Efficacy, Safety of Solution Containing Hyperosmolar Sodium Lactate Infusion for Resuscitation of Patients With Hemorrhagic Shock

Hemorrhagic Shock Clinical Trial

Official title:

The Clinical Efficacy and Safety of a Proprietary Solution Containing Hypertonic Sodium Lactate (Totilac®) Infusion for Resuscitation of Patients With Hemorrhagic Shock Due to Multiple Injuries

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01433276
• Other study ID #: 009/IGK-KAL/09
• Status: Completed
• Phase: Phase 3
• First received: August 10, 2011
• Last updated: September 12, 2011
• Start date: July 2009
• Est. completion date: January 2011

Study information

• Verified date: August 2011
• Source: Innogene Kalbiotech Pte. Ltd
• Contact: n/a
• Is FDA regulated: No
• Health authority: Indonesia: National Agency of Drug and Food Control
• Study type: Interventional

Clinical Trial Summary

Indication: Resuscitation in pts with hemorrhagic shock due to multiple injuries

Prospective, open label RCT in pts. with traumatic hemorrhagic shock in RS Hasan Sadikin Hospital, Indonesia.

PI: Dr. Kiki Lukman, PsBD(K), Surgery, RSHS. Co-PI: (late)Prof. Xavier Leverve MD, PhD, Directeur, INSERM-E0221-Bioenergetique Fondamentale et Appliquée Université Joseph Fourier, France

Hemorrhagic shock is a cause of death in trauma.Fluid resuscitation to ensure stable hemodynamics and microcirculation by rapidly restoring circulating plasma volume could be a cornerstone of managing trauma patients. Excessive fluid accumulation particularly in the interstitial tissue should be avoided. Hypertonic solution shows promise in restoring intravascular volume expansion and microcirculation with less fluid infusion in hypovolemic patients. This study investigated efficacy and safety of hyperosmolar Na lactate(Totilac®) for resuscitating traumatic hemorrhagic shock patients.

Patients with multiple injuries with grade III hemorrhagic shock and RTS ≥4 received std initial fluid resuscitation of upto 2 liters of isotonic crystalloid. They also got similar dose of either hyperosmolar Na lactate or ringer's lactate. Hemodynamic status, fluid balance and and safety was recorded during the study.

Description:

Trauma is still an important cause of death and disability worldwide.Trauma patients often experience fluid deficits. In addition to apparent blood loss, fluid deficit might also occur secondary to generalized alterations of the endothelial barrier, resulting in diffuse capillary leakage and fluid shift from the intravascular to the interstitial compartment. Severe volume deficits after trauma result in hemorrhagic shock that further leads to the decrease of tissue perfusion, especially to vital organs and inadequate delivery of oxygen and nutrients necessary for normal tissue and cellular function. Subsequently, inadequate and inappropriate management of hemorrhagic shock frequently results in the development of post trauma multiple organ failure which increases the morbidity and mortality of the patients. Consequences of hypovolemic shock (hemorrhagic shock) due to bleeding are one of the major causes of death in trauma patients. Therefore, fluid replacement to reverse shock and to restore perfusion to vital organs appears to be fundamental in the management of the trauma patient, after ensuring an adequate airway, oxygenation and ventilation.

Effective control of hemorrhage and adequate intravenous fluid administration to restore intravascular volume and maintain the tissue perfusion is crucial for saving the patient's life and resuscitation can exacerbate cellular injury caused by hemorrhagic shock, if resuscitation is not performed properly. The type of fluid used for resuscitation plays an important role in this injury pattern. However, when, how and which fluids are ideal in regards to fluid resuscitation remains controversial. The concept that early, aggressive large - volume resuscitation by administration of isotonic crystalloids in volumes 2 to 3 times the estimated blood loss has been widely accepted and practiced; it has even became the standard-of-care adopted by the ATLS for the treatment of trauma casualties (ATLS congress). In patients with prolonged hemorrhagic shock frequently associated with interstitial fluid deficits in addition to intravascular blood volume, resuscitation fluids were needed to replace the intravascular volume loss and replenish interstitial deficits. It has been suggested that aggressive fluid resuscitation improved survival with better function of patient's vital organ patient's with less frequent renal failure. However, aggressive fluid resuscitation can lead to fulminant pulmonary failure "Acute Respiratory Distress Syndrome (ARDS)" and appears as an early cause of death after severe hemorrhage. Moreover, it was observed that aggressive fluid resuscitation in uncontrolled hemorrhagic shock to attempt to increase blood pressure to normal resulted in increased bleeding from injured vessels, hemodynamic decompensation, and increased mortality, and led to cellular injury when compared to no fluid resuscitation or hypotensive resuscitation (permissive hypotension). Therefore a novel resuscitation strategy that overcomes those issues in the near future is still required.

