Calcium + Vasopressin for Trauma Bleeding

(CAVALIER Trial)

Recruiting at 7 trial locations

Overseen By Jason Sperry, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Jason Sperry

Disqualifiers: Age > 90, < 18, Pregnancy, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 2

1050 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether calcium and vasopressin (a hormone that helps regulate blood pressure) can safely aid individuals with severe bleeding due to trauma. The researchers aim to determine if these treatments can reduce the risk of hemorrhagic shock, a life-threatening condition caused by excessive blood loss. The study includes different groups: some receive the actual treatments, while others receive a placebo for comparison. Eligible participants have sustained injuries, experience very low blood pressure, and require emergency blood transfusions. As a Phase 2 trial, it measures the treatment's effectiveness in an initial, smaller group, allowing participants to contribute to important research that could enhance trauma care.

Will I have to stop taking my current medications?

The trial information does not specify whether participants need to stop taking their current medications.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Previous studies have shown that calcium gluconate aids blood clotting in trauma patients. It is crucial for treating patients with low calcium levels, a common issue in serious injuries. Research indicates that low calcium can worsen bleeding and lead to poorer outcomes.

Regarding vasopressin, studies have demonstrated its safety for patients with severe blood loss. It stabilizes blood pressure without increasing side effects. Notably, using vasopressin has been linked to a reduced need for blood transfusions in trauma patients.

Both treatments have been studied before, providing evidence of safety in similar situations. This trial specifically aims to gather more information about their safety and effectiveness when used together. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike standard treatments for trauma bleeding, which often involve blood transfusions and fluid resuscitation, the treatments in this trial focus on using calcium gluconate and vasopressin. Calcium gluconate is administered rapidly before hospital arrival, possibly stabilizing patients sooner by helping the blood clot more effectively. Vasopressin, given in the hospital, works differently by narrowing blood vessels to reduce bleeding and maintain blood pressure. Researchers are excited because these approaches could offer faster stabilization and improved outcomes compared to traditional methods.

What evidence suggests that this trial's treatments could be effective for trauma bleeding?

Research has shown that calcium is essential for blood clotting, especially in trauma patients who lose significant blood. In this trial, some participants will receive calcium gluconate, which studies indicate can improve survival rates and reduce the need for blood transfusions in such situations. Trauma patients with low calcium levels often experience worse outcomes, making calcium supplements important.

Other participants in this trial will receive vasopressin. Research has found that vasopressin can stabilize patients with severe blood loss. It improves survival rates in cases of severe bleeding by maintaining steady blood pressure. Although some concerns exist about its effect on blood flow to organs, evidence suggests that low doses can safely reduce the need for blood transfusions. ^{1 2 3 6 7}

Who Is on the Research Team?

Jason Sperry, MD, MPH

Principal Investigator

University of Pittsburgh

Are You a Good Fit for This Trial?

The CAVALIER trial is for adults aged 18-90 who have experienced trauma leading to a risk of hemorrhagic shock. Eligible participants must have low blood pressure and/or high heart rate, require a blood transfusion within an hour of arriving at the hospital, and be expected to go into surgery quickly upon arrival. Pregnant individuals, prisoners, those with severe brain injuries or certain types of accidents are excluded.

Inclusion Criteria

Injured patients at risk of hemorrhagic shock being transported to a participating CAVALIER trial site with systolic blood pressure ≤ 90mmHg and tachycardia (HR ≥ 108) or systolic blood pressure ≤ 70mmHg

I am injured, at risk of severe bleeding, have low blood pressure or a fast heart rate, and need urgent care.

Exclusion Criteria

Isolated fall from standing injury mechanism

Known prisoner

I or my family do not agree to participate in the study.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Prehospital Phase

Participants receive prehospital calcium gluconate or placebo prior to trauma bay arrival

Immediate (2-5 minutes)

1 visit (prehospital)

Early In-Hospital Phase

Participants receive vasopressin or placebo infusion for eight hours

8 hours

1 visit (in-hospital)

Follow-up

Participants are monitored for safety and effectiveness after treatment

30 days

What Are the Treatments Tested in This Trial?

