.) 4 mg/4ml + 5% Dextrose in water 246 ml (total volume 250 ml, final concentration 16 mcg/ml) infuses intravenously via a central catheter or peripheral line with the rate of 10 ml/h (equivalent to 0.05 mcg/kg/min for a 50-kg patient). The drug will be initiated within 1 hour after randomization, infused for 24 hours after randomization, and then discontinued.
* If at any time during the infusion the patient's systolic blood pressure is above 160 mmHg30 for 10 min, the infusion will be held up for 30 min. After 30 min, if the SBP is less than 160, the infusion was resumed at a rate of 5ml/h (50%). If the SBP remains less than 160, the infusion will be increased to the original dose of 10ml/h (100%).
* Medical device: The norepinephrine preparation or placebo will be infused with each institute's syringe or infusion pump available. The ENTHES solution will be infused through a separate peripheral IV access.

Control group:

Placebo: 5% Dextrose in water 250 ml infused intravenously with a rate of 10 ml/h

Both groups will receive standard trauma care based on ATLS guidelines, which includes the following: 2 large-bore intravenous access, a bolus of warm isotonic crystalloids (500-1,000 mL), and consideration of tranexamic acid based on the duration of injury. Bleeding will be controlled, and laboratory investigations, such as iStat, arterial blood gas, base excess, complete blood count, coagulogram, will be performed. The massive transfusion protocol may also be considered. If the attending physician wishes to add or increase the vasopressor dose, it will be prepared separately.

After the ENTHES solution has been infused for 24 hours, if the patients experiences hypotension, either noninvasive or invasive monitoring will be used to assess fluid responsiveness, and standard management will be provided based on the attending physician's judgement. If the cause of hypotension is due to decreased vascular resistance, a vasoactive agent such as norepinephrine or epinephrine will be initiated.

Primary outcome: 24-hour mortality

Secondary outcome: 30-day mortality, survival with favorable outcome at 30 days (defined as modified Rankin Score (mRS) of 0-3), survival to hospital discharge, death in OR, the cumulative volume of blood product in milliliter (ml) transfused within 24 hours (included PRBC, FFP, platelets, and cryoprecipitates), the total volume of crystalloid (in mL) infused within 24 hours, total urine output within 24 hours, vital signs trending over 24 hours, Intake/ output balance over 24 hours, tissue perfusion parameters (e.g., serum lactate in mmol/L, base deficit in mEq/L), estimated blood loss in ml within 24 hours, length of ICU stays (in days), length of hospital stays (in days), and length of mechanical ventilation.

Safety outcome: Adverse events of norepinephrine (e.g. arrhythmia, hypertensive emergency, acute mesenteric ischemia, peripheral vascular ischemia, and drug allergy) and other adverse events (ARDS (according to a new global definition of ARDS 2023), transfusion complication, AKI (KDIGO 2012), acute myocardial infarction, surgical site or wound infection, ventilator-associated pneumonia, compartment syndrome, deep vein thrombosis, pulmonary embolism, rhabdomyolysis and gastrointestinal bleeding)

Discontinuation/withdrawal criteria:

1. The participant or his relative's withdrawal requests
2. The attending physician's judgement to withdraw from the study

Conditions

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Trauma, Multiple

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

After the trauma team notifies the nurse about the patient's enrollment, an independent nurse opens an opaque sealed envelope (randomization). Afterward, he or she will prepare the drug (norepinephrine or placebo) according to the assigned group and send it to the trauma bay/ ward. Both norepinephrine preparation and matched placebo will be given intravenously at the rate of 10ml/h.

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

The independent nurse prepares the drug (norepinephrine or placebo) according to the randomization code associated with the study ID and then sends it to the trauma bay. The appearance of both norepinephrine and placebo preparations will be identical. Both patients and physicians will remain blinded after the intervention assignment. An emergency unblinding service is available if the clinician believes that clinical management depends on knowing whether the patient received norepinephrine or placebo. Attending physicians will also be unblinded in the event of serious adverse events that require discontinuation of the study.

