Balanced versus Unbalanced

Fluids in Critically Ill

Children

Kusum Menon, MD, FRCPC, MSc

Pediatric Intensivist,

Children’s Hospital of Eastern Ontario

Professor, University of Ottawa

Objectives

• To discuss the rationale for studying the use of balanced versus

unbalanced solutions for fluid resuscitation

• To review the theoretical pros and cons of balanced versus

unbalanced fluid administration

• To summarize the evidence on balanced versus unbalanced

fluids in critically ill children

History of IV fluid composition

• 1831: Dr W. O’Shaughnessy (a chemist) noted cholera patients lost a large amount of

neutral saline and free alkali; recommended injection of tepid water holding a solution

of the normal salts.

• 1832: Dr. T. Latta performed the first IV resuscitation with a hypotonic solution of Na+,

Cl-, and HCO3- and revived 8 of 25 patients.

• Following the cholera epidemic IV fluid treatment did not prosper:

1. Public thought deaths were hastened by treatment.

2. Treatment was not repeated sufficiently to maintain fluid balance.

3. Fluid was unsterile, impure and hypotonic.

History of IV fluid composition

• 1914-28: Dr. JL Gamble introduced the concept of extracellular fluid and

described its electrolyte composition.

• 1922: Jakob Hamburger, concluded that “the blood of the majority of

warm-blooded animals, including man, was isotonic with a sodium

chloride solution of 0.9% saline”.

1Hamburger HJ. A Discourse on permeability in physiology and pathology. Lancet. 1921;198(5125):1039–1045.2Karelitz S, Shick B. Treatment of Toxicosis with the aid of a continuous intravenous drip of dextrose solution. Am J Dis Child. 1931;42:781-802.

History of IV fluid composition in children

• 1930s-80s:

• Defining of maintenance electrolyte requirements in children: 3 mEq Na+

and 2 mEq Cl- per 100mL of maintenance IV fluid.

• 1980s-2000:

• Evidence suggesting solutions containing only maintenance electrolyte

requirements were hypotonic (0.25 NS) and caused hyponatremia.

• IV resuscitation and maintenance fluids required isotonic solutions.

IV fluid composition recommendations in children

• The American Association of Pediatrics1 and the World Health

Organization2 recommend use of Ringer’s lactate (RL) or Normal Saline

(NS) for the IV resuscitation of children.

1Evidence-based guideline recommends isotonic solutions for children who need intravenous fluids. AAP news. Nov 26, 20182Duke T, Mason E. Lancet. WHO guidelines on fluid resuscitation in children with shock. 2014 Feb 1;383(9915):411-2.

Balanced versus unbalanced solutions: Does it matter?

• Intravenous (IV) fluids are one of the most commonly administered therapies in

hospital. (5 million litres of crystalloids sold in Ontario/year: Baxter Corp.)

• Normal saline (unbalanced fluid) has been associated with hyperchloremic metabolic

acidosis.

• Ringer’s lactate has been associated with hyponatremia and cerebral edema.

• Cost of IV fluids vary from $1.41/L for normal saline to $1.80/L for Ringer’s lactate.

Balanced Fluid

A multiple electrolyte, isotonic, IV

crystalloid solution which can restore

electrolyte balance and normalize pH.

Unbalanced Fluid

An IV crystalloid solution containing

sodium chloride that does not match the

concentration of ions in plasma and is not

buffered.

Composition of common resuscitation fluids

Fluid pH Serum Osmolality

(mosmol/kgH2O)

Na+

(mEq/L)

K+

(mEq/L)

Cl-

(mEq/L)

Buffer Mg2+

(mEq/L)

Ca2+

(mEq/L)

Normal

saline5.5 3081 154 154 None

Ringer’s

lactate6.5 273 130 4.0 109 Lactate 2.7

5% albumin 6.85-7.0 330 140 ± 15 <2.5HCO3, NaOH

or Acetic Acid

Human

plasma7.35-7.45 289 142 4.0 103 HCO3 2

1This refers to in vitro osmolality, the in vivo osmolality of normal saline is ~285 mosmol/kgH2O

Comparison of Ringer’s Lactate and Normal Saline

Ringer’s lactate Normal Saline

Pros Less acidic

Normochloremic

No potassium

No calcium

No lactate

Isotonic

Less expensive

Cons Slightly hyponatremic

Slightly hypotonic

Contains potassium

Contains calcium

Contains lactate

More expensive

Hypernatremic

Hyperchloremic

No buffer

Pathophysiology of Normal Saline Acidosis

• The SID (Strong Ion Difference) is:

[strong cations] – [strong anions] = [Na+ + K+ + Ca2+ + Mg2+] – [Cl- + lactate- + SO42-]

• Strong ions are cations and anions that exist as charged particles at physiologic pH.

• Strong cations predominate at physiologic pH leading to a net charge of +40.

• The sum of positive charges must equal the sum of negative charges. Therefore the SID must

equal the sum of weak anions (such as bicarbonate, albumin, and phosphate).

• Volume resuscitation with NS results in excess Cl- administration impairing HCO3- resorption

in the kidneys and leading to a larger SID and acidosis.

Pathophysiology of Strong Ion difference of IV fluids

Hayes, W. Pediatric Nephrology (2019) 34:1191–1199

Clinical consequences of hyperchloremic metabolic acidosis

• In pre-clinical models, high chloride in saline associated with:

• Acidosis, inflammation, renal vasoconstriction, acute kidney injury, hypotension,

and death.

