Field Trial of Hypotensive Versus Standard Resuscitation for Hemorrhagic Shock After Trauma

Study Overview
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Brief Summary
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Primary Aim: To determine the feasibility and safety of hypotensive resuscitation for the early treatment of patients with traumatic shock compared to standard fluid resuscitation. Primary Hypotheses: The null hypothesis regarding feasibility is that hypotensive resuscitation will result in the same volume of early crystalloid (normal saline) fluid administration compared to standard crystalloid resuscitation. The null hypothesis regarding safety is that hypotensive resuscitation will result in the same percent of patients surviving to 24 hours after 911 call received at dispatch compared to standard fluid resuscitation. Early resuscitation is defined as all fluid given until 2 hours after arrival in the Emergency Department or until hemorrhage control is achieved in the hospital, whichever occurs earlier.

Detailed Description
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Overview This multi-center pilot trial is designed to determine the feasibility and safety of hypotensive resuscitation for the early resuscitation of patients with traumatic shock compared to standard fluid resuscitation. Blunt and penetrating trauma patients with a prehospital systolic blood pressure (SBP) ≤ 90 mmHg will be eligible. In the hypotensive resuscitation group, an intravenous line (IV) will be placed and a radial pulse will be palpated. If the radial pulse is present or the SBP is greater than or equal to 70, a 250 ml bag of normal saline will be hung and maintained at a keep the vein open rate only. If the radial pulse is absent, the 250 ml of normal saline will be given as a bolus. This process using small bags of fluid will be repeated until a radial pulse is palpable or until 2 hours after Emergency Department (ED) arrival or until hemorrhage control has been achieved. The decision to utilize a SBP versus a radial pulse will be made a priori. Patients in the standard fluid resuscitation group will have an IV placed and a 1000 ml bag of normal saline (NS) will be hung. Fluid will be given as rapidly as possible and continued until hospital arrival. If the prehospital or hospital fluid resuscitation exceeds 2 liters, it will be stopped when the SBP exceeds 110 mmHg and restarted as necessary to maintain a goal SBP of 110 mmHg. This randomization scheme will be continued for 2 hours after hospital arrival or until hemorrhage control is achieved whichever occurs first. The randomization will not affect the indications for the administration of blood products but we hypothesize that less blood products and total fluid will be given in the experimental group due to avoidance of the pop-the-clot phenomenon, less hemodilution and less coagulopathy. Patients who experience ground level falls are characterized as having low injury severity scores. (70) Patients with suspected ground level falls will be excluded in an effort to focus enrollment on the more severely injured patients at risk for trauma related hemorrhagic shock. Patients with severe traumatic brain injury will be excluded due to lack of equipoise. In observational studies (1-5) a relationship between hypotension and poor neurologic outcomes has been observed and EMS personnel as well as researchers at this time believe that it is unethical to withhold resuscitation fluid from patients with traumatic brain injury. Patients with suspected spinal cord injury will also be excluded based on evidence that indicates they are at risk for cardiovascular failure due to hemodynamic compromise correlated with the presence of neurogenic hypotension at the time of hospital admission. (69) All enrolled patients will be retrospectively screened to determine if they had evidence of severe traumatic brain injury with GCS≤8 or spinal cord injury at the time of enrollment. Screening information will be obtained for all potentially eligible patients who meet all inclusion criteria. Screening will also document whether each exclusion criterion is met. The rate at which screened patients were enrolled and later found to have met one or more of the exclusion criteria will be assessed to determine if the inclusion and exclusion criteria need to be adjusted to avoid enrollment of these patients for future studies. These patients will also be assessed to determine if enrollment in the protocol potentially harmed these patients. The study will be a two arm, randomized interventional trial comparing the two resuscitation strategies. Due to obvious differences in the treatment of enrolled patients, the