Scrutinizing long-established practices in medicine is foundational to the culture of continuous improvement, yet requires surprising amounts of energy, diligence, and commitment. IV fluid (IVF) administration, both as a bolus dose to restore compromised circulatory volume, and as maintenance IVF, seem particularly prone to this type of clinical inertia. Although this is true across medicine (1), pediatricians are often forced to make decisions with smaller trials, and use more indirect evidence, generally from adult trials. Data from 1992 were cited as the turning point that informed the 2018 guidelines from the American Academy of Pediatrics which changed the Academy’s guidance on maintenance IVF from hypotonic fluids to isotonic fluids for risk of hyponatremia development (2,3).

Similarly, the choice of bolus fluids in the early management of sepsis is an area of historical controversy in both adult and pediatric practice, where normal saline (NS) has long been the preferred agent. Despite emerging data that balanced crystalloid (BC) fluids with more physiologic concentrations of sodium, potassium, and chloride were safe (4–8), multiple myths persisted about the potassium content causing hyperkalemia and sodium lactate precipitating lactic acidosis and interfering with lactic acid measurements (5,9–11).

In reality, there is no evidenced-based advantage of NS over BC in bolus IVF administration. In fact, a modern IVF researcher with a clean slate, tasked with designing a resuscitation fluid, would doubtless constitute a fluid with physiologic tonicity (BC) not hypertonicity (NS), physiologic chloride concentration (BC) not hyperchloremia (NS), and physiologic pH (BC) not acidic fluid (NS).

Beyond academic thought experiments, there exists published data systematically supporting the use of BC as a bolus fluid in the critically ill adult population. Potura et al (4) showed that patients receiving BC had less hyperchloremia, acidosis, and required less vasopressor support. Weinberg et al (5) showed patients receiving NS were more likely to develop hyperkalemia, hyperchloremia, and metabolic acidosis. Semler et al (8) in the groundbreaking Isotonic Solutions and Major Adverse Renal Events Trial (SMART) trial, took these findings further, demonstrating adverse clinical outcomes attributable to NS bolus administration: in critically ill adults, receiving BC was associated with a lower rate of the composite outcome of death, new renal replacement therapy (RRT), or persistent renal dysfunction. This trial enrolled over 15,000 patients in a multicenter, double-blinded randomized clinical trial (RCT) that rapidly changed fluid administration practices for critically ill adult patients.

It is notable that, while we are staunch believers of the adage that children are not simply small adults, this wisdom may not apply in this particular scenario. Kidneys, after all, have been shown to be functionally equivalent organs in both children and adults in transplant studies (12). Kidneys also appear to be the organ that suffers the most injury from excessive exposure to NS, with data suggesting this is due to the chloride load (13). Taken together, there is no reason to expect that the pediatric kidney will be any less vulnerable to the injury that has been demonstrated with NS. Despite this history, a large study with over 12,000 pediatric patients showed no clinical difference in the administration of NS against BC in critically ill pediatric patients (14), while a smaller retrospective study showed data similar to that found in the adult population: improved survival, decreased renal injury, and decreased vasopressor requirements with BC (15). A large meta-analysis on critically ill adults (n = 19,955) and children (n = 258) performed in 2019 by Antequera Martín et al (16) showed no difference in outcomes between those receiving NS and BC.

Considering both the few direct (pediatric) and the vast indirect (adult) data accumulating in the medical literature, the Surviving Sepsis Campaign International Guidelines for the Management of Septic Shock and Sepsis-Associated Organ Dysfunction in Children updated their 2020 guidance to suggest using BC instead of NS, qualifying this as a weak strength recommendation, with very-low quality evidence (17). In the same publication, they declared this specific question a research priority [Author’s note—One of the authors of this statement, MA, is on the Pediatric Surviving Sepsis Campaign and coauthored the above guideline].

The work by Sankar et al (18), published in this issue of Critical Care Medicine, is a particularly well-designed trial demonstrating the benefit of BC over NS. In their multicenter, double-blind RCT of over 700 patients, their patients received either PlasmaLyte A or 0.9% saline for bolus fluids. Their results are notable not just for demonstrating biochemical abnormalities but also clinical harm associated with NS bolus administration in pediatric sepsis patients. Hyperchloremia developed at an accelerated rate in the NS population compared with BC, with 24-hour rates of 52% versus 38%, 48-hour rates of 61% versus 46%, and 72-hour rates of 63% versus 45%, respectively. Clinically, a 38% reduction in new or progressive acute kidney injury (AKI) (relative risk 0.62; 95% CI, 0.49–0.80; p < 0.001) was seen in the population receiving BCs. There was also an increase in RRT required in those receiving NS versus BC, 16% versus 9%, respectively.

This article’s important findings are tempered by certain limitations in design. First, although a large study by pediatric critical care standards, the study by Sankar et al (18) enrolled only one-tenth of the number of patients in the adult SMART trial, which increases the likelihood of biases, especially selection bias. Maintenance fluid was not controlled in the study by Sankar et al (18), and although there was a similar proportion of bolus to maintenance administered—35% and 34% in the first 24 hours in the NS and BC group, respectively—there remains the significant confounding factor of bolus fluids being a minority of overall fluids administered. Last, it is notable that the principal findings in this trial were substantially similar to the SMART trial: increased risk of new or progressive AKI, and increased risk of RRT with NS bolus administration. However, unlike the SMART trial, there was no difference in mortality between the groups.

Change in healthcare is slow. However, entrenched does not mean permanent; our own institution’s Pharmacy and Therapeutics Committee updated their guidance on bolus administration to encourage consideration of BCs in January 2021, with local practice patterns shifting heavily toward BC since. Sankar et al (18) have added a strong body of evidence supporting institutional change from NS to BC for bolus administration in pediatric septic patients. Further studies are required to expand the population size evaluated, and to determine if a mortality benefit exists as it does in the adult population, indeed one large RCT is currently underway (19). Beyond those areas of research, there is a natural extension to studying maintenance fluids next. Ultimately, this will beg the question: should NS be reserved for specialty cases, as opposed to the default choice? Change in healthcare deserves to be promoted rapidly when the interventions are evidence-based, safe, cheap, and scalable; Sankar et al (18) have presented compelling data to move us in the direction of BCs.

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