Efficacy, Safety of Solution Containing Hyperosmolar Sodium Lactate Infusion for Resuscitation of Patients With Hemorrhagic Shock
Condition: Hemorrhagic Shock
MeSH terms: Shock; Shock, Hemorrhagic
Study type: Interventional
Phase: Phase 3

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.
    

Detailed 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.
    

Intervention name(s): Hyperosmolar sodium lactate; Ringer's lactate
Intervention type(s): Drug; Drug
Intervention description(s): 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; 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
Other intervention name(s): Kalsolac; Lactated Ringer's solution
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Fluid resuscitation; hemorrhagic shock; Totilac; Ringer's; trauma