study will not be blinded. Nevertheless, treatment bags will be packaged in containers such that providers will not be able to identify whether treatment containers house 1000 ml bags or 250 ml bags until the treatment containers are opened. The patient will be considered randomized at the time a study bag is opened regardless of whether any fluid is given or not. Hospitals will be provided with 250 ml bags of NS to continue treatment of those patients randomized to the hypotensive resuscitation arm. The primary outcomes of the study will be volume of prehospital and in-hospital fluid administered from time of injury until 2 hours into the hospital stay or until hemorrhage is controlled to test feasibility and 24 hour survival for the safety hypothesis. Secondary outcomes will include measures of protocol adherence, 24 hour fluid volume, 24 hour blood product requirements, ventilator days, hospital length of stay, intensive care unit (ICU) length of stay, admission base deficit, development of renal failure, admission hematocrit and admission coagulation parameters. The primary goals of this pilot study will be to determine if the described model will result in different early fluid volumes being delivered to the two groups and to determine if these differing volumes impact mortality. If this pilot study shows that hypotensive resuscitation is feasible and safe, a larger trial will be planned to determine the efficacy of hypotensive fluid resuscitation. This study will be conducted by the Resuscitation Outcomes Consortium (ROC) which is a collaboration of 7 regional sites in the United States and Canada and a Data Coordinating Center. This consortium is charged with the task of conducting clinical trials in patients with life threatening trauma and cardiac arrest. The following ROC sites have committed to participating in this trial: Alabama, Dallas, Milwaukee, Ottawa, Pittsburgh, Portland, and Vancouver. Specific Aims and Hypotheses Specific Aim 1: To investigate whether early crystalloid (normal saline) resuscitation volume can be reduced for trauma patients with hemorrhagic shock who receive hypotensive resuscitation versus those who receive standard early resuscitation (feasibility) and whether there are differences in 24-hour survival between the groups (safety). Primary Hypotheses: The null hypothesis is that patients who receive hypotensive resuscitation and patients who receive standard resuscitation will have the same volume of early crystalloid (normal saline) resuscitation administered and will have the same 24-hour survival from 911 call received at dispatch time. Specific Aim 2: To assess protocol adherence and differences in morbidity and adverse events for hypotensive versus standard resuscitation. Secondary Hypotheses: The null hypotheses are that protocol adherence is low and that hypotensive resuscitation versus standard resuscitation will result in the same amount of total fluid volume and total blood product requirements within 24 hours from 911 call received at dispatch, the same base deficit, hematocrit and coagulation parameters on admission to the ED, number of days on a ventilator, duration of hospital stay, ICU length of stay, and incidence of renal failure.

Official Title
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Field Trial of Hypotensive Resuscitation Versus Standard Resuscitation in Patients With Hemorrhagic Shock After Trauma: A Pilot Trial

Conditions
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Blunt Trauma, Penetrating Wound, Hemorrhagic Shock

Intervention / Treatment
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* Drug: 0.9% Sodium Chloride 250 mL bolus
* Drug: 0.9% Sodium Chloride 2000 mL bolus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Included will be those with: Blunt or penetrating injury Age ≥15yrs or weight ≥50kg if age is unknown Prehospital SBP ≤ 90 mmHg Exclusion Criteria: Excluded will be those with: Ground level falls Evidence of severe blunt or penetrating head injury with a Glasgow Coma Scale (GCS) ≤ 8 Bilateral paralysis secondary to suspected spinal cord injury Fluid greater than 250ml was given prior to randomization Cardiopulmonary resuscitation (CPR) by Emergency Medicine Service (EMS) prior to randomization Known prisoners Known or suspected pregnancy Drowning or asphyxia due to hanging Burns over a Total Body Surface Area (TBSA) > 20% Time of call received at dispatch to study intervention > 4 hours

Ages Eligible for Study
