Balanced Crystalloid vs. Saline in Children With Septic Shock

NCT ID: NCT02835157

Last Updated: 2021-12-21

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 708 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-04-01
• Study Completion Date: 2020-01-15

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 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.

Conditions

Septic Shock; Shock

Keywords

Normal saline; Multiple electrolyte solution; Septic shock; Children; Hyperchloremia; Acute kidney injury; 0.9% saline; Balanced crystalloid

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

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.

Group Type: EXPERIMENTAL

Balanced crystalloid solution

Intervention Type: DRUG

Multiple electrolyte solution as boluses would be administered.

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.

Group Type: ACTIVE_COMPARATOR

0.9%sodium chloride

Intervention Type: DRUG

saline as boluses would be administered

Interventions

Balanced crystalloid solution

Multiple electrolyte solution as boluses would be administered.

Intervention Type: DRUG

0.9%sodium chloride

saline as boluses would be administered

Intervention Type: DRUG

Other Intervention Names

Plasma-Lyte A 148; Multiple electrolyte solution; Saline

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

• Minimum Eligible Age: 2 Months
• Maximum Eligible Age: 15 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Post Graduate Institute of Medical Education and Research, Chandigarh

OTHER

Sponsor Role: collaborator

Jawaharlal Institute of Postgraduate Medical Education & Research

OTHER_GOV

Sponsor Role: collaborator

St Johns Medical College Hospital, Bangalore, India

OTHER

Sponsor Role: collaborator

All India Institute of Medical Sciences

OTHER

Sponsor Role: lead

Responsible Party

Jhuma Sankar

Additional Professor Pediatrics

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Jhuma Sankar, MD Ped

Role: PRINCIPAL_INVESTIGATOR

All India Institute of Medical Sciences

Sushil K Kabra, MD Ped

Role: STUDY_CHAIR

All India Institute of Medical Sciences

Rakesh Lodha, MD Ped

Role: STUDY_DIRECTOR

All India Institute of Medical Sciences

Locations

St Johns Medical College and Hospital

Bengaluru, Karnataka, India

All India Institute of Medical Sciences

New Delhi, National Capital Territory of Delhi, India

PGIMER

Chandigarh, , India

JIPMER

Puducherry, , India

Countries

India

References

Sankar J, Muralidharan J, Lalitha AV, Rameshkumar R, Pathak M, Das RR, Nadkarni VM, Ismail J, Subramanian M, Nallasamy K, Dev N, Kumar UV, Kumar K, Sharma T, Jaravta K, Thakur N, Aggarwal P, Jat KR, Kabra SK, Lodha R. Multiple Electrolytes Solution Versus Saline as Bolus Fluid for Resuscitation in Pediatric Septic Shock: A Multicenter Randomized Clinical Trial. Crit Care Med. 2023 Nov 1;51(11):1449-1460. doi: 10.1097/CCM.0000000000005952. Epub 2023 Jun 9.

Reference Type: DERIVED

PMID: 37294145 (View on PubMed)

Other Identifiers

IEC/NP-424/09.10.2015

Identifier Type: -

Identifier Source: org_study_id