Interventions

• Calcium Gluconate
• Saline Placebo
• Vasopressin

Trial Overview This study tests whether giving calcium gluconate before reaching the hospital and vasopressin shortly after arrival can help patients at risk of bleeding out from trauma. Participants will either receive these drugs or saline placebos in a randomized manner without knowing which one they're getting (double-blind).

How Is the Trial Designed?

Group I: Prehospital Intervention Arm Experimental Treatment 1 Intervention

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

Group II: Early In-Hospital Intervention Arm Experimental Treatment 1 Intervention

4 unit vasopressin bolus followed by a vasopressin infusion at 0.04 U/min for eight hours, initiated within approximately two hours of enrollment

Group III: Early In-Hospital Control Arm Placebo Group 1 Intervention

volume matched saline bolus followed by volume matched normal saline placebo infusion for eight hours initiated within approximately two hours of enrollment

Group IV: Prehospital Control Arm Placebo Group 1 Intervention

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

Calcium Gluconate is already approved in United States, European Union for the following indications:

Approved in United States as Calcium Gluconate for:

• Hypocalcemic tetany
• Hypocalcemia related to hypoparathyroidism
• Hypocalcemia due to rapid growth or pregnancy

Approved in European Union as Calcium Gluconate for:

• Hypocalcemia
• Hypocalcemic tetany
• Hypocalcemia related to hypoparathyroidism

Who Is Running the Clinical Trial?

Jason Sperry

Lead Sponsor

Trials

9

Recruited

6,900+

United States Department of Defense

Collaborator

Trials

940

Recruited

339,000+

Published Research Related to This Trial

A single injection of hypertonic NaCl (7.5%) can effectively resuscitate dogs from severe blood loss, demonstrating mechanisms like volume expansion and increased heart function.

The study found that the central angiotensin system plays a significant role in the effectiveness of hypertonic resuscitation, as blocking this system with saralasin reduced recovery, while isotonic saline did not show the same interaction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Central angiotensinergic system and hypertonic resuscitation from severe hemorrhage. Velasco, IT., Baena, RC., Rocha e Silva, M., et al.[2017]

Resuscitation with hypertonic saline (3.0% NaCl) leads to a quicker restoration of mean arterial pressure (MAP) and blood volume restitution (BVR) compared to normal saline (0.9% NaCl), but this improvement is not sustained over time.

Both hypertonic and normal saline can restore MAP effectively, but hypertonic saline causes a temporary increase in BVR and incurs an intracellular water deficit, suggesting that an optimal resuscitation strategy may involve starting with hypertonic saline followed by hypotonic solutions to ensure proper cellular hydration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interaction of sodium and volume in fluid resuscitation after hemorrhage. Gala, GJ., Lilly, MP., Thomas, SE., et al.[2019]

This multicenter, randomized controlled trial aims to evaluate the efficacy of vasopressin in patients experiencing traumatic hemorrhagic shock that does not respond to standard treatments, involving multiple countries and helicopter emergency medical services.

The study will assess key outcomes such as hospital admission rates and hemodynamic variables, providing insights into whether vasopressin can improve blood pressure and reduce fluid resuscitation needs in severe cases of hemorrhagic shock.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Vasopressin for therapy of persistent traumatic hemorrhagic shock: The VITRIS.at study]. Lienhart, HG., Wenzel, V., Braun, J., et al.[2022]

In a study involving 21 anesthetized pigs with severe liver injury, vasopressin significantly increased mean arterial blood pressure and improved short-term survival compared to saline placebo and fluid resuscitation, with all pigs receiving saline or fluid resuscitation dying within the study period.

Vasopressin not only enhanced blood pressure but also improved abdominal organ blood flow without causing additional blood loss, indicating its potential as a more effective treatment for uncontrolled hemorrhagic shock in trauma patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of uncontrolled hemorrhagic shock after liver trauma: fatal effects of fluid resuscitation versus improved outcome after vasopressin. Raedler, C., Voelckel, WG., Wenzel, V., et al.[2021]

A survey of 472 pediatric residents revealed that 78% would choose hypotonic maintenance intravenous fluids (mIVF) for children with arginine vasopressin (AVP) excess, indicating a common preference for these fluids in clinical practice.