Hyperosmolar solutions of various concentrations (1.8%-7.5%) have been investigated as resuscitation solutions in vitro, as well as animal and clinical studies, with promising results. Clinical and experimental studies have demonstrated that small volume of hypertonic saline solution is able to restore hemodynamics in traumatic shock patients. Small volume of hypertonic solutions stabilize arterial pressure and cardiac output, improve microvascular flow (increases renal, mesenteric, total splanchic and coronary blood flow), control intracranial pressure, with no deleterious effects on immune functions. Moreover, in hemorrhagic shock models, Hyperosmolar solution has immunomodulatory effects including attenuation of immune-mediated cellular injury, modulating the post-trauma immune response, decreasing neutrophil excitation, decreasing inflammation, neutrophil-endothelial binding, lung damage, and bowel injury. This hypertonic solution was more effective than isotonic crystalloids in minimizing the inflammatory response (especially neutrophil cyto-toxicity) and in preventing lung and liver reperfusion injury, as well as in improving intestinal blood flow. Improved survival rate in traumatic hemorrhagic shock patients treated with hypertonic solution were reported in several trials. The beneficial effect of hypertonic saline has been shown related to its hypertonicity characteristic.

A proprietary solution containing hyperosmolar sodium lactate (Totilac) is a hyperosmolar solution with a physiological concentration of potassium chloride and calcium chloride. Totilac with small volume administration during volume deficits in post cardiac surgery patients improves cardiac output, oxygen delivery, urine output, attenuates metabolic acidosis and maintains stable hemodynamic better compared to isotonic crystalloid. Administration of small dose of Totilac in patients with dengue shock syndrome also improved hemodynamic status and microcirculation. High lactate content in this solution offered more benefit in shock patients when compared to other hypertonic solutions as lactate has been known to act as energy substrate in mitochondrion containing cells and can be easily metabolized in hypoxia. Hypertonicity related effects of hyperosmolar sodium lactate solution in addition to lactate effect may offer at least similar benefits in hemorrhagic shock patients, though until now there is no clinical study conducted to prove efficacy of Totilac in hemorrhagic shock. This study aimed to evaluate the efficacy and safety of Totilac as resuscitative fluid regimen in traumatic shock hemorrhagic patients.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 71
• Est. completion date: January 2011
• Est. primary completion date: January 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

• Male or female, aged 18-65 years

• Patients with grade III hemorrhagic shock (who fulfilled at least 2 of these following criteria: 1.5-2 L blood loss estimation, MAP <65 mmHg, pulse pressure <20 mmHg, heart rate >120 times/min, respiratory rate 30-40 times/min or urinary output 5-15 ml/hour) due to multiple injuries (simultaneously injuries in two or more organs of the body)

• Survival probability is >50%, predicted by Revised Trauma Score = 4 (scale 0-7.8408)

• Given written informed consent

Exclusion Criteria:

• Patients with burns >20% of body surface area

• Patients with Glasgow Coma Score = 13 (moderate and severe head injury)

• Patients with systemic diseases which were already present before having trauma, such as: cancer, chronic renal failure, liver failure, decompensated heart failure, AIDS (CD4<200/uL) or HIV serology positive with HAAR

• Hemorrhagic shock patients with trias sign: coagulopathy, acidosis and hypothermia that needs blood transfusion immediately

• Patients who were pregnant before having trauma

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Hemorrhagic Shock
• Shock
• Shock, Hemorrhagic

Intervention

Drug:
• Hyperosmolar sodium lactate
1st loading : Upto 2 liters of Ringer's lactate, followed by Totilac which was given 5 mL/kgBW/15 minutes, followed by maintenance 2 mL/kgBW/hour for 3 hours
• Ringer's lactate
1st loading : Upto 2 litres of Ringer's lactate, followed by 5 mL/kgBW/15 minutes,followed by maintenance : 2 mL/kgBW/hour for 3 hours

Locations

Country	Name	City	State
Indonesia	Department of Surgery, Dr. Hasan Sadikin Hospital	Bandung

Sponsors (1)

Lead Sponsor	Collaborator
Innogene Kalbiotech Pte. Ltd

Country where clinical trial is conducted

Indonesia, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Urinary output (UOP)		3 hours	Yes
Secondary	Blood pressure		3 hours	Yes
Secondary	Mean arterial pressure		3 hours	Yes
Secondary	Heart rate		3 hours	Yes
Secondary	Respiration rate		3 hours	Yes
Secondary	Glasgow coma scale value		3 hours	Yes
Secondary	Fluid balance		3 hours	Yes