Calcium + Vasopressin for Trauma Bleeding
(CAVALIER Trial)
Recruiting in Palo Alto (17 mi)
+1 other location
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Jason Sperry
Disqualifiers: Age > 90, < 18, Pregnancy, others
Prior Safety Data
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.
12345Is 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.
14678How 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.
12469Eligibility 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.
+7 more
Trial 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
Participant Groups
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).
4Treatment groups
Experimental Treatment
Placebo Group
Group I: Prehospital Intervention ArmExperimental Treatment1 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 ArmExperimental Treatment1 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 ArmPlacebo Group1 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 ArmPlacebo Group1 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
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Allegheny Health NetworkPittsburgh, PA
University of PittsburghPittsburgh, PA
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Who Is Running the Clinical Trial?
Jason SperryLead Sponsor
United States Department of DefenseCollaborator
References
[Vasopressin for therapy of persistent traumatic hemorrhagic shock: The VITRIS.at study]. [2022]While fluid management is established in controlled hemorrhagic shock, its use in uncontrolled hemorrhagic shock is being controversially discussed, because it may worsen bleeding. In the irreversible phase of hemorrhagic shock that was unresponsive to volume replacement, airway management and catecholamines, vasopressin was beneficial due to an increase in arterial blood pressure, shift of blood away from a subdiaphragmatic bleeding site towards the heart and brain and decrease of fluid resuscitation requirements. The purpose of this multicenter, randomized, controlled, international trial is to assess the effects of vasopressin (10 IU IV) vs. saline placebo IV (up to 3 injections at least 5 min apart) in patients with prehospital traumatic hemorrhagic shock that persists despite standard shock treatment. The study will be carried out by helicopter emergency medical service teams in Austria, Germany, Czech Republic, Portugal, the Netherlands and Switzerland. Inclusion criteria are adult trauma patients with presumed traumatic hemorrhagic shock (systolic arterial blood pressure 60 min before randomization, cardiac arrest before randomization, presence of a do-not-resuscitate order, untreated tension pneumothorax, untreated cardiac tamponade, or known pregnancy. Primary study end-point is the hospital admission rate, secondary end-points are hemodynamic variables, fluid resuscitation requirements and hospital discharge rate.
Treatment of uncontrolled hemorrhagic shock after liver trauma: fatal effects of fluid resuscitation versus improved outcome after vasopressin. [2021]In a porcine model of uncontrolled hemorrhagic shock, we evaluated the effects of vasopressin versus an equal volume of saline placebo versus fluid resuscitation on hemodynamic variables and short-term survival. Twenty-one anesthetized pigs were subjected to severe liver injury. When mean arterial blood pressure was
Vasopressin improves survival in a porcine model of abdominal vascular injury. [2018]We sought to determine and compare the effects of vasopressin, fluid resuscitation and saline placebo on haemodynamic variables and short-term survival in an abdominal vascular injury model with uncontrolled haemorrhagic shock in pigs.
Central angiotensinergic system and hypertonic resuscitation from severe hemorrhage. [2017]Single injections of 4 ml/kg hypertonic NaCl (7.5%) resuscitate dogs from severe blood loss (40-45 ml/kg). Mechanisms involve osmolarity-dependent volume expansion, increased myocardial contractility, and vasodilation. The role of central angiotensinergic pathways in the hemorrhage-hypertonic resuscitation interaction was investigated through experiments performed on male pentobarbital sodium-anesthetized dogs bled to, and held at, 40 mmHg for 30 min. Dogs were treated with 4 ml/kg of 7.5% NaCl or 32 of 0.9% NaCl iv preceded by intracerebroventricular (ICV) injections of 150 micrograms saralasin, 20 micrograms arginine vasopressin inhibitor (AVPI), or 10 micrograms morphine. ICV saralasin and morphine inhibited the full recovery response to hypertonic NaCl, whereas AVPI had no such effect. Saralasin did not inhibit the recovery from hemorrhagic shock produced by large volume isotonic saline reexpansion. These data demonstrate an interaction between the central angiotensin system and small volume hypertonic resuscitation from severe hemorrhagic shock but not between this central system and large volume isotonic reexpansion of circulatory volume. In contrast, the central vasopressinergic system does not appear to be similarly involved.
