Balanced Salt Solutions Versus Normal Saline for Initial Fluid Resuscitation in Children With Septic Shock: A Randomized Controlled Trial

Balanced Salt Solutions vs. Normal Saline in Children With Septic Shock

Sponsors

Lead sponsor: All India Institute of Medical Sciences, New Delhi

Collaborator: Postgraduate Institute of Medical Education and Research
Jawaharlal Institute of Postgraduate Medical Education & Research

Source All India Institute of Medical Sciences, New Delhi
Brief 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 volumes of at least 20 ml/kg in the first hour of resuscitation as boluses 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 the answer to the safety of normal saline which is the most widely preferred initial fluid for fluid resuscitation in children with shock due to sepsis.

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, clearly 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 salt solutions" results in lower incidence of 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 Normal 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, 72 hrs and 7 days of fluid resuscitation.

2. Change in arterial pH between baseline, 6, 24, 48, 72 hrs and 7 days of fluid resuscitation.

3. Change in serum bicarbonate between baseline, 6, 24, 48, 72 hrs and 7 days of fluid resuscitation.

4. Requirement of fluid boluses in first 6 hrs and total fluids in first 24 hours.

5. Proportion of patients achieving the pre-determined therapeutic end points at 6, 24, 48, 72 hours and day 7 after fluid resuscitation.

6. Need for inotrope therapy in first 7 days.

7. Change in SOFA scores and PELOD scores at 24 hours, 48, 72 hours and 7 days.

8. Time to resolution of AKI.

9. In- ICU mortality rates.

Site of study

Pediatric emergency and PICU, Department of Pediatrics, All India Institute of medical Sciences,New Delhi

Proposed other sites

PGIMER, Chandigarh and JIPMER Puducherry

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,

- A decreasing trend in serum lactate from the time of admission

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 baseline, 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. 'Group 1' or 'study group' will receive the balanced fluids and 'Group 2' or 'control group' will receive normal 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.

Overall Status Completed
Start Date April 1, 2017
Completion Date October 15, 2019
Primary Completion Date October 15, 2019
Phase N/A
Study Type Interventional
Primary Outcome
Measure Time Frame
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 From the time of randomization/intervention to 7 days of admission
Secondary Outcome
Measure Time Frame
Change in pH from baseline to 6, 24, 48, 72 hours and 7 days after randomization At admission and at 6, 24, 48, 72 hours and 7 days after randomization
Change in serum bicarbonate from baseline to 6, 24, 48, 72 hours and 7 days after randomization At admission and at 6, 24, 48, 72 hours and 7 days after randomization
Proportion of patients with serum chloride levels > 108 meq/L at admission, 6, 24, 48, 72 hours and 7 days after randomization At admission and at 6, 24, 48, 72 hours and 7 days after randomization
Number of fluid boluses received in the first 6 hours after randomization From the time of randomization to 6 hours
Total fluids received in the first 24 hours in ml/kg after randomization From the time of randomization to 24 hours
Mortality From the time of randomization till death or discharge from hospital, whichever came first assessed upto 100 days
Time to resolution of AKI From the time of onset of AKI after randomization till death or discharge from hospital, whichever came first assessed upto 100 days
Change in SOFA scores from admission to 24, 48, 72 hours and 7 days after randomization At admission and at 24, 48, 72 hours and 7 days after randomization
Change in PELOD scores from admission to 24, 48, 72 hours and 7 days after randomization At admission and at 24, 48, 72 hours and 7 days after randomization
Enrollment 710
Condition
Intervention

Intervention type: Drug

Intervention name: Balanced salt solution

Description: Balanced salt solutions as boluses of 20 ml/kg would be administered.

Arm group label: Balanced salt solution or study group

Intervention type: Drug

Intervention name: Normal saline

Description: Normal saline as boluses of 20 ml/kg would be administered

Arm group label: Normal saline or control group

Eligibility

Criteria:

Inclusion Criteria:

- Children 2 month to ≤ 15 years with features of septic shock - 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

Exclusion Criteria:

- Children receiving fluid boluses before enrollment

- Children with cardiogenic shock

- Known patient with chronic kidney disease with baseline deranged renal function (eGFR < 90 ml/1.73 m2/min)

- Severe malnutrition

- Children whose parents refuse to give an informed consent

Gender: All

Minimum age: 2 Months

Maximum age: 15 Years

Healthy volunteers: No

Overall Official
Last Name Role Affiliation
Location
facility
All India Institute of Medical Sciences
PGIMER
JIPMER
Location Countries

India

Verification Date

October 2019

Responsible Party

Responsible party type: Principal Investigator

Investigator affiliation: All India Institute of Medical Sciences, New Delhi

Investigator full name: Jhuma Sankar

Investigator title: Assistant Professor Pediatrics

Keywords
Has Expanded Access No
Condition Browse
Number Of Arms 2
Arm Group

Arm group label: Balanced salt solution or study group

Arm group type: Experimental

Description: After enrollment, a fluid bolus comprising of 'balanced saline' solution at a dose of 20 ml/kg over 15-20 minutes with careful monitoring for features of fluid overload would be administered to each child. Fluid resuscitation will be targeted at achieving the therapeutic end points as given in study definitions. A second bolus would be repeated with the same fluid at 20 ml/kg over 15-20 minutes in case therapeutic end points are not reached. After this the management protocol will be as per recommendations of the surviving sepsis campaign guidelines for septic shock in children.

Arm group label: Normal saline or control group

Arm group type: Active Comparator

Description: After enrollment, a fluid bolus comprising of 'normal saline' solution at a dose of 20 ml/kg over 15-20 minutes with careful monitoring for features of fluid overload would be administered to each child. Fluid resuscitation will be targeted at achieving the therapeutic end points as given in study definitions. A second bolus would be repeated with the same fluid at 20 ml/kg over 15-20 minutes in case therapeutic end points are not reached. After this the management protocol will be as per recommendations of the surviving sepsis campaign guidelines for septic shock in children.

Patient Data No
Study Design Info

Allocation: Randomized

Intervention model: Parallel Assignment

Primary purpose: Treatment

Masking: Triple (Participant, Investigator, Outcomes Assessor)

Source: ClinicalTrials.gov