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Minimum Age: 15 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 0.9% Sodium Chloride 250 mL bolus<br>0.9% Sodium Chloride 250 mL bolus - A large bore IV will be placed and a 250cc bag of normal saline (NS) will be hung. If IV placement is difficult, NS can be given through an intraosseous line. Using small bags versus large bags will physically limit the amount of fluid given to patients in the experimental group. The requirement to change the smaller bags of fluid and recheck the pulse or blood pressure will limit the amount of fluid given. The procedure will continue until 2 hours after arrival to the hospital or until hemorrhage control is achieved whichever occurs first. Hemorrhage control will be defined as ligation of a bleeding vessel, packing of a solid organ, removal of a solid organ, and angiographic embolization of a bleeding vessel. | Drug: 0.9% Sodium Chloride 250 mL bolus<br>* Emergency Medicine Systems (EMS) agencies and in-hospital providers will be given the option to utilize either systolic blood pressure (SBP) or radial pulse as the endpoint for fluid resuscitation to patients randomized to the experimental group. Patients will receive a 250 ml bolus of normal saline (NS) only if the SBP is less than 70 mmHg or the radial pulse is not palpable. If the SBP is greater than or equal to 70 mmHg or the radial pulse is palpable, NS will be given to keep the vein open. The presence or absence of a radial pulse or the SBP will be documented before and after each bolus. The study will continue repeating the randomization procedure using only 250 ml bags of NS until 2 hours after arrival to the hospital or until hemorrhage control is achieved whichever occurs first.<br>* Other names: normal saline;|
| Active Comparator: 0.9% Sodium Chloride 2000 mL bolus<br>0.9% Sodium Chloride 2000 mL bolus - The treatment of the control group will be consistent with traditional Prehospital Trauma Life Support and Advanced Trauma Life Support guidelines which recommend early aggressive fluid resuscitation. An intravenous line (IV) will be placed and a 1000cc bag of normal saline will be hung. If IV placement is difficult, fluid can be given through an intraosseous line. This procedure will continue until either 2 hours after hospital arrival or until control of hemorrhage is achieved whichever occurs first. Hemorrhage control will be defined as ligation of a bleeding vessel, packing of a solid organ, removal of a solid organ, and angiographic embolization of a bleeding vessel. | Drug: 0.9% Sodium Chloride 2000 mL bolus<br>* Emergency Medicine Systems (EMS) personnel and in-hospital providers will utilize the systolic blood pressure SBP as the endpoint for delivering fluid resuscitation to patients randomized to the control group. If the SBP is equal to or less than 90 mmHg, the EMS personnel will start infusing a 1000 ml bolus of normal saline (NS) and will continue using only 1000 ml bags of NS as needed. If the total fluid resuscitation exceeds 2 liters, fluid will be stopped when the SBP exceeds 110 mmHg and restarted as necessary to maintain a goal SBP of 110 mmHg. The fluid will be given as rapidly as possible. This fluid resuscitation protocol will continue until either 2 hours after hospital arrival or until control of hemorrhage is achieved whichever occurs first.<br>* Other names: normal saline;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Volume of All Crystalloid Given for Early Resuscitation (Feasibility) | The primary feasibility endpoint was early crystalloid volume (ECV) defined as crystalloid infused from Emergency Medical Services (EMS) arrival at the scene until the end of the study period | From time of first intravenous or intraosseous insertion through the first 2 hours after hospital arrival or hemorrhage control, which ever occurs first | 
| 24 Hour Mortality | The 24 hour mortality endpoint for the total number of patients each arm | From time of hospital arrival through the first 24 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Ineligible Patients Enrolled at the Time of Randomization | Eligibility criteria: Inclusion Criteria Included will be those with: Blunt or penetrating injury Age ≥15yrs or weight ≥50kg if age is unknown Prehospital SBP ≤ 90 mmHg 5.3 Exclusion Criteria Excluded will be those with: Ground level falls Evidence of severe blunt or penetrating head injury with a Glasgow Coma Score (GCS) ≤ 8 Bilateral paralysis secondary to suspected spinal cord injury Fluid greater than 250 ml was given prior to randomization Cardiopulmonary resuscitation (CPR) by Emergency Medical Services (EMS) prior to randomization Known prisoners Known or suspected pregnancy Drowning or asphyxia due to hanging Burns Total Body Surface Area (TBSA) > 20% Time of call received at dispatch to study intervention > 4 hours | From the time the paramedic with study drug kit arrived at patient's side to the time kit was opened prior to ED arrival | 