Interaction of sodium and volume in fluid resuscitation after hemorrhage. [2019]Some measures of the efficacy of fluid resuscitation after hemorrhage are blood volume restitution (BVR) and attenuation of the neuroendocrine response. We compared the effectiveness of resuscitation with 0.9% NaCl and 3.0% NaCl in chronically prepared awake dogs after 30% hemorrhage. Each dog was bled on four occasions and resuscitated by four protocols: 1) full resuscitation (infusion to return and maintain mean arterial pressure (MAP) at control +/- 10 mm Hg) with 3.0% NaCl (HS); 2) full resuscitation with 0.9% NaCl (NS); 3) under-resuscitation with a volume of 0.9% NaCl equal to the subject's previous 3.0% NaCl requirement (SV); and 4) no fluid therapy (NR). Approximately three times more volume was needed to restore MAP with NS vs. HS, and thus the amount of Na administered was not different in these groups. Net volume balance was positive in the NS and SV groups but negative in the HS group due to marked saline diuresis. Net Na balance was positive in all three fluid-treated groups, but significantly higher in the HS group (p less than 0.01). MAP remained below baseline in the SV and NR groups (p less than 0.05). BVR exceeded 100% in NS and HS early in resuscitation, but BVR was not sustained in the HS group. Total plasma protein increased in all three fluid treated groups. Responses of all hormones were completely attenuated in the NS group. ACTH, cortisol, and AVP responses were promptly attenuated in the HS group, but remained greater than control. In the SV group, all hormone levels except renin returned to control values, but more slowly than the other groups. ACTH and cortisol correlated best with BVR; AVP, PRA, and aldosterone correlated with MAP restoration. In summary, resuscitation with either HS or NS can achieve similar MAP restoration. Hypertonic saline produces a more rapid increase in BVR and MAP, but the BVR improvement is transient. Resuscitation with HS incurs an intracellular water debt which is aggravated by a saline diuresis. Hormonal attenuation is linked either to BVR (ACTH, cortisol) or to MAP restoration (renin, AVP). Thus the optimal resuscitation regimen may consist of initial infusion of hypertonic saline followed by sufficient hypotonic solution to restore interstitial fluid volume and normal cellular hydration.
Maintenance intravenous fluid prescribing practices among paediatric residents. [2021]To investigate the sodium composition of maintenance intravenous fluids (mIVF) used by paediatric residents throughout the United States in common clinical scenarios of arginine vasopressin (AVP) excess.
Characterisation of the divalent cation channels of the hepatocyte plasma membrane receptor-activated Ca2+ inflow system using lanthanide ions. [2019]The ability of Gd3+ to inhibit vasopressin-stimulated Ca2+ inflow to hepatocytes was compared with its effect on Mn2+ inflow. In the absence of Gd3+, the stimulation of Mn2+ inflow by vasopressin increased with increasing pH of the extracellular medium. Maximal inhibition of vasopressin-stimulated Ca2+ and Mn2+ inflow by saturating concentrations of Gd3+ was 70 and 30%, respectively. Gd3+ also inhibited thapsigargin-stimulated Ca2+ and Mn2+ inflow with maximal inhibition of 70 and 40%, respectively. It is concluded that vasopressin and thapsigargin each activate two types of Ca2+ inflow processes, one which is sensitive and one which is insensitive to lanthanides. The nature of the pore of the lanthanide-sensitive Ca2+ channel was investigated further using different lanthanides as inhibitors. Tm3+, Gd3+, Eu3+, Nd3+ and La3+ each inhibited vasopressin-stimulated Ca2+ and Mn2+ inflow but had no effect on Ca2+ inflow in the absence of an agonist, or on vasopressin-stimulated release of Ca2+ from intracellular stores. Maximal inhibition of vasopressin-stimulated Ca2+ inflow in the presence of a saturating concentration of each lanthanide ranged from 70-90%. An equation which describes a 1:1 interaction of the lanthanide with a putative binding site in the Ca2+ channel gave a good