CAlcium and VAsopressin Following Injury Early Resuscitation (CAVALIER) Trial

Study Overview
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Brief Summary
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The CAlcium and VAsopressin following Injury Early Resuscitation (CAVALIER) Trial is a proposed 4 year, double-blind, mutli-center, prehospital and early in hospital phase randomized trial designed to determine the efficacy and safety of prehospital calcium and early in hospital vasopressin in patients at risk of hemorrhagic shock.

Detailed Description
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Resuscitation strategies for the acutely injured patient in hemorrhagic shock have evolved. Patients benefit from receiving less crystalloid in favor of blood transfusions with balanced ratios of plasma and platelets or whole blood resuscitation. These resuscitation practices are termed Damage Control Resuscitation and have been incorporated into resuscitation protocols in Level I trauma centers across the country. Damage Control Resuscitation represents standard practice for military and civilian trauma. Despite these changes, deaths from traumatic hemorrhage continue to occur in the first hours following trauma center arrival, underscoring the importance of early, novel interventions. Hypocalcemia following traumatic injury is exceedingly common following severe traumatic injury in patients at risk of hemorrhagic shock. During hemorrhagic shock resuscitation, pathways reliant upon calcium such as platelet function, intrinsic and extrinsic hemostasis, and cardiac contractility are disrupted. Citrate containing transfusion products are known to further reduce calcium levels through chelation during trauma resuscitation. Hypocalcemia has consistently been shown to be independently associated with the risk of large volume blood transfusion and mortality. Current management practices include calcium replacement during the in hospital phase of care in patients receiving blood products. Early calcium replacement in patients at risk of hemorrhage and hypocalcemia may mitigate coagulopathy, maintain hemostasis, improve hemodynamics and outcomes, and may reduce complications attributable to hemorrhagic shock. Arginine vasopressin is a physiologic hormone released by the posterior pituitary in response to hypotension and is commonly used as a vasopressor for critically ill patients for the treatment of hypotension due to multiple causes including sepsis. Prolonged hemorrhagic shock has the potential to alter systemic vasomotor tone which can progress to refractory/recalcitrant hypotension. Patients receiving resuscitation for hemorrhage are at risk of vasopressin deficiency. Vasopressin may improve hemostasis by enhancing platelet function and augmenting clot formation. Vasopressin infusion soon after injury in patients in hemorrhagic shock has been demonstrated to be safe and result in a reduction in blood transfusion requirements and a lower incidence of deep venous thrombosis. Whole blood, red cells, and blood components are a precious and limited resource. Trauma resuscitation adjuncts such as early calcium and vasopressin may provide benefit when transfusion products are limited and may provide additional benefit even when transfusion capabilities remain robust. Due to their action on coagulation and hemodynamic cascades in the injured patient, these resuscitation adjuncts have the potential to interact and provide additive benefit to the injured patient. However, safety and efficacy of prehospital calcium and early in hospital vasopressin remain inadequately characterized. Enrolled patients may participate in the prehospital phase (calcium), in-hospital phase (vasopressin), or both. The aims of the CAlcium and VAsopressin following Injury Early Resuscitation (CAVALIER) trial are to determine the efficacy and safety of prehospital calcium supplementation and early in hospital vasopressin infusion as compared to standard care resuscitation in patients at risk of hemorrhagic shock and to appropriately characterize any additive effect of both resuscitation adjunct interventions.

Official Title
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CAlcium and VAsopressin Following Injury Early Resuscitation (CAVALIER) Trial

Conditions
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Trauma, Hemorrhage

Intervention / Treatment
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* Drug: Calcium Gluconate
* Drug: Vasopressin
* Drug: saline placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Prehospital Phase: Injured patients at risk of hemorrhagic shock with: 1A. Systolic blood pressure ≤ 90mmHg and tachycardia (HR ≥ 108) at scene, at outside hospital, or during anticipated transport to a participating CAVALIER trial site OR 1B. Systolic blood pressure ≤ 70mmHg at scene, at outside hospital, or during anticipated transport to a participating CAVALIER trial site Early In-Hospital Phase: Injured patients at risk of hemorrhagic shock with: 1A. Systolic blood pressure ≤ 90mmHg and tachycardia (HR ≥ 108) at scene, at outside hospital, during transport, or in emergency department of a participating CAVALIER trial site OR 1B. Systolic blood pressure ≤ 70mmHg at scene, at outside hospital, during transport, or in emergency department of a participating CAVALIER trial site AND 2.Blood/blood component transfusion initiated in prehospital setting, Emergency Department, or Operating Room within 60 minutes of arrival at the enrolling trauma center AND 3. Taken to the Operating Room within 60 minutes of arrival (laparotomy, thoracotomy, vascular exploration or extremity amputation) at the enrolling trauma center AND 4. Anticipated admission to intensive care unit (ICU) Exclusion Criteria: Wearing NO CAVALIER opt-out bracelet Age > 90 or < 18 years of age Isolated fall from standing injury mechanism Known prisoner Known pregnancy Traumatic arrest with > 5 minutes of CPR without return of vital signs Brain matter exposed or penetrating brain injury Isolated drowning or hanging victims Objection to study voiced by subject or family member at the scene or at the trauma center Inability to obtain IV access

