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

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.

Study Overview

• Status: Recruiting
• Conditions: Hemorrhage; Trauma
• Intervention / Treatment: Drug: saline placebo; Drug: Vasopressin; Drug: Calcium Gluconate

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 1050
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Jason Sperry, MD; Phone Number: 4128028270; Email: sperryjl@upmc.edu

Study Locations

• United States
  • Arizona
    • Tucson, Arizona, United States, 85724
      • Recruiting
      • University of Arizona
      • Contact: Bellal Joseph, MD; Phone Number: 520-626-5056; Email: bjoseph@arizona.edu
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • Recruiting
      • University of Arkansas for Medical Sciences
      • Contact: Joseph Margolick, MD; Phone Number: 214-620-3504; Email: Jmargolick@uams.edu
  • California
    • San Francisco, California, United States, 94110
      • Recruiting
      • Zuckerberg San Francisco General Hospital and Trauma Center at University of California, San Francisco
      • Contact: Lucy Kornblith, MD; Phone Number: 415-609-6924; Email: Lucy.Kornblith@ucsf.edu
  • Colorado
    • Denver, Colorado, United States, 80204
      • Recruiting
      • Denver Health Medical Center
      • Contact: Ernest Moore, MD; Phone Number: 303-602-1820; Email: ernest.moore@dhha.org
  • Florida
    • Miami, Florida, United States, 33136
      • Recruiting
      • University of Miami
      • Contact: Jonathan Meizoso, MD; Phone Number: 305-585-1178; Email: jpmeizoso@med.miami.edu
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • Recruiting
      • University of Maryland, Baltimore
      • Contact: William Teeter, MD, MS; Phone Number: 410-328-9878; Email: William.teeter@som.umaryland.edu
  • Minnesota
    • Minneapolis, Minnesota, United States, 55415
      • Recruiting
      • Hennepin County Medical Center
      • Contact: Michael Puskarich, MD, MS; Phone Number: 612-873-7448; Email: mike.puskarich@hcmed.org
  • Missouri
    • Columbia, Missouri, United States, 65202
      • Recruiting
      • University of Missouri Health Care
      • Contact: Jeffrey Coughenour, MD; Phone Number: 573-882-1379; Email: coughenourj@health.missouri.edu
  • New Mexico
    • Albuquerque, New Mexico, United States, 87131
      • Recruiting
      • University of New Mexico
      • Contact: Ming Li Wang, MD; Phone Number: 505-272-0434; Email: MLWang@salud.unm.edu
  • Ohio
    • Columbus, Ohio, United States, 43213
      • Recruiting
      • Mount Carmel East Hospital
      • Contact: M. Chance Spalding, DO, PhD, FACS; Phone Number: 614.638.6143; Email: mcspalding62@gmail.com
    • Columbus, Ohio, United States, 43210
      • Recruiting
      • The Ohio State University Wexner Medical Center
      • Contact: John Loftus, MD; Phone Number: 614-685-2307; Email: John.Loftus@osumc.edu
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • Recruiting
      • University of Pittsburgh
      • Contact: Jason Sperry, MD; Phone Number: 4126473065; Email: sperryjl@upmc.edu
    • Pittsburgh, Pennsylvania, United States, 15212
      • Recruiting
      • Allegheny Health Network
      • Contact: Philip Nawrocki, MD; Phone Number: 412-487-6590; Email: philip.nawrocki@ahn.org
  • Texas
    • Lubbock, Texas, United States, 79430
      • Recruiting
      • Texas Tech University Health Sciences Center
      • Contact: Jayne McCauley, MD; Phone Number: 806-743-2373; Email: Jayne.mccauley@ttuhsc.edu
  • Washington
    • Seattle, Washington, United States, 98104
      • Recruiting
      • University of Washington Harborview Medical Center
      • Contact: Andrew Latimer, MD, FAEMS; Phone Number: 206-744-5676; Email: alatim@uw.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Prehospital Phase:

Injured patients at risk of hemorrhagic shock being transported from scene or referral hospital to a participating CAVALIER trial site who meet the following criteria:

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 a participating CAVALIER trial site at risk of hemorrhagic shock who meet the following criteria:

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 or deemed clinically indicated within 60 minutes of arrival at the enrolling trauma center

AND 3. Clinical team deems Operating Room for major hemorrhage control procedure (e.g., laparotomy, thoracotomy, vascular exploration or extremity amputation) indicated within 60 minutes of arrival at the enrolling trauma center

AND

4. Anticipated admission to intensive care unit (ICU)

Exclusion Criteria:

Prehospital Phase

1. Wearing NO CAVALIER opt-out bracelet
2. Age > 90 or < 18 years of age
3. Isolated fall from standing injury mechanism
4. Known prisoner
5. Known pregnancy
6. Traumatic arrest with > 5 minutes of CPR without return of vital signs
7. Brain matter exposed or penetrating brain injury
8. Isolated drowning or hanging victims
9. Objection to study voiced by subject or family member at the scene or at the trauma center
10. Inability to obtain IV/IO access