• Observational studies involving critically ill adults:

• higher rates of acute kidney injury, renal-replacement therapy and death

• Limited data in children

1Kellum JA et al. Etiology of metabolic acidosis during saline resuscitation in endotoxemia. Shock. 1998; 9:364–8. 2Kellum JA et a;. Effects of hyperchloremic acidosis on arterial pressure and circulating inflammatory molecules in experimental sepsis. Chest. 2004; 125:243–8. 3Krajewski ML et al. Meta-analysis of high- versus low-chloride content in perioperative and critical care fluid resuscitation. Br J Surg. 2015; 102:24–36. 4Sen A et al. Chloride content of fluids used for large-volume resuscitation is associated with reduced survival. Crit Care Med. 2017; 45(2):e146–e153. 5Rochwerg B et al. Fluid type and the use of RRT in sepsis: a systematic review and network meta-analysis. Int Care Med. 2015; 41:1561–71.

Potential limitations of Ringer’s Lactate

• Increased serum lactate

• Incompatible with blood and ceftriaxone administration.

• Increased serum potassium

• Hypo-osmolar

1Feldman Z et al. Brain edema and neurological status with rapid infusion of lactated Ringer's or 5% dextrose solution following head trauma. J Neurosurg.

1995;83(6):1060–6. 2Rowell SE et al. The impact of pre-hospital administration of lactated Ringer’s solution versus normal saline in patients with traumatic brain injury. J

Neurotrauma. 2016;33(11):1054–9.

Clinical consequences of Ringer’s Lactate use

• Lactate content may increase lactic acidosis in shock patients

• Increased serum potassium may limit use in patients with

renal dysfunction

• Lower osmolarity may contribute to cerebral edema in DKA

and TBI patients.

1Feldman Z et al. Brain edema and neurological status with rapid infusion of lactated Ringer's or 5% dextrose solution following head trauma. J Neurosurg.

1995;83(6):1060–6. 2Rowell SE et al. The impact of pre-hospital administration of lactated Ringer’s solution versus normal saline in patients with traumatic brain injury. J

Neurotrauma. 2016;33(11):1054–9.

Systematic Review

• Buffered solutions versus 0.9% saline for resuscitation in critically

ill adults and children. Antequera Martin AM et al. Cochrane Database Syst Rev.

2019 Jul 19;7.

• Included 21 RCTs (20,213 participants) and three ongoing studies.

• Three adult RCTs contributed 94.2% of participants.

• 16 included trials were conducted in adults, 4 in children and one trial had no age limits

specified.

• 14 trials reported results on mortality, and nine reported on acute renal injury.

• Buffered solutions made little or no difference to overall mortality;

• Buffered solutions probably make little/no difference in reducing the

number of patients with worsening kidney function;

• Uncertain whether buffered solutions reduce impairment of other

organs, electrolyte disturbances and the need to receive blood

transfusions.

Systematic Review: Results

Systematic Review: Limitations

• Combined adults and children for all analyses except mortality

which they assessed by age.

• Results biased by 3 adult RCTs which contributed 94.2% of

participants.

• In children, only identified 4 of 6 existing RCTs and excluded

observational studies.

Pediatric Systematic Review

Population 28 day – 18year old critically ill children needing fluid bolus therapy

Intervention Balanced solution >20 mL/kg IV

Comparator 0.9% saline >20 mL/kg IV

Outcome Improvement in metabolic acidosis

Impact of balanced versus unbalanced fluid resuscitation on clinical outcomes in

critically ill children: a systematic review and meta-analysis.Lehr A, Rached-d’Astous S, Parker M, McIntyre Lauralyn, Sampson, M, Hamid, Jemila Menon, K.

Figure 1. Screening flow chart

Table 1. Included Study characteristicsFirst author Design

Center(n)

PopulationBalanced Solution

Patients (n)Unbalanced Solution

Patients (n)Acidosis Outcome

Gutierrez-Camacho, 1994retrospective

observational8

Severe acute

gastroenteritis14 6 ∆ bicarbonate

Dung, 1999 RCT 1Dengue shock

syndrome13 12 not reported

Nhan, 2001 RCT 1Dengue shock

syndrome55 56 not reported

Mahajan, 2012 RCT 1Severe acute

gastroenteritis11 11 ∆ bicarbonate and pH

Allen, 2016 RCT 1Severe acute

gastroenteritis39 38 ∆ bicarbonate

Weiss, 2016retrospective matched

cohort382

Severe sepsis/ septic

shock459 459 not reported

Emrath, 2017retrospective matched

cohort43

Severe sepsis / septic

shock1000 6000 not reported

Kartha, 2017 RCT 1Severe acute

gastroenteritis34 34

∆ bicarbonate, pH, base deficit

and pH ≥7.35

Samransamruajkit, 2017prospective

observational1

Severe sepsis/ septic

shock15 20 ∆ base excess

Yung, 2017 RCT 1Moderate to severe

DKA38 39

time to bicarbonate ≥15 mmol/L

and pH of 7.3

Figure 2. Change in serum bicarbonate from baseline

Pediatric systematic review: results

Figure 3. Follow up serum pH

Pediatric systematic review: results

Figure 4. Association of resuscitative fluid composition with mortality in

acutely ill children.

Pediatric systematic review: results

Conclusions• No current evidence to support use of Ringer’s Lactate versus Normal Saline for fluid

resuscitation in children

• Evidence suggests a trend toward higher serum bicarbonate levels and correction of acidosis in

critically ill children after fluid bolus therapy with balanced compared to unbalanced fluids.

• However, studies are limited in methodology and size.

• Future studies would be useful regardless of findings:

• If no benefit to balanced solutions, limiting their use could decrease costs.

• If there is a benefit, it could impact patient care and healthcare resource utilization.