Electrolyte derangements in critically ill children receiving balanced versus unbalanced crystalloid fluid resuscitation

Fluid resuscitation with crystalloid solutions is a mainstay of therapy in critically ill children [1]. The most frequently utilized crystalloid in both adult and pediatric patients is 0.9% sodium chloride (0.9%NaCl) [2], despite a growing body of evidence to suggest potential harm from its use, including higher rates of mortality, acute kidney injury (AKI), and electrolyte and acid–base disturbances [3‐10]. The detrimental effects of resuscitation with 0.9%NaCl are hypothesized to be secondary to supraphysiologic amounts of chloride compared to plasma (154 mEq/L versus ~ 100 mEq/L) in unbalanced crystalloids [11]. As a result, the use of balanced crystalloids such as lactated ringers (LR) (110 mEq/L chloride) and plasma-lyte 148 (PL) (98 mEq/L chloride) is becoming increasingly more common in critically ill patients, including children. However, the lower concentrations of sodium (130 mEq/L in LR and 140 mEq/L in PL, compared to 154 mEq/L in 0.9%NaCl) and higher amounts of potassium (4 mEq/L in LR and 5 mEq/L in PL, compared to none in 0.9%NaCl) in these balanced crystalloid solutions have led to theoretical concerns for hyponatremia and hyperkalemia if used for resuscitation. While small adult studies [4, 12, 13] and studies in specific pediatric diseases [14, 15] have evaluated and dispelled some of these concerns, there remains a paucity of data regarding the association between balanced crystalloids and electrolyte derangements following resuscitation in heterogeneous populations of critically ill children.

The purpose of this study was to examine the incidence of hyperkalemia, hyponatremia, hyperchloremia, and acidosis in critically ill children who primarily received balanced crystalloids compared to those who received 0.9%NaCl for resuscitation. We hypothesized a priori that use of balanced crystalloids for fluid resuscitation would be associated with a lower incidence of electrolyte derangements and acidosis when compared to 0.9%NaCl.

In this large, two-center prospective observational study, we found that resuscitation with LR was not associated with significant electrolyte abnormalities when compared to the use of 0.9%NaCl. While there were no clinically significant differences in daily median electrolyte values between patients, those who received LR had a lower incidence of extreme hyperkalemia and acidosis compared to those who received 0.9%NaCl or mixed fluids, and suffered no instances of severe hyponatremia. Taken together, the results of our study suggest that LR appears to be a safe alternative to 0.9%NaCl as a resuscitative fluid in a heterogeneous population of critically ill children. This adds to the known literature demonstrating that balanced crystalloids are associated with fewer electrolyte derangements in critically ill adults [4, 12].

Evaluating the impact of fluid selection on the rates of clinically meaningful hyperkalemia and hyponatremia in critically ill children is necessary, as a single instance of either of these events can have important clinical consequences. For instance, one episode of hyponatremia can lead to seizures and other neurologic sequelae, while an instance of severe hyperkalemia can result in cardiac dysrhythmia and/or arrest [27, 28]. In this large study, there were no episodes of extreme hyperkalemia (≥ 6 mmol/L) or hyponatremia (≤ 125 mmol/L) in patients resuscitated with predominantly LR fluids; conversely, there were episodes of extreme hyperkalemia (≥ 6 mmol/L) and hyponatremia (≤ 125 mmol/L) in those receiving 0.9%NaCl. While this provides some evidence that LR is safe for use in a heterogeneous cohort of critically ill children, the observational nature of this study makes the significance of these findings difficult to interpret. Specifically, we are unable to delineate whether the administration of 0.9%NaCl caused the aforementioned electrolyte derangements, or if a physician chose 0.9%NaCl precisely because of those findings (i.e., selecting 0.9%NaCl to resuscitate a patient with hyponatremia).

While the causative nature of these findings cannot be established, the finding that LR, which contains a minimal amount of potassium (4 mEq/L), leads to fewer instances of hyperkalemia than 0.9%NaCl (which contains no potassium) does have a physiologic basis. First, administering LR to a patient with hyperkalemia will dilute the amount of extracellular potassium through a weighted average. For example, a 15 kg patient has a total body water estimated at 10 L, of which one third is extracellular (3.25 L). If this patient has an initial potassium level of 5 mmol/L and receives 60 ml/kg of fluid resuscitation with LR, the extracellular fluid compartment will increase to 4.15 L. In this scenario, the final serum potassium level would actually decreaseto 4.78 mmol/L, due to the relatively greater expansion of the extracellular fluid compartment compared to potassium load. Additionally, most of the body’s potassium is intracellular, and thus any potassium shifting into the extracellular compartment will lead to an increased serum potassium level. Since the pH of 0.9%NaCl is 5, it can induce a metabolic acidosis [29‐32], resulting in intracellular shifts of hydrogen ions in exchange for potassium, which increases extracellular potassium levels [33]. This effect has been demonstrated previously in kidney transplant recipients, where patients who received 0.9%NaCl had higher rates of acidosis and hyperkalemia compared to those who received either LR [3, 34, 35] or PL [13, 36]. Our study adds to this body of evidence, as severe acidosis (pH < 7.1) was indeed seen more commonly in patients who received both 0.9%NaCl and mixed fluids, and these same groups also had a higher incidence of severe hyperkalemia (potassium ≥ 6 mmol/L) compared to those receiving LR. While it is unclear the reasons these patients developed severe acidosis it is likely multifactorial and includes both the significantly higher volume compared to LR fluids and/or severity of illness.

This study has important limitations. First, this was an observational study, and thus the type of fluid administered was based on the clinical judgement of the physician and not assigned at random. Additionally, practice variations suggested by the subgroup analysis in resuscitative fluid selection at the two study sites may have resulted in bias, although there were relatively equal numbers of patients included from each center. Fluid selection also differed based on admission diagnosis. Notably, our database did not reliably capture the timing of electrolyte measurement as compared to fluid administration on Day₀, and thus there is the potential that the type of fluid bolus chosen was based on the admission electrolyte values. Additionally, we were unable to capture other sources of fluid intake such as medication volume, although were able to include both maintenance and bolus fluids in our analysis. Maintenance and bolus fluids were considered similarly due to inconsistent charting in the EHR that often made it difficult to consistently determine whether a fluid was “bolus” or “maintenance”. However, this allowed us to capture a more robust image of the fluid exposure given to these patients.

The interpretation of the non-parametric approach (Kruskal–Wallis test) to comparing daily electrolyte value may have indicated group differences in distributions; however, given there were no clinically significant differences in median Day₀ sodium, chloride, potassium or pH values between groups, it seems unlikely that this led to significant bias. Finally, the type of acidosis was not determined, and respiratory acidosis may have contributed to the lower pH seen in our analysis.

Our study also has several important strengths. This is the first study to examine differences in resultant electrolytes in a heterogeneous population of critically ill children receiving resuscitation with balanced versus unbalanced crystalloids. Additionally, given inclusion of patients from two large quaternary care hospitals, it is likely that these findings may be more generalizable across the general PICU population.

In a heterogeneous population of critically ill children undergoing fluid resuscitation, the incidence of significant electrolyte derangements was small, and less common in patients receiving LR compared to those receiving 0.9% NaCl or mixed fluids. This study provides important information regarding resuscitative fluid safety in this unique population, and supports comparing the use of LR, 0.9% NaCl, and a mixed fluid group in a prospective interventional trial, such as is currently ongoing in pediatric sepsis [37].