Balanced Crystalloid vs. Saline in Children With Septic Shock
Condition: Septic Shock; Shock
MeSH terms: Shock, Septic; Shock
Study type: Interventional

Summary: 
      Fluid resuscitation is the cornerstone of pediatric shock management; current practices of
      fluid resuscitation in children are not evidence based. Normal saline is the preferred
      crystalloid recommended during initial resuscitation in shock, as the incidence of
      hyponatremia is lower with normal saline compared to all other fluids available and commonly
      used. However, normal saline has its own set of undesired physicochemical actions. Emerging
      data strongly indicate the increased incidence of hyperchloremia, metabolic acidosis and
      consequently, acute kidney injury associated with infusion of large volumes of normal saline.
      Balanced salt solutions or crystalloids, which have composition resembling plasma but lower
      chloride concentrations than normal saline, clearly decrease the risk of hyperchloremia and
      metabolic acidosis in adult as well as pediatric studies when used during the peri-operative
      period. The results favored balanced solutions in comparison to normal saline. Recent
      systematic reviews comparing balanced or buffered versus non-buffered fluids for surgery in
      adults favored the former solution as the metabolic derangements were less with the use of
      this type of fluid. In adult patients, the two solutions have been compared in various other
      settings as well such as in traumatic brain injury and in shock. The results favored balanced
      solutions in comparison to normal saline. However, in the non-surgical setting there is a
      paucity of evidence on the use of these solutions in children with shock and more evidence
      needs to be generated to support or refute the use of this fluid as compared to normal
      saline.

      Given this background, the investigators decided to compare the effect of two solutions on
      the incidence of acute kidney injury in children resuscitated with either of the two fluids.
      Children receiving at least one fluid bolus at 20 ml/kg in the first hour would be enrolled
      and followed up for the proposed outcome variables. The investigators plan to enroll 708
      patients over a period of 3 years. The investigators believe that the proposed study will
      provide answer to the research question of which of the fluids could be preferred for
      resuscitation.
    

Detailed description: 
      Background

      Fluid resuscitation is the cornerstone of pediatric shock management; current practices of
      fluid resuscitation in children are not evidence based. Emerging data strongly indicate the
      increased incidence of hyperchloremic metabolic acidosis and consequently, acute kidney
      injury associated with infusion of large volumes of normal saline in critically ill adults in
      shock. Balanced salt solutions or crystalloids, which have composition resembling plasma but
      lower chloride concentrations than normal saline, have shown to decrease the risk of
      hyperchloremia and metabolic acidosis in adult as well as pediatric studies when used during
      the peri-operative period. In adult patients, the two solutions have been compared in various
      other settings as well such as in traumatic brain injury and in shock. The results favored
      balanced solutions in comparison to normal saline. However, in the non-surgical setting there
      is a paucity of evidence on the use of these solutions in children with shock and more
      evidence needs to be generated to support or refute the use of this fluid as compared to
      normal saline.

      Objectives

      Primary To examine if use of 'balanced crystalloids (multiple electrolyte solution)" results
      in lower incidence of new or progressive Acute kidney injury (defined as increase in serum
      creatinine by > 0.3mg/dL within 48 hours or to 1.5 times baseline or more within the last 7
      days or urine output less than 0.5 mL/kg/h for 6 hours) in the first seven days after initial
      fluid resuscitation as compared to saline.

      Secondary

      To evaluate the difference if any, between two fluid types with regard to the following
      secondary objectives such as:

        1. Incidence of hyperchloremia (defined as serum chloride levels >108 mEq/L) at 6, 24, 48
           and 72 hrs of fluid resuscitation.

        2. Incidence of metabolic acidosis at 6, 24, 48 and 72 hrs of fluid resuscitation.

        3. Requirement of fluid boluses in first 6 hrs and total fluids in first 24 hours, 48 hours
           and 72 hours.

        4. Proportion of patients achieving the pre-determined therapeutic end points at 6, 24, 48
           hours and 72 hours after fluid resuscitation.

