Balanced Crystalloid vs. Saline in Children With Septic Shock

Multiple Electrolyte Solution vs. Saline in Pediatric Septic Shock

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.

Study Overview

• Status: Completed
• Conditions: Shock; Septic Shock
• Intervention / Treatment: Drug: Balanced crystalloid solution; Drug: 0.9%sodium chloride

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.

• Study Type: Interventional
• Enrollment (Actual): 708
• Phase: Not Applicable

Contacts and Locations

Study Locations

• India
  • Chandigarh, India
    • PGIMER
  • Puducherry, India, 605006
    • JIPMER
  • Delhi
    • New Delhi, Delhi, India, 110029
      • All India Institute of Medical Sciences
  • Karnataka
    • Bengaluru, Karnataka, India, 560034
      • St Johns Medical College and Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 months to 15 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Balanced crystalloid or multiple electrolyte solution group; After enrollment, a fluid bolus comprising of 'multiple electrolyte solution (Plasma-Lyte P)' solution at a dose of 20 ml/kg over 15-20 minutes (recommended) 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. After this the management protocol will be as per recommendations of the American College of Critical Care Medicine 2017 for septic shock in children.	Drug: Balanced crystalloid solution; Multiple electrolyte solution as boluses would be administered.; Other Names: Plasma-Lyte A 148; Multiple electrolyte solution
Active Comparator: 0.9% saline or saline group; After enrollment, a fluid bolus comprising of 'saline' solution at a dose of 20 ml/kg over 15-20 minutes (recommended) 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. After this the management protocol will be as per recommendations of the American College of Critical Care Medicine 2017 for septic shock in children.	Drug: 0.9%sodium chloride; saline as boluses would be administered; Other Names: Saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	Incidence of new or progressive AKI in first 7 days after randomization/ intervention	From the time of randomization/intervention to 7 days of admission

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of patients with serum chloride levels > 108 meq/L at admission, 6, 24, 48 and 72 hours	Incidence of hyperchloremia	At 6, 24, 48 and 72 hours after randomization
Number of fluid boluses received in the first 6 hours after randomization	Total number of fluid boluses received in the first 6 hours after randomization/intervention	From the time of randomization to 6 hours
Total fluids received in the first 24 hours, 24-48 hours and 48-72hrs in ml/kg after randomization	Total fluids received in first 24 hours, 24-48 hours and 48-72 hours	From the time of randomization to 72 hours
Mortality (serious adverse event)	Death during ICU course	From the time of randomization till death or discharge from ICU, whichever came first assessed upto 100 days
Time to resolution of AKI	Time taken for 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
SOFA scores at 24 and 48 hours after randomization	Comparison of SOFA scores in both groups at 24 hours and 48 hours after randomization	At 24 and 48 hours after randomization
PELOD scores at 24 and 48 hours after randomization	Comparison of PELOD scores in both groups at 24 hours and 48 hours after randomization	At 24 and 48 hours after randomization
Incidence of metabolic acidosis at 6, 24, 48 and 72 hours after randomization	Comparison of number of children in both groups with acidosis at 6, 24, 48 and 72 hours after randomization	At admission and at 6, 24, 48 and 72 hours after randomization

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety outcome 1	New or progressive AKI requiring dialysis (serious adverse event)	From the time of randomization/intervention to 7 days of admission
Safety outcome 2	IN-ICU mortality in patients with AKI (serious adverse event)	From the time of randomization/intervention to mortality
Safety outcome 3	Infusion related adverse events- fever, rash, extravasation, hypervolemia/fluid overload	From the time of initiating the bolus to its completion

Collaborators and Investigators

• Sponsor: All India Institute of Medical Sciences, New Delhi
• Collaborators: Postgraduate Institute of Medical Education and Research; Jawaharlal Institute of Postgraduate Medical Education & Research; St Johns Medical College Hospital, Bangalore, India
• Investigators: Principal Investigator: Jhuma Sankar, MD Ped, All India Institute of Medical Sciences, New Delhi; Study Chair: Sushil K Kabra, MD Ped, All India Institute of Medical Sciences, New Delhi; Study Director: Rakesh Lodha, MD Ped, All India Institute of Medical Sciences, New Delhi

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2017
• Primary Completion (Actual): January 15, 2020
• Study Completion (Actual): January 15, 2020

Study Registration Dates

• First Submitted: March 1, 2016
• First Submitted That Met QC Criteria: July 14, 2016
• First Posted (Estimate): July 15, 2016

Study Record Updates

• Last Update Posted (Actual): December 21, 2021
• Last Update Submitted That Met QC Criteria: December 6, 2021
• Last Verified: December 1, 2021

More Information

Terms related to this study

• Keywords: Children; Septic shock; Acute kidney injury; Normal saline; Hyperchloremia; Multiple electrolyte solution; 0.9% saline; Balanced crystalloid
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Shock, Septic; Shock; Pharmaceutical Solutions
• Other Study ID Numbers: IEC/NP-424/09.10.2015

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Individual patient data will not be shared

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No