IV Fluid Selection

Normal saline (0.9% NaCl) has been the default intravenous fluid in hospitals worldwide since its introduction in the 19th century, despite being neither normal nor physiological — it contains 154 mEq/L each of sodium and chloride, 50% higher chloride concentration than plasma. Animal and observational human studies demonstrated that high-volume normal saline administration caused hyperchloremic metabolic acidosis, renal vasoconstriction, decreased renal blood flow, and potentially acute kidney injury. Balanced crystalloids like Ringer's lactate and Plasma-Lyte, with electrolyte compositions closer to plasma, were hypothesized to reduce these adverse renal effects. However, despite decades of theoretical concern, the clinical significance of fluid choice remained unproven in rigorous trials.

The SMART trial (2018), a pragmatic cluster-randomized trial at Vanderbilt, assigned 15,802 critically ill adults to balanced crystalloids (Ringer's lactate or Plasma-Lyte) vs normal saline. Balanced crystalloids reduced the composite of death, new renal replacement therapy, or persistent renal dysfunction (14.3% vs 15.4%), with the largest benefit in sepsis patients. The companion SALT-ED trial in 13,347 non-critically ill ED patients showed a similar direction of benefit. These were the first large-scale randomized data demonstrating a clinical difference between crystalloid types. However, the absolute difference was modest (1.1% in SMART), and the unblinded pragmatic design left room for debate about whether the benefit was clinically meaningful enough to justify universal fluid switching.

Two large international RCTs then challenged the SMART findings. The BaSICS trial (2021), conducted in 10,520 ICU patients in Brazil, found no difference between balanced solutions (Plasma-Lyte) and normal saline for 90-day mortality or AKI. The PLUS trial (2022), a double-blind RCT in 5037 ICU patients across Australia and New Zealand, similarly found no mortality difference between Plasma-Lyte and saline. These neutral mega-trials created genuine equipoise, suggesting that the modest benefit seen in SMART may have been influenced by its unblinded design or specific patient population. The debate became more nuanced, with emerging evidence suggesting that fluid choice may matter more in specific subpopulations (sepsis, large-volume resuscitation, hyperchloremia) than as a universal policy.

The Surviving Sepsis Campaign 2021 guidelines made a weak recommendation to use balanced crystalloids over normal saline for resuscitation in sepsis and septic shock, acknowledging the low certainty of evidence. Most institutional fluid committees have adopted a pragmatic approach, with many hospitals switching their default crystalloid to balanced solutions based on the theoretical physiological advantage and the absence of harm signal. However, specific situations still favor normal saline: neurosurgical and neurocritical care (concern about cerebral edema with hypotonic balanced solutions), hyperkalemia, and as a drug diluent. The lack of a definitive answer from mega-trials has resulted in practice variation across institutions.

The crystalloid debate remains genuinely unsettled. The totality of evidence suggests that balanced crystalloids are at least equivalent to normal saline, with possible modest benefit in sepsis and large-volume resuscitation. A context-dependent approach is emerging: balanced crystalloids as default for most patients, normal saline for brain injury and hyperkalemia, and clinical judgment for specific scenarios. Individual patient-level meta-analyses combining SMART, BaSICS, and PLUS data are ongoing and may identify subgroups that differentially benefit. The broader lesson is that even the most basic medical interventions can remain inadequately studied, and that practice based on physiological reasoning alone (the hyperchloremia hypothesis) may overestimate clinical impact.