Early In-Hospital Phase:

1. Wearing NO CAVALIER opt-out bracelet
2. Age > 90 or < 18 years of age
3. Isolated fall from standing injury mechanism
4. Known prisoner
5. Known pregnancy
6. Traumatic arrest with > 5 minutes of CPR without return of vital signs
7. Brain matter exposed or penetrating brain injury
8. Isolated drowning or hanging victims
9. Objection to study voiced by subject or family member at the scene or at the trauma center
10. Inability to obtain IV access

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Prehospital Intervention Arm; 1 gram calcium gluconate provided via intravenous or intraosseous access over approximately 2-5 minutes, initiated prior to trauma bay arrival and infused to completion following arrival if needed	Drug: Calcium Gluconate; 1 gram calcium gluconate provided via intravenous or intraosseous access over approximately 2-5 minutes
Placebo Comparator: Prehospital Control Arm; Identical volume saline placebo to prehospital intervention arm provided via intravenous or intraosseous access over approximately 2-5 minutes, initiated prior to trauma bay arrival and infused to completion following arrival if needed	Drug: saline placebo; saline placebo volume matched to prehospital or in hospital phase
Placebo Comparator: Early In-Hospital Control Arm; volume matched saline bolus followed by volume matched normal saline placebo infusion for eight hours initiated within approximately two hours of enrollment	Drug: saline placebo; saline placebo volume matched to prehospital or in hospital phase
Experimental: Early In-Hospital Intervention Arm; 4-unit vasopressin bolus followed by a vasopressin infusion at 0.04 U/min for 8 hours. Administration of the bolus will be initiated as soon as feasible and within approximately 2 hours of enrollment. The infusion will be initiated within approximately 30 minutes of the bolus.	Drug: Vasopressin; 4 unit vasopressin bolus followed by vasopressin infusion at 0.04 U/min for eight hours

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with 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
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
Number of participants with 6-hour mortality	all cause mortality within 6 hours	from randomization to death or 6 hours, whichever comes first
Number of participants with 24-hour mortality	all cause mortality within 24 hours	from randomization to death or 24 hours, whichever comes first
Number of participants with In-hospital mortality	death prior to hospital discharge	In hospital mortality from time of randomization to death or 30 days, whichever comes first
Number of participants with Death from hemorrhage	Death from hemorrhage adjudicated by the site investigator	from randomization to death or 30 days, whichever comes first
Number of participants with Death from brain injury	Death from brain injury adjudicated by the site investigator	from randomization to death or 30 days, whichever comes first
Ionized calcium measurements	Ionized calcium collected as part of clinical care or as research lab	Measured in the first 60 minutes (+/- 3 hours), when feasible, during early stage resuscitation in emergency department or operating room

Collaborators and Investigators

• Sponsor: Jason Sperry
• Collaborators: United States Department of Defense
• Investigators: Principal Investigator: Jason Sperry, MD, University of Pittsburgh

Study record dates

Study Major Dates

• Study Start (Actual): June 30, 2024
• Primary Completion (Estimated): March 1, 2027
• Study Completion (Estimated): March 1, 2028

Study Registration Dates

• First Submitted: July 14, 2023
• First Submitted That Met QC Criteria: July 14, 2023
• First Posted (Actual): July 24, 2023

Study Record Updates

• Last Update Posted (Actual): June 3, 2026
• Last Update Submitted That Met QC Criteria: June 1, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: trauma; vasopressin; hemorrhagic shock; calcium gluconate
• Additional Relevant MeSH Terms: Urogenital Diseases; Endocrine System Diseases; Pathologic Processes; Male Urogenital Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Pituitary Diseases; Shock; Pathological Conditions, Signs and Symptoms; Wounds and Injuries; Hemorrhage; Diabetes Insipidus; Shock, Hemorrhagic; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Peptide Hormones; Neuropeptides; Peptides; Amino Acids, Peptides, and Proteins; Oligopeptides; Nerve Tissue Proteins; Proteins; Organic Chemicals; Carbohydrates; Sugar Acids; Acids, Acyclic; Carboxylic Acids; Hydroxy Acids; Pituitary Hormones, Posterior; Pituitary Hormones; Gluconates; Vasopressins; Calcium Gluconate
• Other Study ID Numbers: STUDY23040043; W81XWH-6-D-0024 (Other Grant/Funding Number: Department of Defense)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified data may be shared with the funding agency as well as other researchers upon request to the Principal Investigator
• IPD Sharing Time Frame: Data will become available after publication of the primary manuscript
• IPD Sharing Access Criteria: Requests for data will be submitted in writing and reviewed by the Principal Investigator
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No