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 90 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: Sequential Assignment
Interventional Model Description: permuted block design
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Prehospital Intervention Arm<br>1 gram calcium gluconate provided intravenously over approximately 5 minutes, initiated prior to trauma bay arrival and infused to completion following arrival if needed | Drug: Calcium Gluconate<br>* 1 gram calcium gluconate provided intravenously over approximately 5 minutes<br>|
| Placebo Comparator: Prehospital Control Arm<br>Identical volume saline placebo to prehospital intervention arm provided intravenously over approximately 5 minutes, initiated prior to trauma bay arrival and infused to completion following arrival if needed | Drug: saline placebo<br>* saline placebo volume matched to prehospital or in hospital phase<br>|
| Experimental: Early In-Hospital Intervention Arm<br>4 unit vasopressin bolus followed by a vasopressin infusion at 0.04 U/min for eight hours, initiated within approximately two hours of hospital arrival | Drug: Vasopressin<br>* 4 unit vasopressin bolus followed by vasopressin infusion at 0.04 U/min for eight hours<br>|
| Placebo Comparator: Early In-Hospital Control Arm<br>volume matched saline bolus followed by volume matched normal saline placebo infusion for eight hours initiated within approximately two hours of arrival | Drug: saline placebo<br>* saline placebo volume matched to prehospital or in hospital phase<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 30-day mortality | all cause mortality within 30 days | from randomization to death or 30 days, whichever comes first | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 6-hour mortality | all cause mortality within 6 hours | from randomization to death or 6 hours, whichever comes first | 
| 24-hour mortality | all cause mortality within 24 horus | from randomization to death or 24 hours, whichever comes first | 
| In-hospital mortality | death prior to hospital discharge | In hospital mortality from time of randomization to death or 30 days, whichever comes first | 
| Death from hemhorrage | Death from hemorrhage adjudicated by the site investigator | from randomization to death or 30 days, whichever comes first | 
| Death from brain injury | Death from brain injury adjudicated by the site investigator | from randomization to death or 30 days, whichever comes first | 
| Blood and blood component transfusion requirements in the initial 6 hours | number of units transfused and type | from randomization to 6 hours | 
| Blood and blood component transfusion requirements in the initial 24 hours | number of units transfused and type | from randomization to 24 hours | 
| Incidence of Multiple Organ Failure (MOF) | Evaluated via the Denver Post injury Multiple Organ Failure Score, characterized as an incidence rate (percentage) and as MOF free days. Patients never admitted to ICU or with length of stay less than 48 hours will have a score of 0. A summary Denver score of >3 will be classified as MOF. | Scores determined daily until up to Day 7 or ICU discharge, whichever comes first | 
| Incidence of nosocomial infection | Utilizing the CDC criteria for diagnosis of hospital acquired pneumonia and blood stream infection | from randomization to death or 30 days | 
| Time to hemostasis | Determined by ability to reach nadir transfusion requirement of 1 unit of red blood cells in a 60 minute period in the first 4 hours following arrival. In the absence of ability to obtain hemostasis within the first 4 hours, the patient will be designated non-hemostasis | hospital arrival to 4 hours | 
| Incidence of coagulopathy by thromboelastography (TEG) | TEG date collected only when obtained as part of clinical | within 4 hours of arrival plus or minus 12 | 
| Incidence of coagulopathy by thromboelastography (TEG) | TEG date collected only when obtained as part of clinical | within 24 hours of arrival plus or minus 12 | 
| ICU free days | number of days the patient is alive and not admitted to ICU subtracted from 30 | From hospital arrival to death or 30 days | 
| Hospital free days | number of days the patient is alive and not admitted to hospital subtracted from 30 | From hospital arrival to death or 30 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hemorrhagic shock, trauma, calcium gluconate, vasopressin