        5. Need for inotrope therapy in first 7 days.

        6. Change in SOFA scores and PELOD scores at 24 hours and 48 hours.

        7. Time to resolution of AKI.

        8. In- ICU mortality rates.

        9. Ventilator free days, ICU free days and Hospital free days.

      Site of study

      Pediatric emergency and PICU, Department of Pediatrics, All India Institute of medical
      Sciences,New Delhi

      Other sites

      PGIMER, Chandigarh, JIPMER Puducherry and St Johns Medical College Bengaluru

      Study Design

      Randomized controlled trial (safety and superiority for kidney injury). Multicenter trial.

      Study Duration

      3 years

      Study definitions

      Septic shock is defined as children who have a suspected infection manifested by hypothermia
      or hyperthermia and have at least two clinical signs of decreased perfusion with or without
      hypotension such as decreased mental status, prolonged capillary refill of >2 secs (cold
      shock) or flash capillary refill (warm shock), diminished (cold shock) or bounding (warm
      shock) peripheral pulses, mottled cool extremities (cold shock), or decreased urine output of
      <1 ml/kg/hr).

      Therapeutic end points

        -  Normal heart rate

        -  Appropriate-for-age mean arterial pressure (MAP) measured non-invasively;

        -  Normal pulses with no difference between peripheral and central pulses, warm
           extremities;

        -  Capillary refill time <2 seconds;

        -  Normal mental status;

        -  Urine output ≥ 1mL/kg/hr,

      Hyperchloremia: Defined as serum chloride value of >108 meq/L, based on our laboratory cut
      off of 98-108 meq/L Metabolic acidosis: pH of less than 7.35 with serum bicarbonate < 24
      meq/L with low to normal pCO2 (<40 mm Hg)

      Acute kidney injury: An abrupt (within 48-hr) reduction in kidney function defined as an
      absolute increase in serum creatinine of more than or equal to 0.3 mg/dl, an increase in
      serum creatinine of more than or equal to 1.5 fold from the value preceding the abnormal
      value, or reduction in urine output (oliguria of less than 0.5 ml/kg per hour for >6-hr).

      Enrollment

      All children with features of shock as per standard definitions will be screened for
      eligibility. Of these, children who require at least one fluid bolus of 20 ml/kg will be
      enrolled. The eligible participants would be enrolled after obtaining informed consent from
      one of the parents.

      Randomization

      Once enrolled, the participants would be randomized into 2 groups. 'MES' or 'study group'
      will receive the balanced fluids and 'saline' or 'control group' will receive 0.9% saline.
      Process of randomization will be done by an investigator who will have no further role in
      collecting the baseline variables, applying intervention or analysis of outcome(s). Block
      randomization will be done in varying block sizes of 2 to 8. The random number table
      generated from computer software would be used for this purpose.

      Sample size estimation

      The investigators calculated that a sample size of 354 patients in each group (708 total)
      would be required to detect an absolute reduction in incidence of AKI from 25% (current
      incidence in children with shock in the unit) to 15% assuming a two-sided α level of 0.05 and
      a statistical power of 90%. The sample size was calculated using Stata 11. The investigators
      expect the required sample size to be collected within 3 years period in the three centers.
    

Intervention name(s): Balanced crystalloid solution; 0.9%sodium chloride
Intervention type(s): Drug; Drug
Intervention description(s): Multiple electrolyte solution as boluses would be administered.; saline as boluses would be administered
Other intervention name(s): Plasma-Lyte A 148; Multiple electrolyte solution; Saline
Intervention MeSH terms: Pharmaceutical Solutions
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: The enrolled children will be randomized to either balanced crystalloid (Plasma-Lyte A or multiple electrolyte solutions or MES group) or 0.9% saline (saline group).
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Normal saline; Multiple electrolyte solution; Septic shock; Children; Hyperchloremia; Acute kidney injury; 0.9% saline; Balanced crystalloid