Calcium + Vasopressin for Trauma Bleeding

(CAVALIER Trial)

Recruiting at 1 trial location

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

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

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

What data supports the effectiveness of the drug Calcium + Vasopressin for trauma bleeding?

Research shows that vasopressin can help increase blood pressure and improve survival in cases of severe bleeding, such as traumatic hemorrhagic shock, by directing blood flow to vital organs like the heart and brain. This suggests that vasopressin, as part of the treatment, may be effective in managing trauma-related bleeding. ^{1 2 3 4 5}

Is the combination of calcium and vasopressin safe for treating trauma bleeding?

Vasopressin has been studied for its effects in managing traumatic hemorrhagic shock, showing benefits in increasing blood pressure and reducing fluid needs, which suggests it is generally safe in controlled settings. However, the safety of combining calcium with vasopressin specifically for trauma bleeding is not directly addressed in the available research. ^{1 4 6 7 8}

How is the drug Calcium + Vasopressin for Trauma Bleeding different from other treatments?

This drug is unique because it combines calcium gluconate and vasopressin to manage trauma-related bleeding, potentially improving blood pressure and reducing the need for fluid resuscitation, which can worsen bleeding in uncontrolled hemorrhagic shock. ^{1 2 4 6 9}

Research Team

Jason Sperry, MD, MPH

Principal Investigator

University of Pittsburgh

Eligibility Criteria

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

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

Treatment Details

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).

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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 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]

References

1. Germany pubmed.ncbi.nlm.nih.gov

[Vasopressin for therapy of persistent traumatic hemorrhagic shock: The VITRIS.at study]. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Treatment of uncontrolled hemorrhagic shock after liver trauma: fatal effects of fluid resuscitation versus improved outcome after vasopressin. [2021]

3. England pubmed.ncbi.nlm.nih.gov

Vasopressin improves survival in a porcine model of abdominal vascular injury. [2018]

4. United States pubmed.ncbi.nlm.nih.gov

Central angiotensinergic system and hypertonic resuscitation from severe hemorrhage. [2017]

5. United States pubmed.ncbi.nlm.nih.gov

Interaction of sodium and volume in fluid resuscitation after hemorrhage. [2019]

6. Norway pubmed.ncbi.nlm.nih.gov

Maintenance intravenous fluid prescribing practices among paediatric residents. [2021]

7. Netherlands pubmed.ncbi.nlm.nih.gov

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

8. United States pubmed.ncbi.nlm.nih.gov

Vasopressin mediates the pressor effect of hypertonic saline solution in endotoxic shock. [2007]

9. United States 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. [2013]