Study Groups

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Norepinephrine

Norepinephrine bitartrate (LEVOPHEDR, Pfizer inc.) 4 mg/4ml + 5% Dextrose in water 246 ml (total volume 250 ml, final concentration 16 mcg/ml) infuses intravenously via a central catheter or peripheral line with the rate of 10 ml/h (equivalent to 0.05 mcg/kg/min for a 50-kg patient). The drug will be initiated within 1 hour after randomization, infused for 24 hours after randomization, and then discontinued.

Group Type ACTIVE_COMPARATOR

Norepinephrine

Intervention Type DRUG

Norepinephrine bitartrate (LEVOPHEDR, Pfizer inc.) 4 mg/4ml + 5% Dextrose in water 246 ml (total volume 250 ml, final concentration 16 mcg/ml) infuses intravenously via a central catheter or peripheral line with the rate of 10 ml/h (equivalent to 0.05 mcg/kg/min for a 50-kg patient). The drug will be initiated within 1 hour after randomization, infused for 24 hours after randomization, and then discontinued.

Placebo

5% Dextrose in water 250 ml infused intravenously at a rate of 10 ml/h. The drug will be initiated within 1 hour after randomization, infused for 24 hours after randomization, and then discontinued.

Group Type PLACEBO_COMPARATOR

Placebo

Intervention Type DRUG

5% Dextrose in water 250 ml infused intravenously at a rate of 10 ml/h. The drug will be initiated within 1 hour after randomization, infused for 24 hours after randomization, and then discontinued.

Interventions

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Norepinephrine

Norepinephrine bitartrate (LEVOPHEDR, Pfizer inc.) 4 mg/4ml + 5% Dextrose in water 246 ml (total volume 250 ml, final concentration 16 mcg/ml) infuses intravenously via a central catheter or peripheral line with the rate of 10 ml/h (equivalent to 0.05 mcg/kg/min for a 50-kg patient). The drug will be initiated within 1 hour after randomization, infused for 24 hours after randomization, and then discontinued.

Intervention Type DRUG

Placebo

5% Dextrose in water 250 ml infused intravenously at a rate of 10 ml/h. The drug will be initiated within 1 hour after randomization, infused for 24 hours after randomization, and then discontinued.

Intervention Type DRUG

Eligibility Criteria

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Inclusion Criteria

1. Adult trauma patients aged 18 to 65 years
2. Significant bleeding from traumatic events including

1. Exsanguinous external bleeding (500 ml or more), or
2. Evidence of internal bleeding (e.g., FAST positive, hemothorax, or bleeding seen on CT scan)
3. Hemorrhagic shock is defined as:

1. Hypotensive event suspected from hemorrhagic shock, characterized by

* Systolic blood pressure less than 90 mmHg,
* Mean arterial pressure less than 65 mmHg, or
* A decrease in blood pressure from baseline more than 30 mmHg (as recorded in the trauma bay, resuscitation room of the emergency department at Ramathibodi Hospital, trauma unit at Siriraj Hospital, or trauma ward/ ICU) OR
2. Signs of shock, including:

* Capillary refill time greater than 2 seconds,
* Base excess less than -6 mEq/L,
* Lactate level greater than 2 mmol/L)

Exclusion Criteria

1. Prehospital cardiopulmonary resuscitation or cardiopulmonary resuscitation at the trauma bay.
2. Persistent shock for more than 12 hours prior to randomization.
3. Severe traumatic brain injury with Glasgow Coma Scale (GCS) score less than 9 (GCS 3-8)
4. Traumatic limb injury with acute limb ischemia
5. A history of limb ischemia, chronic heart disease, chronic lung disease, or chronic renal disease
6. Pregnant patients
7. Documented "Do Not Resuscitate" (DNR) order or who declined life-sustaining intervention before randomization
8. Allergic to norepinephrine or contraindications for its use (e.g., peripheral vascular thrombosis, mesenteric thrombosis, and fatal tachyarrhythmia)
9. Current use of ergotamine, monoamine oxidase inhibitors (MAOIs), or tricyclic antidepressants (TCAs)
10. Prior vasopressor administration before randomization.
11. Weight less than 30 kilograms (Extremely low body weight may increases the risk of weight-based dosing issues)

Minimum Eligible Age

18 Years

Maximum Eligible Age

65 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No