fit to dose-response curves for the inhibition of vasopressin-stimulated Ca2+ inflow by each lanthanide. Lanthanides in the middle of the series exhibited the lowest dissociation constant (Kd) values. The Kd for Gd3+ increased with increasing extracellular Ca2+ concentration, suggesting competitive inhibition of Ca2+ binding by Gd3+. In the absence of lanthanide, vasopressin-stimulated Mn2+ inflow was substantially reduced when the plasma membrane was depolarised by increasing the extracellular K+ concentration. Changing the membrane potential had little effect on the maximum inhibition by Gd3+ of vasopressin-stimulated Mn2+ inflow. The Kd for inhibition of vasopressin-stimulated Ca2+ inflow by Gd3+, measured at the lowest attainable membrane potential, was about 6-fold lower than the Kd measured at the highest attainable membrane potential. The idea that there is a site in the vasopressin-stimulated lanthanide-sensitive Ca2+ channel composed of carboxylic acid groups which bind Ca2+, Mn2+ or a lanthanide ion is consistent with the data obtained using the different lanthanides.
Vasopressin mediates the pressor effect of hypertonic saline solution in endotoxic shock. [2007]The administration of lipopolysaccharide (LPS) to experimental animals results in a septic shock-like syndrome characterized by hypotension, and the hemodynamic management includes the restoration of adequate tissue perfusion by administration of resuscitation fluids to achieve an effective circulating volume. In the present study, we sought to investigate the effects of hypertonic saline solution administration on vasopressin secretion and mean arterial pressure in endotoxic shock. The pressor response to isotonic saline solution (0.9% sodium chloride) or hypertonic saline (7.5% sodium chloride, 4 mL/kg i.v.) was evaluated 4 h after LPS (1.5 mg/kg) administration. At this moment, plasma vasopressin did not differ from control; however, the blood pressure was lower in the LPS-treated group. The hypertonic saline administration was followed by an immediate recovery of blood pressure and also by an increase in plasma vasopressin levels compared with isotonic saline solution. The vasopressin V1 receptor antagonist (10 microg/kg, i.v., 5 min before infusion) blocked the pressor response to hypertonic saline solution. These data suggest that the recovery of blood pressure after hypertonic saline solution administration during endotoxic shock is mediated by vasopressin secretion.
Small doses of arginine vasopressin in combination with norepinephrine "buy" time for definitive treatment for uncontrolled hemorrhagic shock in rats. [2013]Implementation of fluid resuscitation and blood transfusion are greatly limited in prehospital or evacuation settings after severe trauma or war wounds. With uncontrolled hemorrhagic shock rats, we investigated if arginine vasopressin (AVP) in combination with norepinephrine (NE) is independent (or slightly dependent) of fluid resuscitation and can "buy" time for the subsequently definitive treatment of traumatic hemorrhagic shock in the present study. The results showed that AVP (0.4 U/kg) alone or with NE (3 μg/kg) with one-eighth and one-fourth volumes of total blood volume of lactated Ringer's infusion significantly increased and maintained the mean arterial pressure. Among all groups, 0.4 U/kg of AVP + NE (3 μg/kg) with one-eighth volume of lactated Ringer's infusion had the best effect: it significantly increased and maintained hemodynamics and prolonged the survival time. This early treatment strategy significantly improved the effects of subsequently definitive treatments (after bleeding controlled): it increased the subsequent survival, improved the hemodynamic parameters, improved the cardiac function, and increased the tissue blood flow and oxygen delivery. These results suggested that early application of small doses of AVP (0.4 U/kg) + NE before bleeding control can "buy" time for the definitive treatment of uncontrolled hemorrhagic shock, which may be an effective measure for the early treatment of traumatic hemorrhagic shock.