| Total Fluid Requirement During First 24 Hours | Total volume of fluid administered during the first 24 hours inclusive of crystalloids, blood products, 3% saline, mannitol, and other colloids | From ED arrival through the first 24 hours | 
| Total Blood Product Requirements in First 24 Hours | Total amount of blood products required: packed red blood cells (PRBC), fresh frozen plasma (FFP), platelets (plts), cryoprecipitate (cryo) | From ED arrival through the first 24 hours | 
| Base Deficit on Admission to the Emergency Department (ED) | The first base deficit value reported from arterial blood lab work drawn after arrival in the final Emergency Department. This measure reflects the acid-base balance in the arterial blood. A negative number indicates that the blood is more acid that normal. | From final Emergency Department arrival time through first 24 hours | 
| Hemoglobin on Admission to the Emergency Department | The first hemoglobin value reported from blood drawn in the final Emergency Department | From final Emergency Department arrival time through first 24 hours | 
| Platelet Value on Admission | First platelet value from blood drawn in the the first 24 hours after arrival | From final Emergency Department arrival time through first 24 hours | 
| International Normalized Ratio (INR) on Admission to the Emergency Department | The first International normalized ratio (INR) value reported from blood drawn within the first 24 hours from arrival | From final Emergency Department arrival time through first 24 hours | 
| Hemorrhage Control Procedure Within 2 Hours of ED Arrival | Hemorrhage control procedures include blood vessel ligated or embolized, organ packed or removed, laparotomy or thoracotomy | From ED arrival through the first 2 hours | 
| Acute Renal Failure Classification Score of Risk Without Glomerular Filtration Rate (GFR) | Increased plasma creatinine > 1.5 x reference measure (ED admission). Urine criteria is based on 6-hour periods for this level of the RIFLE and cannot be assessed since study data are collected for 24-hour periods. This row includes patients who met the Injury and Failure criteria as well. Only measured for patients with at least 2 days of ICU stay assessed. | From ED arrival through Day 28 | 
| Acute Renal Failure Classification Score of Injury Without Glomerular Filtration Rate (GFR) | Increased plasma creatinine > 2 x reference measure (ED admission) or urine output < 0.5 mL/kg/h x 24h. The RIFLE urine criterion for this level actually specifies a 12 hour period of assessment but study data are collected for 24-hr periods. This row includes patients who met the Failure criteria as well. Only measured for patients with at least 2 days of ICU stay assessed. | From ED arrival through Day 28 | 
| Acute Renal Failure Classification Score of Failure Without Glomerular Filtration Rate (GFR) | Increased plasma creatinine > 3 x reference measure (ED admission) or acute plasma creatinine = 350 umol/L or acute rise = 44 umol/L or urine output < 0.3 mL/k/h x 24h. Only measured for patients with at least 2 days of ICU stay assessed. | From ED arrival through the first 24 hours | 
| Ventilator Free Days Through Day 28 | The number of days beginning with the day of the 911 call counted as Day 0 through Day 28 during which the patient did not require mechanical ventilation. Deaths are assigned the worst score (0). | From day of the 911 call through Day 28 | 
| Days Alive Out of the Intensive Care Unit (ICU) Through Day 28 | The number of days beginning with the day of the 911 call counted as Day 0 through Day 28 during which the patient is alive and not being cared for in the intensive care unit | From day of the 911 call through Day 28 | 
| Days Alive Out of the Hospital Through Day 28 | The number of days beginning with the day of the 911 call counted as Day 0 through Day 28 during which the patient is alive and not being cared for in the hospital | From day of the 911 call through Day 28 | 
| Blunt Trauma 24 Hour Mortality | The 24 hour mortality endpoint for the total number of patients injured by blunt mechanisms in each arm. | From time of hospital arrival through first 24 hours | 
| Penetrating Trauma 24 Hour Mortality | The 24 hour mortality endpoint for the total number of patients injured by penetrating mechanisms in each arm. | From time of hospital arrival through first 24 hours | 
| In-hospital Mortality | Number of patients who died prior to discharge. | From day of the 911 call through hospital discharge | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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fluid volume resuscitation, trauma, hemorrhagic shock