Isotonic mIVF were more frequently selected for older children and those with meningitis, suggesting that clinical scenarios significantly influence fluid choice among pediatric residents.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Maintenance intravenous fluid prescribing practices among paediatric residents. Freeman, MA., Ayus, JC., Moritz, ML.[2021]

In a study on rats with uncontrolled hemorrhagic shock, the combination of arginine vasopressin (AVP) and norepinephrine (NE) significantly improved mean arterial pressure and prolonged survival time, even with minimal fluid resuscitation.

The early administration of small doses of AVP and NE enhanced the effectiveness of subsequent treatments for traumatic hemorrhagic shock, leading to better hemodynamics, improved cardiac function, and increased tissue blood flow and oxygen delivery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Small doses of arginine vasopressin in combination with norepinephrine "buy" time for definitive treatment for uncontrolled hemorrhagic shock in rats. Liu, L., Tian, K., Xue, M., et al.[2013]

In a study investigating the effects of hypertonic saline on endotoxic shock in experimental animals, hypertonic saline (7.5% sodium chloride) significantly improved blood pressure and increased vasopressin levels compared to isotonic saline (0.9% sodium chloride).

The blood pressure recovery from hypertonic saline was shown to be mediated by vasopressin secretion, as blocking the vasopressin V1 receptor prevented this pressor response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vasopressin mediates the pressor effect of hypertonic saline solution in endotoxic shock. Giusti-Paiva, A., Martinez, MR., Bispo-da-Silva, LB., et al.[2007]

In a study involving 19 pigs with uncontrolled hemorrhagic shock, vasopressin treatment significantly improved mean arterial blood pressure and ensured short-term survival, with all 7 treated pigs surviving compared to only 6 out of 7 in the fluid resuscitation group and 5 out of 5 in the placebo group.

Fluid resuscitation initially increased blood pressure but led to a rapid decline afterward, while the placebo group showed no improvement, highlighting the superior efficacy of vasopressin in managing severe hemorrhagic shock.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vasopressin improves survival in a porcine model of abdominal vascular injury. Stadlbauer, KH., Wagner-Berger, HG., Krismer, AC., et al.[2018]

Gd3+ effectively inhibits vasopressin-stimulated Ca2+ inflow in hepatocytes by up to 70%, indicating its potential as a competitive inhibitor in calcium channel activity.

The study reveals that vasopressin activates two types of Ca2+ inflow processes, with Gd3+ and other lanthanides showing significant inhibition, suggesting a specific binding site in the Ca2+ channel that interacts with these ions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterisation of the divalent cation channels of the hepatocyte plasma membrane receptor-activated Ca2+ inflow system using lanthanide ions. Fernando, KC., Barritt, GJ.[2019]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7808849/

Damage control strategy in bleeding trauma patients - PMC Calcium is an important cofactor of the coagulation cascade. In bleeding trauma patients who need blood transfusion, hypocalcemia may be a problem because of ...

2. journalofsurgicalresearch.com journalofsurgicalresearch.com/article/S0022-4804(24)00094-5/fulltext

Higher Doses of Calcium Associated With Survival in ... Higher doses of calcium given per blood product transfused were associated with improved 30-d survival and decreased blood product transfusions.

3. clinicaltrials.gov clinicaltrials.gov/study/NCT06820645

Calcium Administration in Life-saving Management During ... This study evaluates the feasibility of conducting a larger study on the impact of treating massive hemorrhage with calcium in trauma patients.

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0099176723003471

Trauma Diamond of Death: Adding Calcium to the Lethal ... Trauma patients with hypocalcemia exhibit worsening hemorrhagic shock and have worse outcomes than patients with normal calcium level.3. Since hypocalcemia ...

5. tsaco.bmj.com tsaco.bmj.com/content/10/4/e001800

Association between hypocalcemia and mortality in trauma ... Trauma patients with hypocalcemia had a statistically significant increase in mortality (OR 2.79; 95% CI 2.01 to 3.89). ... Notably, hypocalcemia ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11995200/

Administration of Calcium and Magnesium in Acute ... The aim of this study was to attain and sustain target levels of serum calcium and magnesium for three days following admission.

7. clinicaltrials.gov clinicaltrials.gov/study/NCT06235749

Administration Of Calcium Gluconate for The Reduction ... Hypocalcemia is a poor prognostic factor in actively bleeding patients. Calcium has a positive inotropic effect both on skeletal muscle and smooth muscle.